Gastric Cancer

Epidemiology
• Globally Gastric cancer (GC) is the 5th most common cancer

• With nearly 1 million cases annually

• 3rd leading cause of cancer mortality and leading cause of infection-associated cancer
mortality

• Most GC are sporadic

• Aggregation within families occurs in approximately 10% of cases.

• Truly hereditary (familial) gastric cancer accounts for 1-3% , comprises at least three
major syndromes:
– hereditary diffuse gastric cancer (HDGC),
– gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS),
– familial intestinal gastric cancer (FIGC).
• Worldwide incidence of GC has declined rapidly over the
recent few decades

• However there is a rise in incidence of non-cardia GC

among those at 25 to 39 years.

• More common in men than in women, M > F

• Intestinal type GC - Females were 10-20yrs older than men

– possible protective role of Estrogen

• No such difference in Diffuse GC.

• Peak incidence after 6th decade.

• Over 70% of gastric cancers occur in developing
countries – coincides with H-pylori infection

• High incidence in Eastern Asia, Eastern Europe, and

South America, while the lowest rates are in North
America and parts of Africa

• A difference in incidence and mortality from north to

south has been observed - northern areas having a
higher mortality risk than the south.

• Higher geographic latitudes are associated with a

higher gastric cancer risk.
 In India

• GC in India – 5% when
compared to 13.6% in
Japan.

• However National Cancer

registry in India covers only
7% Indians – hence
numbers are misleading

• 80-90% prevalence of
H.pylori with GC developing
in 0.1-3%

• Male : Female ratio was

70:30
RISK FACTORS / PATHOGENESIS
• Risk factors can be broadly grouped as
– Precursor lesions
– Environmental factors
– Host-related factors.

•  Helicobacter pylori infection and family history of gastric cancer are the

two main risk factors for gastric cancer.
 Precursor Lesions

• Intestinal type of GC is associated with well-defined

precursor lesions - Chronic Gastritis and Atrophic
gastritis

• Diffuse type has no clearly defined precancerous

lesions.

• The CORREA cascade describes a stepwise progression

of conditions within the stomach that were thought to
result in GC.

• The initial step in the Correa cascade is the

development of Chronic gastritis (CG).
 Chronic gastritis
• a.k.a Non-atrophic gastritis

• Longstanding chronic superficial gastritis caused by chronic H.

pylori infection, pernicious anemia, or possibly, a high-salt diet

• leads eventually to chronic atrophic gastritis and intestinal metaplasia.

• It is more common with h.pylori infection - predominates in the antrum

and is characterized by a dense, band-like infiltrate of lymphocytes,
macrophages, and plasma cells. Occasionally, lymphoid follicles are
formed.

• CG is not related to an increased GC risk.

• However, it may progress to atrophic gastritis/ intestinal metaplasia and

GC in 0.1 – 0.9% of patients
 Gastric Atrophy (GA)
• a.k.a as Metaplastic atrophic gastritis

• loss of parietal cell mass and therefore a reduction in acid production

(hypochlorhydria or achlorhydria)

• a compensatory increase in serum gastrin - a potent inducer of gastric

epithelial cell proliferation.

• The magnitude of the risk is variable in the literature, with estimates

ranging from 3 to 18 times greater than an age-matched population. 

• Atrophic gastritis predisposes to metaplasia and dysplasia with an end

result of GC.

• There are two types of Metaplastic atrophic gastritis based on etiology

– Autoimmune (AMAG)

– Environmental (EMAG)
• AMAG
– Antibodies against Parietal cells

– results in the replacement of the normal oxyntic mucosa leading

to a corpus predominant atrophic gastritis

– reduced or absent acid and pepsin production and loss of

intrinsic factor which may progress to a severe form of vitamin
B12-deficiency anemia known as pernicious anemia (PA).

– Laboratory abnormalities that are associated with AMAG include

• hypergastrinemia,
• iron deficiency anemia,
• antibodies to parietal cells and intrinsic factor,
• vitamin B12 deficiency.

– Patients with AMAG have an increased risk for gastric

neuroendocrine tumors and gastric adenocarcinoma
• EMAG - due to the adverse effects of environmental factors, such as H.
pylori infection and perhaps dietary constituents, on the gastric mucosa.

• Patients with EMAG may be asymptomatic, but many of them have

dyspepsia.

• In contrast to AMAG, fasting serum gastrin levels are not markedly

elevated in EMAG

• autoantibodies to parietal cell and intrinsic factor and PA are absent. 

• AMAG is confined to the gastric body and fundus.

• Mucosal changes in patients with EMAG affect both the body/fundus and
the antrum in a multifocal distribution

• but with heaviest involvement of the antrum.

 Intestinal Metaplasia

• GA is diagnosed histopathologically by two specific features:

– the presence of chronic inflammatory cells, including lymphocytes and plasma
cells that expand the lamina propria,
– the loss of the pre-existent gastric glands.

• Native gastric glands can be replaced by two types of structures

1. Intestinal-type glands (enterocytes, goblet and Paneth cells; ie, IM)

Type I - complete or small intestinal type. Sialomucins &intestinal mucin -

MUC2 +ve. Gastric mucins MUC 1, 5AC, 6 are negative

Types II and III - incomplete or colonic type

• Several studies have associated colonic type IM (mostly III) with the
highest risk for neoplastic transformation.
2. Pyloric-type glands (‘pseudo-pyloric metaplasia’)

• also known as Spasmolytic polypeptide-expressing metaplasia –

SPEM –

• refers to the replacement of parietal and chief cells in the oxyntic

mucosa by epithelial mucus-secreting cells of the type normally
found in the antral (ie, pyloric) mucosa.

• These epithelial cells appear to arise from chief cells surviving in

damaged oxyntic glands, rather than from stem cells.

• The pseudopyloric glands have the coiled architecture seen in

normal antrum, but are smaller, less numerous, contain less mucin,

• do not have antral-type endocrine cells, especially G cells.

• There is evidence that pseudopyloric metaplasia is a precursor for

IM
• Most intestinal-type gastric cancers
develop in atrophic mucosa; thus, the
assessment of gastric mucosal atrophy
is a crucial step in the identification of
at-risk patients.

• Both endoscopic and histological

assessments of atrophy continue to
play the central role in clinical practice.

• Operative Link for Gastritis Assessment

(OLGA) and the Operative Link on
Gastric Intestinal Metaplasia (OLGIM)
staging systems are adequate and are
most useful when accompanied by
sampling of any visible lesions.

• Biopsy of the stomach for screening

atrophic gastritis follows a systematic
pathway as recommended by the
SYDNEY PROTOCOL.
• The OLGA staging system ranks the histological
phenotypes of gastritis along a scale - 0–IV of
increasing mucosal atrophy.

• The cancer risk associated with stages 0, I and II -

is extremely low

• while stages III and IV (characterised by extensive

atrophy of both antral and oxyntic mucosa) are
associated with high risk of intestinal-type gastric
cancer.

• OLGIM is a modification of OLGA staging system.

 Gastric Dysplasia

• The endoscopic prevalence of gastric dysplasia varies from 0.5% to 3.7% in Western countries and
from 9% to 20% in areas with a high incidence of gastric adenocarcinoma

• Possibility of synchronous gastric cancer - up to 30%.

• Patients with HGD - 30% to 85% - progress to cancer with follow-up periods of up to 5years with
an estimated annual incidence of 6%

• Patients with LGD - 0-33% progress to cancer with follow-up periods of up to 5years with an
estimated annual incidence of 0.6%

• Recommended endoscopic resection of visible LGD and HGD

• For LGD – Surveillance interval of 1 yr with high quality systematic Endoscopy

• For those with HGD undergoing surveillance, we recommend a repeat high-quality endoscopy,
repeated 6-monthly thereafter.

• All visible dysplasia should be resected where appropriate

• Risk of Synchronous / metachronous lesions after ESD / EMR – 10-20%. Hence follow up
endoscopy after 6 months – if no lesions – then Endoscopy every 1 yr
GASTRIC EPITHELIAL POLYPS
 Fundic gland Polyps

• FGPs are the most prevalent type of gastric polyps (13–77%).

• Typically multiple, small (<1cm) located in fundus & body.

