Gastric cancer

epidemiology
• 5th most common cancer, 2nd major cause of
cancer death
• Men> women
• Peak : 7th decade
• Most common cancer in japan
 Risk factors
• Nutritional • Medical
– Low fat or protein consumption – Prior gastric surgery
– Salted meat or fish – Helicobacter pylori and Epstein-Barr virus
infection
– High nitrate consumption – Hereditary predisposition
– Obesity – Prior abdominal irradiation
– High complex carbohydrate consumption – Atrophic gastritis
– Adenomatous polyps
• Environmental
• Other
– Poor food preparation (smoked, salted) – Male sex
– Lack of refrigeration
– Poor drinking water (e.g., contaminated • PROTECTIVE
well water) – Raw vegetables
– Smoking and alcohol – Citrus fruits
– Antioxidants
• Social – Selenium, zinc, iron
– Low socioeconomic class – Green tea
 H pylori
• sixfold increased risk of developing gastric cancer.
• Chronic inflammation.
– atrophic gastritis or chronic active gastritis.
– progresses to intestinal metaplasia, dysplasia, and ultimately intestinal-type
adenocarcinoma.
• Molecular alterations
– overexpression of cyclooxygenase-2 and cyclin D2, p53 mutations, microsatellite instability,
decreased p27 expression, and alterations in transcription factors such as CDX1 and CDX2. 19

• Host inflammatory responses: higher levels of interleukin-1β and tumor necrosis

factor-α expression
• The presence of the cytotoxin associated gene A upregulates proinflammatory
response, cellular migration, and elongation, leading to increased virulence and
risk of gastric cancer.
 Dietary factors
• High-salt foods, particularly salted or smoked meats that contain
high levels of nitrate - salt damages the stomach mucosa.
• low intake of fruits and vegetables: ascorbic acid removes
carcinogenic N nitroso compounds and oxygen free radicals
• N-nitroso compounds
– Foods containing nitrate
– tobacco smoke, another
• Fresh fruits and vegetables
• Synergy b/w h pylori infectoin and high salt diet
• Refrigeration – meat preservation by salt decreased
• Processed meat: class I carcinogen
Hereditary risk factors and cancer genetics
• hereditary diffuse gastric cancer:
– E-cadherin (CDH1)mutation: 60% to 70% lifetime incidence of developing gastric cancer.
– Prophylactic total gastrectomy prior to age 30.
– higher risk of lobular breast cancer and screening should begin by age 30, with consideration of prophylactic risk-reducing
bilateral mastectomy.
• gastric adenocarcinoma and proximal polyposis of the stomach
• familial intestinal gastric cancer
• In familial adenomatous polyposis: fundic or body sessile polyps, with 40% of these polyps having some degree
of dysplasia
• Li-Fraumeni syndrome(p53 mutation AD)
– risk for gastric cancer, sarcoma, breast cancer, brain tumors, and adrenocortical carcinomas.
• HNPCC (Lynch syndrome)
– risk of gastric and endometrial cancers