• At endoscopy they appear pale, smooth, glassy, and transparent or

translucent.

• FGPs are not associated with increased risk of cancer unless in the context
of FAP.

• However larger FGPs > 1cm have been shown to be dysplastic in 1.9% and
contain focal cancer also in 1.9%.

• FGPs are associated with long-term PPI use and can spontaneously regress
when PPIs are stopped.

• There is no association with background H. pylori infection or gastritis.

• On Endoscopy - Number, location, morphology and the size of the largest
polyp should be documented.

• Representative pictures of the polyps should be taken.

• Diagnosis is easily made from the endoscopic appearance, as described

above, but biopsy confirmation should be sought when in doubt.

• Large numbers of polyps (>20), young age (<40yrs), dysplastic appearing

polyps, presence duodenal adenomas – exclude FAP.

• FGPs do not require excision unless they have atypical features.

– Size of >1 cm,
– antral location,
– ulceration or an unusual appearance

• Targeted biopsies should be taken where excision is not undertaken.

• There is no role for surveillance gastroscopy for FGPs, except in the setting
of FAP.
 Hyperplastic Polyps
• constitute 18–70% of all gastric polyps

• are usually single or few in number and are more frequently observed in the antrum
or adjacent to ulcers, stomas and gastrectomy sites.

• They appear as smooth, red buttered with whitish exudates (fibrin) and are dome-
shaped.

• They are usually small (0.5–1.5cm), but may be larger and present as lobulated and
pedunculated masses covered with superficial erosions.

• They are typically associated with H. pylori gastritis (25%), GA and Gastric Intestinal
metaplasia.

• Regression generally occurs after eradication of H. pylori (up to 70%).

• Gastric hyperplastic polyps can reveal dysplasia (1.9–19%) and malignant

transformation (0.6–2.1%), especially when >1cm and in the postgastrectomy
stomach.

• A dysplastic hyperplastic polyp is associated with an increased risk of synchronous

neoplastic lesions in the surrounding mucosa of approximately 6% of cases.
• Diagnosis of hyperplastic polyps and the absence of dysplasia should be
confirmed by histology.

• The remainder of the stomach should be carefully evaluated for

synchronous neoplasia, degree and extent of GA and H. pylori.

• H. pylori eradication should be considered in all cases before endoscopic

resection as many polyps will regress, and a repeat endoscopy carried out
3–6months after eradication.

• Polyps of >1cm, pedunculated polyp morphology or symptomatic polyps

(obstruction, bleeding) should be completely resected.

• Even when H. pylori is present, those polyps >3cm should always be

resected as the risk of dysplasia and cancer is high.

• Endoscopic surveillance is recommended to monitor the risk of further

gastric neoplasia where there is evidence of dysplasia, GA or GIM.

• The endoscopic surveillance interval should be determined by the stage

of CAG.
 Adenomatous Polyp
• are usually single (82%), small (< 2cm) and located in antrum and incisura.

• Endoscopically they have a velvety pink lobulated appearance and can be sessile or
pedunculated.

• prevalence varies between 0.5% and 10%.

• They are normally associated with a background of GA and GIM.

• Coexistence of a synchronous gastric adenocarcinoma has been found in up to 30%.

• 50% of adenomatous polyps >2cm contain foci of adenocarcinoma.

• Histologically, gastric adenomas have been subdivided into

– intestinal,
– foveolar,
– pyloric,
– oxyntic types.

• The most common are the intestinal type, which is often associated with chronic
gastritis and gastric cancer. 
• Significant risk of progression to cancer and should be resected where appropriate.

• Diagnosis of adenoma and degree of dysplasia should be histologically confirmed

before treatment is undertaken.

• Careful evaluation of the stomach should be carried out to identify synchronous

neoplasia (30%), GA and GIM.

• Endoscopic resection is the preferred mode of treatment.

• An en bloc excision with ESD is advisable for sessile polyps >15mm as the possibility
of invasive neoplasia in the adenoma is high and ESD reduces the risk of recurrence
compared with EMR.

• A follow-up gastroscopy should be performed at 6–12months after endoscopic

resection of adenomas.

• Patients with adenomas should continue to have surveillance gastroscopy at yearly

intervals where appropriate, depending on
– number of polyps,
– size
– highest grade of dysplasia.
ENVIRONMENTAL FACTORS
 Helicobacter pylori
• H. pylori represents the archetypal cause of CG

• Infected patients in some studies having > 10-fold higher chance of developing GC.

• Corpus-predominant gastritis with multifocal gastric atrophy develops in

approximately 1% of subjects infected with H. pylori.

• Several hypotheses have been proposed to explain the role of H. pylori in
carcinogenesis - although the exact mechanism is incompletely understood
Bacterial properties
– Strains producing VacA and CagA cause more intense
tissue inflammation
– induce cytokine production, predominantly IL8.
– CagA strains are more commonly seen in patients
developing GC.

Host Immune responses

• Cytokine pleomorphisms
• Neutrophil activation
• Epithelial responses
• Cell signalling events

Environmental factors - Complex H-pylori interactions with

variety of dietary factors
• Eradication of H.pylori in patients with chronic gastritis and
atrophic gastritis resulted in normalisation of gastric mucosa and
reduced risk of GC.

• Whereas the impact of H.pylori eradication once intestinal

metaplasia and dysplasia has occurred is not favourable with
many studies reporting no effect on progression to GC.

• Current high-quality data therefore suggest that while eradication

of H. pylori reduces subsequent gastric adenocarcinoma risk in
patients who have non-atrophic or GA, these benefits are not
consistently maintained in patients who have developed GIM,
dysplasia or cancer.

• Nevertheless H.pylori eradication is advised even in patients with

IM and Dysplasia to prevent metachronus GC in high incidence
areas.
 Dietary & other factors

• Salt and salt preserved foods

• Nitroso compounds

• Antioxidants & Vitamins

• Refrigeration

• Smoking

• Occupational exposures 

• NSAIDS

• Reproductive hormones 
• Epstein-Barr virus 
– 5-10% of GC
– Characterized by DNA methylation of the promoter region of various
cancer-associated genes, which silences the expression of these genes.
– Have distinct clinicopathologic characteristics including
• male predominance
• preferential location in the gastric cardia or postsurgical gastric stump
• lymphocytic infiltration
• lower frequency of lymph node metastasis
• more favorable prognosis
• diffuse type of histology in most, but not all series. 

• Gastric Surgery
– increased risk of gastric cancer after gastric surgery.
– Billroth II procedure carries a higher risk than the Billroth I procedure.
– Although the exact cause of the increased risk is unknown, it is thought
to be due to regurgitation of alkaline bile and pancreatic juice.
– The risk increases with time after gastric surgery with incidence of GC
within 5yrs surgery of GC and 15 yrs after surgery for benign diseases.
HOST RELATED FACTORS
 Hereditary diffuse gastric cancer  

• HDGC is an inherited form of diffuse type gastric cancer,

• highly invasive tumor characterized by late presentation and a poor prognosis.

• Germline truncating mutations in the cadherin 1 (CDH1) gene, which encodes the cell adhesion
protein E-cadherin, have been identified in approximately 19 to 50% of affected kindreds.

• The end result is loss of expression of the cell adhesion molecule E-cadherin. HDGC is AD with
high penetrance.

• The cumulative risk for gastric cancer by age 80 for CDH1 mutation carriers is up to 70% in men
and up to 56% in women.

• Affected patients generally are diagnosed with gastric cancer at an early age - average age 38.

• Women in these affected families are also at high risk of developing breast cancer, predominantly
lobular.

• The risk of GC in asymptomatic carriers of CDH1 mutation who belong to families with highly
penetrant HDGC is sufficiently high to warrant prophylactic gastrectomy.

• Surgery is usually recommended between the age of 18 and 40.

• CDH-1 carriers not undergoing prophylactic gastrectomy should undergo 6-12 monthly endoscopy
and random biopsies.
• GAPPS 
–  Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was
initially identified in 2012

– Characterized by the AD

– is restricted to the proximal stomach, with no evidence of duodenal or colorectal

polyposis or another hereditary gastrointestinal cancer syndrome.

– It is characterized by incomplete penetrance.

– The finding of inherited point mutations in exon 1B of APC gene reveals this to
be a variant of familial adenomatous polyposis

• Familial intestinal gastric cancer 

–  FIGC should be considered a potential diagnosis when histopathologic reports
denote intestinal type gastric cancers that segregate within families without
gastric polyposis.

– An AD inheritance pattern has been noted in many such families.

– The genetic cause is unknown, and few recommendations are available for the
clinical management of these patients.
• Other hereditary cancer syndromes
•   
– Lynch syndrome /HNPCC – 1-13% risk of GC. GC second most common
extra-colonic cancer, next to endometrial cancer.

– FAP – 1-2% risk of GC

– Li-Fraumeni syndrome

– Peutz-Jeghers syndrome – 29% risk of GC – start UGI scopy in late

teenage and every 2-3yrs

– Juvenile polyposis syndrome – lifetime risk of 21% for GC – start UGI

scopy at 15yrs – if polyps present – then annual scopy otherwise once
in 2-3yrs

– Hereditary breast and ovarian cancer syndrome

– Phosphatase and tensin homolog (PTEN) hamartoma tumor (Cowden)

syndrome
• Genetic polymorphisms - Certain polymorphisms have been
associated with gastric cancer.
– The human interleukin 1 beta (IL-1B) gene is the most important
candidate gene in the host that could affect the clinical outcome of H.
pylori infection because it is upregulated by infection, profoundly
proinflammatory, and the most powerful acid inhibitor known.
– Interferon gamma (IFN-gamma) signaling has an essential role in
human H. pylori infection, more prevalent in Africans than in whites,
which might in part explain why H. pylori infection is highly prevalent in
Africa but is relatively less pathogenic.
– Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have
been associated with gastric cancer, mainly in East Asians

• Blood group  
– Individuals of blood group A have been known for decades to show an
approximately 20% excess of gastric cancer compared with those of
group O, B, or AB.
– They also show a similar increase in the rate of pernicious anemia.
– Some data suggest that group A may be particularly associated with
diffuse-type gastric cancer.
– It is possible that the observed associations are not due to the blood
group antigens themselves but to the effects of genes closely associated
with them.
• Hypertrophic gastropathy and immunodeficiency syndromes — 
Ménétrier's disease and various immunodeficiency syndromes
have been linked with gastric cancer. However, the strength of
these associations remains undefined.

• Gastric ulcer — An association between benign gastric ulcers and

gastric cancers probably reflects common risk factors (ie, mainly H.
pylori infection).
– The risk of gastric cancer was increased among patients with benign
gastric ulcers (incidence ratio 1.8
 
• Acid Suppression therapy
– "iatrogenic" achlorhydria induced by long-term use of histamine 2
receptor antagonists or proton pump inhibitors has not been associated
with an increased risk of either gastric adenocarcinomas or
neuroendocrine tumors.

– An association between maintenance therapy with omeprazole and the

development of atrophic gastritis in individuals with H. pylori infection
has been suggested, but the data are inconclusive.
CLINICAL FEATURES
• The presenting symptoms of early gastric cancer (EGC) are nonspecific.
• Patients may be asymptomatic or they may present with dyspepsia, mild epigastric
pain, nausea, or anorexia

• Most patients with Advanced gastric cancer are symptomatic.

• Weight loss and persistent abdominal pain are the most common symptoms at initial
diagnosis
• Approximately 25% of patients with gastric cancer have a history of gastric ulcer.
• Weight loss - usually results from insufficient caloric intake, rather than increased
catabolism - attributable to anorexia, nausea, abdominal pain, early satiety, and/or
dysphagia.
• Abdominal pain tends to be epigastric, vague, and mild in early disease but more
severe and constant as the disease progresses.
• Dysphagia is a common presenting symptom in patients with cancers arising in the
proximal stomach
• Nausea or early satiety may result from the tumor mass. In cases of an aggressive
form of diffuse-type gastric cancer called linitis plastica, these symptoms arise from
the inability of the stomach to distend.
• Vomiting results when patients develop gastric outlet obstruction from an advanced
distal tumor.
• Occult gastrointestinal bleeding, with or without iron deficiency anemia, is not
uncommon, while overt bleeding (ie, melena or hematemesis) is seen in fewer than
20 percent of cases
• Patients may also present with signs or symptoms of distant metastatic disease.

• The most common sites of metastatic disease are the liver, the peritoneal surfaces,
and the nonregional or distant lymph nodes.

• Less commonly, ovary, central nervous system (brain or leptomeningeal), bone,

intrathoracic (pleural or parenchymal), or soft tissue metastases can occur:
– In patients with lymphatic spread, the physical examination may reveal a left supraclavicular
lymph node - Virchow's node , which is the most common physical examination finding of
metastatic disease, a periumbilical nodule (Sister Mary Joseph's node ), or a left axillary
node (Irish node).

– Peritoneal spread can present with an enlarged ovary (Krukenberg tumor) or a mass in the
cul-de-sac on rectal examination (Blumer's shelf). While there are patients with ovarian
metastases without other peritoneal disease, these are usually a harbinger of later
development of visible peritoneal disease.

– Ascites can also be the first indication of peritoneal carcinomatosis.

– A palpable liver mass can indicate metastases, but not always, associated with an elevation
in the serum alkaline phosphatase concentration.

– Jaundice or clinical evidence of liver failure, if seen, suggests advanced metastatic disease.

– However, jaundice is also occasionally seen with locally advanced distal tumors, and these
patients typically also have gastric outlet obstruction.
• More rarely, patients with gastric cancer may present with complications that result from direct
extension of the gastric cancer through the gastric wall.

• As an example, feculent emesis or passage of recently ingested material in the stool can be seen
with malignant gastrocolic fistula, although this is quite rare.

• More commonly, colonic obstruction may occur.

• Development of a palpable abdominal lump or ascites are findings of advanced disease.

Paraneoplastic manifestations — Systemic manifestations of gastric cancer
related to paraneoplastic phenomena are rarely seen at initial presentation.

• Dermatologic findings may include the sudden appearance of

– Diffuse seborrheic keratoses (sign of Leser-Trélat)
– Acanthosis nigricans - which is characterized by velvety and darkly pigmented patches on
skin folds.

• Neither finding is specific for gastric cancer, and they may be associated with other
gastrointestinal malignancies or simply a benign process.

• Microangiopathic hemolytic anemia

• Membranous nephropathy

• Polyarteritis nodosa has been reported as the single manifestation of an early and
surgically curable gastric cancer 

• Hypercoagulable states -Trousseau's syndrome, Pulmonary emboli

DIAGNOSIS
 Endoscopy
• Upper GI endoscopy is the investigation of choice to diagnose GC.

• Tissue diagnosis and anatomic localization of the primary tumor

are best obtained by endoscopy,

• Eearlier endoscopy in symptomatic patients results in higher rate

of detection of early gastric cancers.

• The typical appearance of gastric cancer is a friable, ulcerated

mass.

• gastric ulcer suspicious of malignancy

– folds surrounding the ulcer crater are nodular, clubbed, fused, or stop
short of the ulcer margin,
– together with the presence of overhanging, irregular, or thickened ulcer
margins
• Linitis plastica
– Gastric mucosa may appear normal.
– Extensive submucosal spread responsible for non-diagnostic endoscopy.
– Poor distensibility of the stomach may be the only finding on
endoscopic evaluation
– Needs jumbo biopsies / strip and bite biopsy / well biopsy

• Atleast 7 biopsies are needed to improve the diagnostic accuracy

to 98%, while a single biopsy has an accuracy of only 78%

• NCCN - EMR / ESD should be done for small lesions / nodules <
2cm. gives information regarding
– Depth of invasion – there by differentiating mucosal – submucosal
lesions
– Degree of differentiation
– LVI
 Barium studies
• Can identify both malignant gastric ulcers and infiltrating lesions

• Has been employed in eastern countries as a screening tool for GC

• False negative rates are as high as 50%

• One scenario in which a barium study may be superior to endoscopy is in patients

with linitis plastica.

• The decreased distensibility of the stiff, "leather-flask" appearing stomach is more

obvious on barium study, and the endoscopic appearance may be relatively normal.