• Genetic alterations
– The c-met proto-oncogene, Kras and HER2 overexpression
– Inactivation of the tumor suppressor genes p53
– Adenomatous polyposis coli gene mutations
– Ecadherin loss
– Microsatellite instability
 Polyps
• common incidental finding during upper
endoscopy (5%)
• usually asymptomatic.
• polyp greater than 1 cm: complete
polypectomy.
• multiple polyps, the largest should be and
biopsy remaining polyps along with Biopsies of
normal mucosa for dysplasia and H pylori
• Adenomatous polyps
– > 30% risk of carcinoma and increases with increasing size
– Pedunculated: Endoscopic removal
– Polyp is larger than 2 cm, is sessile, or has a proven focus of invasive carcinoma,
operative excision is warranted.
• Fundic gland polyps
– benign lesions d/t glandular hyperplasia and decreased luminal flow.
– associated with PPI use and occur in one third of patients by 1 year.
– Dysplasia rare
• Hyperplastic polyps
– H. pylori infection and chronic gastritis,
– malignancy rate of under 2%.
• Peutz-Jeghers syndrome
– 2% to 3% malignancy rate
 PPIs
• Long-term PPIs, the low-acid environment
allows H pylori to colonize the gastric body,
leading to corpus gastritis – atrophic gastritis -
gastric ca
• H pylori eradication before Long term PPI use
 Other risk factors
• Pernicious anemia
• Obesity: cardia ca
• Epstein-Barr virus infection
• Smoking
• Prior abdominal irradiation
 Pathology:Borrman classification
• Gross appearance of
endoscopic findings
– 1: polypoidal
– 2: fungating
– 3 ulcerative
– 4 diffuse infiltrating
Histologic clasification
 WHO,2010
• Papillary
• Tubular
• Mucinous
• Poorly cohesive (including signet cell)
• Uncommon
 Symptoms
• Vague and non specific
• Epigastric pain: constant and non radiating,
not relieved by foods
• early satiety, weight loss
• Gastric outlet obstruction: distal
• Dysphagia: proximal
• Anemia
 Examination
• Supraclavicular lymph node (Virchow)
• Axillary (irish)
• Periumbilical (sister mary joseph nodule)
• Hepatomegaly
• Jaundice
• Ascites
• Krukenberg tumor (drop mets)
• Blummer shelf
 Screening
• Upper endoscopy: sensitive
• Barium radiography
 Staging: AJCC 8th TNM
Primary Tumor (T) Regional Lymph Nodes (N)
TX: Primary tumor cannot be assessed
NX: cannot be assessed
T0 No evidence of primary tumor N0: No metastasis
N1: 1–2 nodes
Tis Carcinoma in situ; intraepithelial tumor without invasion of the lamina N2: 3–6 nodes
propria, high-grade dysplasia
N3: 7 or more
T1 Tumor invades lamina propria, muscularis mucosae, or N3a: 7–15 nodes
submucosa N3b: 16 or more nodes
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa

T2 Tumor invades muscularis propria

Distant Metastasis (M)
T3 Tumor penetrates subserosal connective tissue without M0 No distant metastasis
invasion of visceral peritoneum or adjacent structures M1 Distant metastasis

T4 Tumor invades serosa (visceral peritoneum) or adjacent

structures
T4a Tumor invades serosa (visceral peritoneum)
T4b Tumor invades adjacent structures
• Number of nodes for N staging not location
• Minimum of 16 nodes for accurate staging

• R status
• R0: microscopically margin-negative resection,
in which no gross or microscopic tumor remains
in the tumor bed.
• R1 indicates removal of all macroscopic disease,
but microscopic margins are positive for tumor.
• R2 indicates gross residual disease.
 Siewert classification
• Adenocarcinoma in close proximity to GE jxn
• aggressive tumors
• Type I tumors are tumors of the distal esophagus, within 1 to
5 cm above the GE junction;
• type II tumors have a tumor center located from 1 cm above
the GE junction to 2 cm below;
• type III tumors are located between 2 and 5 cm caudad to the
GE junction.
• Treatment
– types I and II tumors: similar to esophageal adenoca
– type III tumors similar to gastric adenocarcinoma
 Staging
• The goals of preoperative staging
– gain information on prognosis,
– to counsel the patient effectively, and
– to determine the extent of disease to decide the most
appropriate course of therapy.
• Treatment pathways:
– upfront resection (with or without subsequent adjuvant
therapy),
– neoadjuvant therapy followed by resection,
– treatment of systemic disease without resection
Staging work up
 Endoscopy
• Visualization of the tumor,
• provides tissue for pathologic diagnosis,
• treat patients with obstruction or bleeding
• NCCN guidelines six to eight biopsy specimens
from different areas of the lesion
• Resection of small lesions (≤2 cm in diameter)
– endoscopic mucosal resection (EMR) or
– endoscopic submucosal dissection (ESD,
 EUS
• Recommended when no evidence of metastatic disease.
• 5 concentric layers:
– first three layers: mucosa and submucosa (T1)
– Fourth layer : muscularis propria, (T2)
– Beyond 4th layer(T3)
– Fifth layer: serosa loss of line (T4a)
– Direct invasion of surrounding structures, (T4b) tumor.
• Nodes:
– size and ultrasound appearance
– FNA
• Ascites: FNA – peritoneal spread
• sensitivity and specificity :
– T discrimination: 86% and 90%,
– nodal :83% and 67%
 CT
• CT of the chest, abdomen, and pelvis with oral
and IV contrast –
– evaluate of metastasis: primary role
– locoregional staging (less accurate than EUS, 43%
to 82%,).
 PET
• locally advanced disease
• considered for neoadjuvant therapy
• NCCN guidelines
– Recommend considering PET/CT as part of staging
for patients with greater than T1 disease without
evidence of metastatic disease on initial CT.
– Better identifies occult mets
 Staging laparoscopy
• integral part of the standard workup
• High rate of occult peritoneal mets : 20% to
30% of patients with T2
• sensitivity greater than 95%.
• alters management in 9% to 60% of cases,
• avoid an unnecessary laparotomy
• safe, low-risk procedure
• planned as a single-stage procedure with
resection.
• benefits of avoiding laparotomy,
– avoiding a delay in starting chemotherapy for
patients with metastatic disease.
• staging laparoscopy prior to initiation of
neoadjuvant therapy
• repeat staging laparoscopy after neoadjuvant
therapy prior laparotomy for curative intent.
 Resection with curative intent

• Complete resection of a gastric tumor with a wide margin of

normal stomach
• Patients without metastatic disease or invasion of
unresectable vascular structures such as the aorta, celiac
trunk, proximal common hepatic, or proximal splenic arteries
• Open or laparoscopic approach
• Laparoscopic:
– technically demanding
– Early return of bowel function short LOS, comparable lymph node
retrieval and morbidityand comparable oncologic outcome for early
cancer
• Proximal lesions of • Distal stomach: distal
gastrectomy
fundus and cardia not – Proximal margin: 2-3 cm for early
involving GE jxn cancer; 4-6 cm for advanced
– Total gastrectomy with cancer
– Distal margin: proximal
Roux-en-Y
duodenum just distal to pylorus
esophagojejunostomy – Reconstruction: Roux-en-Y less
– Proximal gastrectomy – postgastrectomy syndromes.
higher anastomotic – Pylorus preserving segmental
stenosis and reflux gastrectomy for early cancers in
mid third stomach : comparable
esophagitis – not oncologic outcome and less
preferred postgastrectomy syndrome
 ERAS
• No routine use of NG/nasojejunal
decompression
• Avoiding perianastomotic drains
• Minimal invasive technique if possible
• Early oral feeding
• Similar rates of total complication,
perioperative mortality and reoperation
• Higher readmission rates
 Endoscopic resection: criteria
• Standard criteria • Expanded criteria
– Intestinal-type – Any differentiated
adenocarcinoma mucosal tumor
– Tumor confined to the without ulceration
mucosa – Mucosal tumors upto
– Absence of 3 cm with ulceratoin
lymphovascular
– Undifferentiated
invasion
– Nonulcerated tumor
tumors upto 2 cm
– Less than 2 cm in – Slight submucosal
diameter invasion
Endoscopic mucosal resection(EMR)
• Perforation less
• Bleeding: 15% controlled endoscopically
• Enbloc rescetion preferred
• Piecemeal – recurrence
• Positive lateral margins: reendoscopic therapy
• Positive vertical margins, lymphovascular
invasion or submucosal invasion - surgery
Endoscopic submucosal dissection (ESD)
• Limited submucosal involvement
• Marking borders – electrocautery
• Submucosal injxn of epinephrine with indigo carmine dye
– hydrodissection
• Remove en bloc by insulated knife
• Higher risk of perforation