• Malignant Ulcers have characteristic signs on barium study

– Hendek’s Niche – Classic ulcer crater outlined by barium
– Ulcus Callosum – Chronic ulcer producing induration of gastric wall
– Carman’s sign – Meniscoid ulcer crater produced by an intraluminal tumor separating it
from barium filled stomach
 CECT
• All patients in whom a gastric cancer is suspected or histologically confirmed should
undergo cross-sectional imaging of the chest, abdomen, and pelvis, typically with a
contrast-enhanced (typically oral plus IV) CT scan.

• To evaluate metastatic disease, especially hepatic or adnexal metastases, ascites, or

distant nodal spread.

• Patients who have CT-defined visceral metastatic disease can avoid unnecessary
surgery, although biopsy confirmation is recommended because of the risk of false-
positive findings.

• Metastatic lesions < 5mm are missed on CT.

• Thus 20-30% of patients with negative CECT may have peritoneal metastasis on
laparoscopy / Exploration

• Limited sensitivity for T- staging in early lesions, but sensitivity is high for advanced
lesions.

• Limited sensitivity for nodal staging – small nodes < 8mm or inflammatory nodes
 EUS

Standard 4 EUS criteria for malignant

• EUS is the most reliable nonsurgical method available for nodes

evaluating the depth of invasion of primary gastric cancers.  Hypoechoic,

round,
smooth border
• EUS is recommended by both NCCN and ESMO for pre- SAD >0.5-10mm.
treatment evaluation of all patients with GC who have no  
radiographic evidence of metastatic (M1) disease and have
otherwise potentially operable disease

• Sensitivity of EUS in differentiating mucosal and submucosal

lesions is lower than differentiating T1 from T2 lesions. Yet it is
more accurate than CT for T staging.

• Accuracy for nodal staging is only slightly greater for EUS as

compared with CT.

• EUS-guided FNA of suspicious nodes and regional areas adds

to the accuracy of nodal staging 

• Limited diagnostic ability post treatment

 FDG – PET

• NCCN - PET in all patients without evidence of radiographic metastases, if clinically

indicated

• ESMO - PET may not be informative in patients with mucinous or diffuse tumors

• Yield of PET/CT would be extremely low in a patient with a clinical T1 tumor

• FDG-PET is more sensitive than CT for the detection of distant metastases. PET-CT
identified approximately 10% of radiologically occult metastatic lesions in patients
with locally advanced disease (> T3 or > N1)

• PET/CT can also be useful to confirm malignant involvement of CT-detected

lymphadenopathy

• The sensitivity of PET scanning for peritoneal carcinomatosis is only approximately

50%. It is therefore not an adequate replacement for staging laparoscopy.

• PET/CT is only helpful if the tumor is FDG avid - most diffuse-type gastric cancers
(signet ring carcinomas) are not FDG avid

• In patients with Renal insufficiency / contrast allergy where CECT is prohibitive

 Staging Laparoscopy

• Indicated in all > T1a lesion on EUS

• Indicated in all patients planned for Neo-adjuvant therapy

• ESMO - suggests diagnostic laparoscopy, with or without peritoneal

washings, for all ≥T2N0 tumors that are considered potentially resectable

• Between 20 – 30% of patients who have disease that is beyond T1 stage

on EUS will be found to have peritoneal metastases despite having a
negative CT scan

• Another advantage of laparoscopy is the opportunity to perform

peritoneal cytology or washings in patients who have no visible evidence
of peritoneal spread.

• Staging laparoscopy is more useful in patients with diffuse tumors of the

stomach, gastroesophageal (GE) junction, and those with
lymphadenopathy.
 Serologic Markers

• Serum tumor markers are of limited utility in selected patients.

• CEA, CA 125, CA 19-9, and CA 72-4 – may be used in patients planned for Neo-
adjuvant treatment, where a drop in previously raised levels may correlate with
response
– Pre-op elevations of these markers are an independent indicator for adverse prognosis.
– However no serologic finding should be used to exclude a patient from surgical
consideration.

• No NCCN recommendation for tumor markers, except for MSI, Her2nu, PDL1

• Alpha-fetoprotein – Some gastric cancers are associated with elevated serum levels
of alpha-fetoprotein (AFP); they are referred to as AFP-producing gastric cancers.
– A subset, hepatoid adenocarcinoma of the stomach, has a histologic appearance that is
similar to that of hepatocellular cancer.
– Regardless of morphology, AFP-producing gastric cancers are aggressive and associated
with a poor prognosis.
 Biomarkers and Gastric cancer

• Measurement of serum pepsinogen I and serum pepsinogen I/II ratio alone or in combination with
H. pylori serology, and/or gastrin-17 can identify individuals with extensive atrophic gastritis. But
use of biomarkers as screening tool in low incidence areas of GC is not recommended.

• Serum pepsinogen I (PgI) and pepsinogen II (PgII) are the most reliable markers of functional
mucosal atrophy:
– PgI, synthesised and secreted by chief cells, reflects the functional status of the oxyntic mucosa;
– PgII is produced by both oxyntic, antral mucosa and Brunner’s glands.

• Approximately 1% of pepsinogens are present in serum. Multiple studies have shown a lower PgI/PgII ratio in
patients with corpus atrophy, irrespective of its etiology.

• When integrated with the serological evaluation of antibodies against Helicobacter, parietal cells andintrinsic
factor, the Pg values and their ratio can provide a non-invasive and affordable estimate of gastric function and
morphology.

• Some authors have referred to this battery of tests as the ‘serological biopsy’.

• The most frequently used values for these studies are a Pg I <70 ng/mL and a Pg I/II ratio ≤3.

• Trefoil factor 3 (TFF3) is produced in intestinal metaplasia in the stomach and indicates risk of
gastric cancer. TFF3 had more sensitivity (63.5%), proving to be a better non-endoscopic
biomarker.

• GastroPanel combines PGI, PGII, gastrin-17 and H. pylori serology. This has a negative predictive
value was 91% and the positive predictive value was 86% in predicting Chronic atrophic gastritis
(CAG).
PATHOLOGY
 Classification
• Anatomical location
– TNM – AJCC
– Japnese

• Disease Extent – Early / Locally Advanced / Metastatic

• Histology
– Macroscopic
• Borman
• Japnese

– Microscopic
• Lauren’s
• WHO
• Nakamura
• Japnese
• Endoscopic – Paris classification

• Molecular classification
Early GC
• The concept of early gastric cancer (EGC) originated in Japan in 1962 and
was defined as a GC that could be successfully treated with surgery.

• EGC is now defined more specifically as an adenocarcinoma that is

restricted to the mucosa or submucosa, irrespective of lymph node
metastasis (T1, any N)

• These cancers have a significantly better prognosis (approx 90% 5yr

survival)

• 0-15% of EGC may have nodal metastasis and are considered EGC only

• Lymph node metastasis have two implications

1. Such EGC patients are not candidates for endoscopic treatment

2. Adjuvant treatment is required after surgical resection

Type I & IIa lesions may appear similar.

• Type I lesions extend above the mucosa more than 2.5 mm (the width of the closed cups of a
biopsy forceps).

• Pathologically, the height of type I lesion is more than double the thickness of the adjacent
mucosa.

• Type IIa lesions are slightly elevated, but their height is less than 2.5 mm.

Type IIc and III lesions may also appear similar.

• Type IIc lesions are slightly depressed with a normal epithelial layer or superficial erosions.

• Type III lesions are characterized by ulceration, with loss of the mucosa and possibly submucosa.

Favourable features of EGC for ER

High probability of en bloc
resection
Well differentiated tumor
Tumor confined to mucosa
No LVI
< 2cm without ulcer
< 1cm if ulcerated
Intestinal GC Diffuse GC
Environmental factors Heredirary / Familial

Precursor lesions – Atrophic gastritis, Intestinal metaplasia No precursor lesions. Blood group A

M>F M=F

Incidence increases with age – Older patients Younger patients

Macro – Exophytic, bulky lesion Ulcerating, Diffusely infiltrating

Hematogenous spread Direct / Transmural & Lymphatic spread

Histology – Gland forming Poorly cohesive / undifferentiated pattern

Molecular – MSI, APC mutation + CDH-1 mutation – absent E-Cadherin +

inactivation of P53 & P16 inactivation of P53 & P16
 Molecular Classification
• Epstein–Barr virus positive – EBV – 9% of GC - with extreme DNA hypermethylation,
– Characteristics of these tumors include CDKN2A promoter hypermethylation and nonsilent mutation
of PIK3CA (in 80%).
–  Mutation of ARID1A - which encodes for an antiapoptotic protein. 
– JAK2 and ERBB2 (HER2) amplifications are also common.
– Also involves mutation of CD274 and PDCD1LG2 which encode PD-L1 and programmed cell death ligand 2
(PD-L2). These two proteins help the neoplastic cells to escape from the body's antitumoral immune
response, by binding to programmed cell death receptor 1 (PD-1), which is expressed on cytotoxic T cells.
These molecules are of particular relevance as targets for immune checkpoint inhibitor immunotherapy.
– Best prognosis.

• Microsatellite unstable tumors – MSI - 22% of GC, dMMR, associated with high mutation rates
(avg of 50 mutations per tumor).
– Hypermutations are frequent in KRAS, Anaplastic Lymphoma Kinase (ALK), ARID1A, PI3K-PTEN
mechanistic target of rapamycin (mTOR) pathway.
– Tumors affect women disproportionately, mostly in antrum with intestinal phenotype

• Genomically stable tumors – GS – 20% of GC, CDH-1 mutation in 35%, diffuse histology,
Aneuploidy, Earlier age presentation, ARID1A & RhoA mutations. Worst prognosis
 
• Tumors with chromosomal instability – CSI – 50% of GC, intestinal histology,
– P53 mutations in 70%,
– other genes – CCNE1n MYC, ERBB2 (Her2), KRAS.
– 10-20% of GC are Her2 +ve.
 Clinical Implications of Molecular subtyping
• HER2 overexpression — approximately 10 – 20% of GC HER2 gene
amplification
– In general, HER2 amplifications are more common in adenocarcinomas of the
EGJ junction compared with gastric adenocarcinomas, and in the Lauren
intestinal subtype compared with the diffuse subtype.
– HER2 gene amplifications are enriched in the MSS/TP53-negative subtype
– The benefit of adding Trastuzumab for patients with HER2-ovexpressed tumors
was initially shown in the ToGA trial.  

• PD-L1 overexpression and deficient mismatch repair — 

– The benefit of adding Pembrolizumab for patients with PD-1 tumors was initially
shown in the KEYNOTE trial.  

– Patients with metastatic gastric cancer whose tumors are MSI-H or dMMR (but
not those with proficient mismatch repair [pMMR] tumors) as well as those with
a high tumor mutational burden experience clinical benefit from PD-1 inhibitors,
and some responses are durable.

–  Pembrolizumab is now approved for treatment of advanced disease in a variety

of tumor types, including gastric cancer, with either dMMR or high levels of
tumor mutational burden.
AJCC 8
Staging
TREATMENT OF GC
 Overview
• In case of surgery alone, the 5-year survival rate can be as low as 25%. Relapse has
been noted in 70–90% patients even after tumor resection with negative margins.
Multi-modal therapy should now be universally applied tumor ≥stage T2

• Neoadjuvant / Peri-operative therapy for - bulky T3/T4 tumors, visible perigastric

nodes by preoperative imaging studies, or a linitis plastica appearance

• Upfront surgery followed by adjuvant therapy remains an accepted approach- in

nonbulky T2 or T3 tumors with no visible perigastric nodes.

• There are no randomized trials demonstrating better outcomes from neoadjuvant

therapy versus initial surgery followed by any form of adjuvant therapy

• Neoadjuvant chemoradiotherapy is not recommended until favourable data are

available.

• The best chemotherapy regimen for neoadjuvant therapy is not established, and
practice is variable
• For most patients with a good performance status and without significant
comorbidities who are able to tolerate intensive chemotherapy - the FLOT
(preferred) or ECF / ECX regimen

• For patients with a lower performance status or multiple comorbidities – FOLFOX or

CAPOX are appropriate alternative regimens.

• For patients who have already undergone potentially curative gastric resection with
no neoadjuvant therapy - adjuvant therapy is recommended for all N+ patients
(which would include pathologic T1N1 ) and for those with pathologic T3-4N0
disease

• The optimal management of patients with locally advanced, initially unresectable,

but nonmetastatic gastric cancer is uncertain, and there is no standard approach.
The role of induction therapy is unclear.

• An initial attempt at downstaging with chemotherapy, chemoradiotherapy, or a

combination, followed by careful restaging and surgical exploration in responders
who have no evidence of metastatic disease, is a reasonable approach.

• Trastuzumab should be added to the first line chemotherapy for HER2

overexpressing metastatic tumors
 Work-up

1. History & examination

2. UGI scopy & biopsy
3. Chest/abdomen& pelvis CT with oral & IV contrast
4. FDG-PET – if no evidence of M1 disease and if clinically
indicated
5. CBC and Routine labs
6. EUS – to differentiate early and advanced GC
7. EMR – for Early GC – differentiate T1a from T1b
8. Biopsy of metastatic disease
9. MSI by PCR/MMR + HER2 + PD-L1 testing – if metastasis is
documented or suspected
10. Assess Siewert category
11. Prehabilitation – Stop smoking + Nutrition + Exercises
12. Screen for family history
CHEMOTHERAPY /
CHEMO-RADIOTHERAPY
 Neoadjuvant / Perioperative
• For patients with T2N0 or higher.

• Meta-analysis concluded that NACT was associated with

– A statistically significant benefit in terms of both OS and PFS
– A significantly higher R0 resection rate

• Did not significantly worsen operative complications, periop

mortality or Gr 3or 4 adverse effects

• Timing of adjuvant therapy — Optimal timing is not established.

– Most prefer to start within 6 to 8 weeks of surgery.
– In practice, however, only a minority of patients are sufficiently recovered
from surgery to start adjuvant chemotherapy within 8 weeks
– many more are able to start within 12 weeks.
– Whether a delay in starting adjuvant chemotherapy beyond 8 or even 12
weeks compromises outcomes is not clear.
MAGIC trial – Peri-Op Chemo FLOT trial – Peri-Op Chemo

Place: Europe Place: Germany

Study population: 503. GC (74%), Distal EAC (11%), GEJ AC Study population: 716. GC (44%), GEJ AC (56%). Follow-up – 43
(15%) months

Randomisation: Surgery alone vs. ECF 3 cycles pre & Post-OP Randomisation: ECF or ECX + surgery + ECF or ECX vs.
4 cycles FLOT + surgery + 4 cycles FLOT
Conclusion: only 42% completed protocol. (FLOT – Docetaxel - 50mg/m2 + Oxaliplatin – 85mg/m2 +
5yr OS 23% vs 36%. infusional 5FU – 2600mg/m 2 over 24hr)

Peri-op chemo arm had - Higher R0 resection (79% vs 70%), Conclusion: OS - 35 mo vs 50 mo

lesser local recurrence & mets. 3yr OS – 48% vs. 57%
12% had grade 3 / 4 toxicity grade 3 / 4 toxicity – 16% vs. 7%

French FNCLCC and FFCD trial – Peri-Op Chemo NeoAdjuvant chemoRT - TOPGEAR trial, CRITICS-II
trial, ESOPEC trial are underway
Study population: 224.

Randomisation: Surgery alone vs. Chemo (Cisplatin

POET trial – Germany – Neoadjuvant CRT
+ 5FU) + Surgery – followup – 5.7 years
PLF + Surgery vs. PLF/RT + Surgery (PLF – Cisplatin +
Conclusion: Closed prematurely due to low accrual Leucovorin + 5FU)
5yr OS 24% vs 38%. 3yr OS – 27.7% vs 47.4%
5yr DFS – 19% vs. 34%
 
 Adjuvant therapy
• Adjuvant therapy =
Chemotherapy +
Chemoradiotherapy
or Chemotherapy
alone

• Guidelines from the

ESMO suggest
adjuvant therapy for
all patients with
resected stage IB
disease, including
those with pathologic
T2N0 tumors
INT 0116 (SWOG) / McDonald trial – Adjuvant Chemoradiotherapy vs ACTS GC trial – Japanese S1 trial - Adjuvant Chemotherapy vs Observation in stage
Observation II & III GC

Place: North America Place: Japan

Study population: 559. GC (74%), Distal EAC (11%), GEJ AC (15%) Study population: 1059.

Randomisation: Surgery alone (227) vs. Surgery + 5FU/LV/RT (282) Randomisation: Surgery alone (530) vs. Surgery + S1 (529)

Conclusion: 5yr OS – 28% vs 43% S1 – 80 – 120 mg daily for 4 weeks, repeated every 6 weeks for 1year

3yr DFS – 31% vs 48% S1 – includes – Tegafur + Gimeracil + Oteracil

Median OS - 27 months vs 36 months
Conclusion: 3yr OS – 80.1% vs 70.1%
Lesser local recurrence.
JACCRO GC- 07 trial – S1 alone vs. S1 + Docetaxel in adjuvant chemotherapy
Limitations – only 10% pts had D2 dissection. Only 64% of cases completed
treatment 3yr RFS – 50% vs 66%
 

ARTIST trial – Adjuvant Chemoradiotherapy CLASSIC trial – Adjuvant Chemotherapy vs Observation in stage II / III GC
Place: South Korea Place: South Korea

Study population: 458 Study population: 1035

Randomisation: Surgery (D2 resection) + XP(Capec+Cisplatin) vs. Surgery (D2
resection) + XP + ChemoRT (45Gy + Capec 825mg/m2 BD).
 
Followup – 84 months
 
Conclusion: 3yr DFS – 72% vs 76%
ARTIST II trial - 900 patients. S1+Oxaliplatin Vs S1+Oxaliplatin+RT.
37 months followup – no difference in DFS
 
Randomisation: Surgery alone vs. Surgery + CAPEOX (8- 21 day cycles of Capec
100mg/m2 BD on days 1 to 14 + Oxali 130mg/m2 on day 1).
Followup – 34 months
Conclusion: 3yr OS – 78% vs 83%. 5yr OS – 69% vs. 78%
3yr DFS – 59% vs 74%
CALGB 80101 trial – Adjuvant Chemoradiotherapy

Place: North America

Randomisation: 5FU/LV + RT vs. ECF + RT

Conclusion: no difference in OS and DFS

SURGICAL MANAGEMENT
 Endoscopic treatment for Early GC
(European Society of Gastrointestinal Endoscopy (ESGE) guidelines / Japanese Guidelines)

• Around 10%-15% of gastric cancers are diagnosed as EGC.

• ESD – Endoscopic Submucosal Dissection - as the treatment of choice for most superficial
neoplastic gastric lesions.

• ESD should be consid­ered for lesions with very low risk of lymph node metastasis, no matter if it
meets the absolute or expanded indication criteria.

• Absolute Indication
– EMR – for Non ulcerated, differentiated T1a lesion < 2cm.

– ESD - for Non ulcerated, differentiated adenocarcinoma, T1a lesion > 2cm
– - for ulcerated lesion, differentiated adenocarcinoma T1a lesion ≤ 3 cm

• Expanded Indication
– for non ulcerated, undifferentiated ,T1a lesion ≤ 2 cm

• Relative indicaton
- for elderly with comorbidites unfit for surgery who do not meet absolute / expanded indication.

• Enbloc resection – done with ESD – 98.4% cure rate. While R0 resection – with EMR – 90.2% cure
rate
 Curability of Endoscopic Resection (Japanese Guidelines)

• Two factors should be considered for curability assessment:

– Completeness of the primary tumor removal

– Possibility of lymph node metastasis.

• Endoscopic curability A (eCuraA)

– Any size - UL0 + Enbloc resection +Differentiated + pT1a + negative H &
V margins (HM0, VM0) + no Lymphovascular invasion (Ly0, V0)
 
– UL1 - < 3cm + Enbloc resection +Differentiated + pT1a + negative H & V
margins (HM0, VM0) + no Lymphovascular invasion (Ly0, V0)
 
– No further treatment – observation enough
• Endoscopic curability B (eCuraB)
– UL0 - < 2cm + Enbloc resection + UnDifferentiated
+ pT1a + negative H & V margins (HM0, VM0) +
no Lymphovascular invasion (Ly0, V0)
 
– < 3cm + Enbloc resection +Differentiated + pT1b
(sm < 500um) + negative H & V margins (HM0,
VM0) + no Lymphovascular invasion (Ly0, V0)
 
– No further treatment – observation enough
• Endoscopic curability C1 (eCuraC1) – ecura A or eCuraB with positive
margins

– If HM1 (horizontal margin +ve on submucosal side) – Gastrectomy.

– If incomplete ESD/EMR – Re-ESD / APC / Observation

• Endoscopic curability C2 (eCuraC2)

– < 3cm + Enbloc resection + UnDifferentiated + pT1b (sm < 500um) + negative H
& V margins (HM0, VM0) + no Lymphovascular invasion (Ly0, V0)

– UL1 - < 3cm + Enbloc resection +Differentiated + pT1a + negative H & V margins
(HM0, VM0) + no Lymphovascular invasion (Ly0, V0)

– Patient should undergo Gastrectomy after eCuraC2

 Advanced GC
• Standard gastrectomy - is the principal surgical procedure performed with curative intent. It
involves resection of at least two-thirds of the stomach with a D2 lymph node dissection

• Non‑standard gastrectomy - In non-standard gastrectomy, the extent of gastric resection and/or

lymphadenectomy is altered according to tumor stages. It includes modifed surgery and extended
surgery.

– Modifed surgery - The extent of gastric resection and/or lymphadenectomy is reduced (D1, D1+, etc.)
compared to standard surgery.

– Extended surgery
• Gastrectomy with combined resection of adjacent involved organs.
• Gastrectomy with extended lymphadenectomy exceeding D2.

• Non‑curative surgery - is offered to the patients who are considered to be incurable. It can be
semi-classified into either palliative surgery or reduction surgery depending on the aim of surgery.

– Palliative surgery - Serious symptoms such as bleeding or obstruction - in a patient with advanced/
metastatic gastric cancer - Palliative gastrectomy or gastrojejunostomy . Stomach-partitioning
gastrojejunostomy has been reported to result in superior function compared to simple
gastrojejunostomy

– Reduction surgery - is defined as gastrectomy performed for patients incurable disease (liver /
peritoneal mets), when there are no symptoms such as bleeding and obstruction. REGATTA trial failed
to prove survival benefit of reduction surgery. Therefore, surgeons are strongly advised not to perform
this type of surgery any more
 Extent of gastric resection

• Total gastrectomy of the stomach including the cardia and pylorus.

• Distal gastrectomy - Stomach resection including the pylorus. The cardia is preserved. In the
standard gastrectomy, two-third of the stomach is resected.

• Pylorus-preserving gastrectomy (PPG) - Stomach resection preserving the upper third of

the stomach and the pylorus along with a portion of the antrum.

• Proximal gastrectomy (PG) - Stomach resection including the cardia (esophagogastric

junction). The pylorus is preserved.

• Segmental gastrectomy - Circumferential resection of the stomach preserving the cardia

and pylorus.

• Local resection - Non-circumferential resection of the stomach.

• Non-resectional surgery - bypass surgery, gastrostomy, jejunostomy.

• Completion gastrectomy - Total resection of the remnant stomach including the cardia or
pylorus depending on the type of previous gastrectomy.

• Subtotal resection of remnant stomach - Distal resection of the remnant stomach

preserving the cardia.
 Criteria for Unresectability

• Locoregionally advanced
– Disease infiltrating root of mesentery

– Para-aortic nodes positive

– Invasion / encasement of major vascular structures – Aorta, CHA, HA, CA except distal SA/SV

– Relative - Patients who have bulky adenopathy fixed to the pancreatic head that might
indicate the need for a Whipple procedure are at a high risk for occult metastatic disease. 

• Distant metastasis
– Multiple liver /peritoneal metastasis, including positive peritoneal cytology

– Distant organ metastasis

– Lymph nodes behind or inferior to the pancreas, aorto-caval region, into the mediastinum,
or in the porta hepatis.
 Resection margin

Proximal margin of at least

• 3 cm is recommended for T2 or deeper tumors with an expansive growth pattern

(Bormann types 1 and 2)

• 5 cm for those with an infiltrative growth pattern (types 3 and 4).

• For tumors invading the esophagus, resection margin >5 cm is not necessarily
required, but frozen section examination of the resection line is preferable to ensure
an R0 resection.

• For T1 tumors, a gross resection margin of 2 cm should be obtained.

• When the tumor border is unclear and difficulties in deciding on the resection line
are expected, preoperative endoscopic marking by clips of the tumor border based
on the biopsy results would be helpful.
 Selection of Gastrectomy

• The standard surgical procedure for clinically node-positive (cN+) or T2–

T4a tumors is either total or distal gastrectomy.

• Distal gastrectomy is selected when a satisfactory proximal resection

margin can be obtained. When obtaining proximal resection margin is not
possible, total gastrectomy is selected.

• Even in a case that a satisfactory proximal resection margin can be

obtained, pancreatic invasion by tumor requiring pancreaticosplenectomy
necessitates total gastrectomy regardless of the tumor location.

• Total gastrectomy with splenectomy should be considered for tumors that

are located along the greater curvature and harbor metastasis to no. 4sb
lymph nodes, even if the primary tumor could be removed by distal
gastrectomy.

• For adenocarcinoma involving proximal stomach and GEJ, esophagectomy

of the middle and distal esophagus + proximal gastrectomy with gastric
tube reconstruction should be considered, similar to EAC.
For cT1N0 tumors, the following types of gastric resection can be considered according
to tumor location.

• Pylorus-preserving gastrectomy (PPG): for tumors in the middle portion of the

stomach with the distal tumor border at least 4 cm proximal to the pylorus.

• Proximal gastrectomy: for proximal tumors where more than half of the distal
stomach can be preserved.

• Local resection of the stomach and segmental gastrectomy should still be regarded
as investigational treatments.

NCCN prefers

• subtotal gastrectomy for distal GC

• Total or Proximal gastrectomy for proximal GC

• Placement of FJ in select patients, especially if adjuvant chemoradiation is planned

• Limited gastric resection even with +ve margins is acceptable with unresectable
tumors for palliation of symptomatic bleeding.
 Landmarks for Distal and Subtotal Gastrectomy
Procedure On Lesser curvature On Greater Curvature

Distal Gastrectomy Incisura 3rd branch of RGEA

Subtotal For PUD 2nd last branch of LGA 2nd last branch of LGEA
Gastrectom
y

For GC 1 or 2 or 3 cm below Midpoint between –

EGJ depending on Last SGA /1st LGEA and
margin status Jn of RGEA / LGEA
 Reconstruction after gastrectomy

• Total gastrectomy Pylorus‑preserving gastrectomy

– Roux-en-Y esophagojejunostomy.
– Jejunal interposition. Gastro-gastrostomy.
– Double tract method.

• Distal gastrectomy
– Billroth I gastroduodenostomy.
– Billroth II gastrojejunostomy.
– Roux-en-Y gastrojejunostomy.
– Jejunal interposition.
Proximal gastrectomy
∙ Esophagogastrostomy.
∙ Jejunal interposition.
∙ Double tract method.
LYMPHADENECTOMY
Indications for lymph node dissection
• In principle, D2 lymphadenectomy is indicated for cN+
or ≥cT2 tumors and a D1 / D1+ for cT1N0 tumors.

• Since pre and intraoperative diagnoses regarding the

depth of tumor invasion and nodal involvement
remain unreliable, D2 lymphadenectomy should be
performed whenever the possibility of nodal
involvement cannot be dismissed.

• NCCN – Goal of examining 16 or more LNs. Patients

who had > 15 LNs examined had the best long-term
survival outcomes.
D1 lymphadenectomy - is indicated for

• cT1a tumors that do not meet the criteria for EMR/ESD

• cT1bN0 tumors that are < 1.5 cm and differentiated type.

D1+ lymphadenectomy - is indicated for cT1N0 tumors other than the above.

D2 lymphadenectomy - is indicated for potentially curable cT2–T4 tumors as

well as cT1N+ tumors.

• Spleen should be preserved in total gastrectomy for advanced cancer of

the upper stomach provided the tumor does not involve the greater
curvature.

• The role of splenectomy for tumors invading the greater curvature

remains equivocal.
D2+ lymphadenectomy

Gastrectomy with extended lymphadenectomy beyond D2 is classified as a non-standard

gastrectomy, and could be considered for the following cases although hard evidence is
lacking, on the condition that it can be conducted safely

• Dissection of No. 10 (splenic hilar lymph nodes) with or without splenectomy for
cancer of the upper stomach invading the greater curvature (D2 + No. 10).

– This procedure had been defined as D2 lymphadenectomy in the previous editions of the
Japanese Gastric Cancer Treatment Guidelines

• Dissection of No. 14v (SMV lymph node) for cancer of the distal stomach tumor with
metastasis to the No. 6 lymph nodes (D2 + No. 14v).

• Dissection of No. 13 (posterior pancreas head lymph node) for cancer invading the
duodenum (D2 + No. 13).

– Metastases to the No. 13 nodes, which are not included in the regional lymph nodes for
gastric cancer, should usually be classified as M1.

– However, since the No. 13 nodes are among the regional lymph nodes for cancer of the
duodenum according to the TNM classification and the Japanese Classification of Gastric
Carcinoma 15th edition, these should be regarded as regional lymph nodes once gastric
cancer invades the duodenum
D3 Lymphadenectomy - is a superextended
lymphadenectomy.
• 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 to 16).

• AJCC classify disease in these regions as distant metastasis and do

not recommend removing nodes in these areas during a potentially
curative gastrectomy.
 Extent of Lymphadenectomy

The arguments in favour of extended lymphadenectomy (ie, D2 or D3

versus D1) are that

• Removing a larger number of nodes more accurately stages

disease extent

• Failure to remove these nodes leaves behind disease (which would

be a potentially fatal event) in as many as one-third of patients.

• A consequence of more accurate staging is to minimize stage

migration (the "Okie phenomenon," as described by Will Rodgers).
The resulting improvement in stage-specific survival may explain,
in part, the better results in Asian patients.
Total gastrectomy

• D0: Lymphadenectomy less than D1.

• D1: No. 1–7.

• D1+: D1 + No. 8a, 9, 11p.

• D2: D1 + No. 8a, 9, 11p, 11d, 12a.

• For tumors invading the esophagus,

resection of No. 110* should be added to
D1+, and resection of Nos. 19, 20, 110* and
111 to D2.

Proximal gastrectomy

• D0: Lymphadenectomy less

than D1.
•
• D1: No. 1, 2, 3, 4sb, 4sb, 7.

• D1+: D1 + No. 8a, 9, 11p

Distal gastrectomy

• D0: Lymphadenectomy less than

D1.

• D1: No. 1, 3, 4sb, 4d, 5, 6, 7.

• D1+: D1 + No. 8a, 9.

• D2: D1 + No. 8a, 9, 11p, 12a.

Pylorus‑preserving gastrectomy
• D0: Lymphadenectomy less than
D1.
• D1: No. 1, 3, 4sb, 4d, 5, 6, 7.
• D1+: D1 + No. 8a, 9.
 D1 vs. D2 dissection
•  At the National Cancer Center (NCC) in Japan, and in Korea gastric cancer surgeons routinely perform D2 or greater
lymphadenectomies

• Since the late 1980s, Japanese investigators have tracked the rates of gastric cancer metastasis to specific nodal
stations 

• In 1989, the NCC database of 3,843 cases was used to create the Maruyama computer program

• This program estimates the risk of metastasis to each lymph node station based on the input of 8 variables:
– Sex
– Age
– endoscopic or Bormann’s classification
– depth of invasion
– maximal diameter
– location (upper, middle, or lower third)
– position (lesser or greater curvature, anterior or posterior wall, or circumferential)
– WHO histological classification.

• By matching input variables to a large database of patients, the program gives a percent likelihood of disease in each
of the lymph node stations.

• Maruyama Index (MI) – of unresected disease – is defined as – Sum of regional nodal disease percentages for
stations (1-12) not removed by surgeon

• MI was developed to predict survival of GC patients after surgery based on patient and tumor characteristics
combined with information on removed LN stations.

• MI < 5 - associated with significantly higher survival and reduced relapse risk.
MRC trial 
- RCT - 400 patients undergoing potentially curative resection to a
D1 or a D2 lymphadenectomy.

- Postoperative morbidity was significantly greater in the D2 group

(46% vs 28%), as was operative mortality (13% vs 6%).

- The excess morbidity and mortality were clearly associated with

the liberal use of splenectomy and distal pancreatectomy to
achieve complete node dissection.

- With long-term follow-up, survival rates were comparable despite

the doubling of operative mortality – 5yr OS- 33% vs 35%
Dutch trial - The largest randomized trial came from the Dutch Gastric Cancer Group and compared
D1 with D2 lymphadenectomy in 711 patients who were treated with curative intent.

• A Japanese surgeon trained 11 Dutch surgeons on systematic D2 dissection. However both under
removal and over removal of required nodal stations occurred.

• Post-op morbidity – 43% vs 25% and mortality – 10% vs 4% - higher in D2 group.

• No statistically significant survival advantage was observed.

• A stratified analysis showed that a large proportion of the morbidity and mortality in the D2
group was related to synchronous splenectomy and pancreatectomy while in the subgroup of
patients without pancreaticosplenectomy the risk of relapse was significantly lower in the D2
compared to D1 group. 

A 15yr follow up update of Dutch trial –

• The difference in overall survival is still not statistically significant (22% vs 28% in the D1 and D2
arms)

• GC - related death rate is significantly higher in the D1 arm (48% vs 3%), while death rates due to
other causes were not different.

• Lower locoregional recurrences and GC related deaths in D2 group

• Conclusion – With safer spleen preserving D2 dissections when applied in experienced centers is
the recommended surgical approach for patients with resectable GC
Cochrane analysis - The most recent meta-analysis included
five randomized trials of D1 versus D2 dissection.

• There was no significant advantage for D2

lymphadenectomy for overall survival or disease-free
survival

• There was a significant difference in disease-specific

survival, favouring D2 lymphadenectomy

• The quality of the evidence was judged as moderate.

• However, D2 lymphadenectomy was also associated with a

high postoperative mortality rate
 D2 versus D3 dissection
JCOG trial 9501 – randomly assigned 523 patients to D2 versus D3
(D2 + PAND) dissection.

• The overall perioperative complication rate in the D3 group was

significantly higher (28.1 vs 20.9 %).

• There were no differences in major complications (anastomotic

leak, pancreatic fistula, abdominal abscess, pneumonia) and
perioperative mortality was very low (0.8 %) in both groups.

• 5 yr RFS - 63% in both groups and OS – 70 vs 69% were no better

after extended lymphadenectomy

• Data from the JCOG trial as well as those from other groups
suggest that a D2 dissection can be performed safely with a
perioperative mortality rate that is under 2%
Meta-analysis – The 2015 Cochrane analysis of the JCOG trial and
two other smaller randomized trials of D2 versus D3 (with PAND)
dissection concluded that

• Resection of the paraaortic nodes did not provide any significant

survival benefit.

• While there was no significant difference in perioperative

mortality with extended lymphadenectomy, the 95% confidence
intervals were very wide and included the possibility of a nearly
sevenfold increase in the risk of perioperative mortality.

• Thus, paraaortic lymphadenectomy should not be considered a

routine practice for surgical treatment of gastric cancer.
 Sentinel lymph node biopsy for EGC

• Proposed to identify those patients undergoing surgical rather than

endoscopic management who need more extensive surgery.

• At least in theory, patients with positive SLNs should undergo partial or

total gastrectomy with requisite D2 lymphadenectomy

• While those with a negative SLN biopsy are recommended for a more
limited gastric (eg, wedge or segmental) resection with a D1 or no formal
lymphadenectomy.

• However, the available data on the accuracy of SLN mapping for early
gastric cancer are conflicting.  

• Due to relatively low sensitivity for detection of LN metastases, the use of

SLN mapping for early gastric cancer remains investigational at best and
should be limited to clinical trials.
 Miscellaneous

Vagal nerve preservation - In case of PPG, the hepatic branch should

be preserved to maintain the pyloric function

Omentectomy - Removal of the greater omentum is usually

integrated in the standard gastrectomy for T3 or deeper tumors.

• For T1/ T2 tumors, the omentum more than 3 cm away from the
gastroepiploic artery may be preserved.

Bursectomy - for tumors penetrating the serosa of the posterior

gastric wall had been performed with the aim of removing
microscopic tumor deposits within the omental cavity.
• However, survival benefit of this procedure has been denied by a
large-scale randomized trial (JCOG1001), not only for all patients
registered but also for subsets with T4a tumors and tumors
located in the posterior wall.
Combined resection of adjacent organ(s) - For tumors in which the primary
or metastatic lesion directly invades adjacent organs, combined resection of
the involved organ may be performed to obtain an R0 resection.

Approaches to the lower esophagus - For gastric cancers invading less than

3 cm of the distal esophagus, a transhiatal abdominal approach is
recommended (JCOG9502).

• Where a greater length of esophagus is involved, a transthoracic approach

should be considered if the surgery is potentially curative.

Laparoscopic surgery – Results of a Meta-analysis involving 9337 patients

(5000 lap / 4337 open gastrectomy) showed less blood loss, and faster
recovery times.

• However there was no difference in operative time, number of harvested

LNs, post-op mortality, or 5yr survival.

• Chinese CLASS-01 trial (Locally advanced GC), Japanese JCOG0912 trial

(stage I), Korean KLASS-01 (stage I) trial – all confirmed non inferiority of
Laparoscopic gastrectomy with comparable oncological outcomes.
 Linitis Plastica

• 5% of primary GC

• Involves – diffusely or a broad region of stomach. Nodal involvement is frequent.

• In rare circumstances, metastasis from Lobular Ca breast can present like linitis
plastica

• 50-60% present with metastasis, mainly peritoneal.

• Extremely Poor prognosis – due to early spread, advanced stage at presentation and
microscopic positive margins

• Peri-op treatment is advised

• Patients undergoing R0 resection have similar Longterm survival as non linitis

counterparts
SURVEILLANCE
 Tis (successfully treated with ER)

• H&P every 3-6 mo for 1-2yr, every 6-12 mo for 3-5

yr and annually thereafter

• CBC and chemistry profile as clinically indicated

• UGI scopy every 6 mo for 1 yr and then annually

for 3 yrs

• CECT chest & abdomen as clinically indicated.

 T1a / T1b, N0-N1 ( stage I) – treated with ER / Surgical resection

• H&P every 3-6 mo for 1-2yr, every 6-12 mo for 3-5 yr and annually
thereafter

• CBC and chemistry profile as clinically indicated

• Post ER - UGI scopy every 6 mo for 1 yr and then annually for 5 yrs

• Post- resection – UGI scopy as clinically indicated

• CECT chest & abdomen as clinically indicated.

• Monitor for nutritional (B12, Fe, Ca, Folate) deficiencies and

correct.
 Stage II/III – treated with NADCT/Adjuvant Rx
• H&P every 3-6 mo for 1-2yr, every 6-12 mo for 3-5 yr and annually
thereafter

• CBC and chemistry profile as clinically indicated

• Post- partial / subtotal gastrectomy – UGI scopy as clinically

indicated

• CECT chest & abdomen every 6-12 mo for first 2 yrs and then
annually upto 5yrs and / or PETCT as clinically indicated

• Monitor for nutritional (B12, Fe, Ca, Folate) deficiencies and

correct.
 Palliative care

Bleeding –
• Endoscopic management with APC, clips, injection, heat probes – High chance of
recurrences
• Interventional radiology – angioembolisation
• EBRT – for both acute and chronic bleeds
• No evidence for PPI use
• Palliative resection – if resectable

Obstruction -
• Primary goals – to reduce nausea / vomiting and allow oral diet
• Endoscopic placement of SEMS
• Surgery – Gastrectomy / GJ
• EBRT
• Chemotherapy
• Feeding Gatsrostomy / Jejunostomy

Pain – EBRT / Chemotherapy / Pain control as per NCCN guidelines