• Endoscopic procedures: higher recurrence and

metachronous lesion with similar 5 yr survival
• Less morbidity
Lymph node dissection
• D1: perigastric lymph nodes (1-7)
• Extended D2: clearance of celiac axis +/-
splenectomy (1-12a)
– Routine splenectomy and distal pancreatectomy
not standard
– Recommended by NCCN for surgery with curative
intent
• Superextended D3: complete clearance of
celiac axis and periaortic nodes (1 -16)
 Locally advanced Gastric Cancer
• unresectable because of adjacent organ
involvement
• multiorgan resection is beneficial in a highly
selected patient population
• Neoadjuvant and extensive surgery needed
 Adjuvant therapy
• Biologically aggressive cancer
• high recurrence
– Distant
– Peritoneal
– Locoregional
• Adjuvant therapy aims to reduce recurrence
– 1st line chemotherapy regimens:
• ECF
• CAPOX
• FOLFOX
 Adjuvant radiotherapy
• Addresses local recurrence and nodal disease
• Considered for patients with less than D2
lymphadenectomy and with positive nodes
• Mcdonald protocol: regimen of 5-FU-based
chemoradiotherapy
 Neoadjuvant therapy
• MAGIC TRIAL
• FLOT4 STUDY
• STUDIED THE ROLE OF NEOADJUVANT
THERAPY WITH PROMISING RESULTS
 Palliative and systemic therapy
• 50% pts present with metastatic/unresectable disease with 3-5
month median survival
• Bleeding:
– endoscopic management
– Angiographic embolization
• Obstruction :
– endoscopic enteral stent
– Radiation and systemic chemo
– Surgery- gastrojejunostomy
– Venting gastrostomy tube
• Perforation:
– closure with healthy omentum or gastrectomy if feasible
 Systemic therapy
• NCCN:
– doublet regimen: 4-FU and cisplatin or oxaliplatin
– Triplet reserved for medically fit patient s with good
performance status

• Newer targeted therapies:

– Cetuximab: EGFR
– Ramucirumab: VEGF
– Trastuzumab: HER 2 (NCCN recommends testing HER2 for all patients
with metastatic disease)
– Immunotherapy: nivolumab and pembrolizumab
 Outcome
• 5 year survival :30%
• 63%: not candidates for resection
• Potentially curative resection: 25-75%
– Early gastric ca : 80%

• Recurrence:
– high 30 – 90%
– 1st 2 years
– Locoregional 40% most common – anastomotic site, gastric
bed and regional LN basin
 Surveillance
• NCCN:
• Complete history and physical examination
– every 3 to 6 months for 1 to 2 years,
– every 6 to 12 months for 3 to 5 years, and
– annually thereafter.
• Laboratory tests: CBC, LFT as clinically indicated.
• CT or PET/CT: clinical suspicion of recurrence,
• Annual endoscopy: subtotal gastrectomy or
endoscopic resection.
 GIST
• Most common mesenchymal neoplasm of GI tract
• Derived form interstitial cells of Cajal. GI
pacemaker cell
• KIT: 95% GIST overexpress KIT(CD117)
• PDGFRA: KIT negative GIST
• Location:
– Stomach(40-60%)
– Small intestine(20-40%)
– Colon/rectum(5-15%)
• Usually >50 yrs
• 5% familial GIST mutn in KIT or PDGFRA
• Nonspecific symptoms: early satiety, bloating,
vague abdominal pain
• Bleeding: melena or hematemesis
• Tumor rupture – rare
• Incidental finding
 evaluation
• Upper endoscopy
– Smooth appearing round submucosal tumor often
with central area of ulceraration
– Low yield of endoscopic biopsy
• EUS –directed FNA
• Preop biopsy not needed if high suspicion of
GIST and patient fit for surgery
• CECT with iv and oral contrast for metastatic
evaluation
 Pathology
• Smooth appearance on
endoscopy
• Spindle or epitheloid cell
• Immunohistochemical
staining
– CD117
– CD34
– PDGFRA
 Treatment
• Resection for
– symptomatic or greater than 2 cm in diameter
– less than 2 cm with high risk features on
endoscopy and EUS,
• irregular borders, ulceration, echogenic foci, and
heterogeneity,
• Observation with repeat endoscopy (6 -12
monthly) for
– Less than 2 cm tumors without high risk features
 Surgical options
• Wide local excision
• Enucleation
• Sleeve gastrectomy
• Total gastrectomy
• R0 resection
• No lymph node dissection
 Laparoscopic resection
• Tumor size less than 5 cm size

Laparoscopic transgastric
resection
Laparoscopic staple
partial gastrectomy

Laparoscopic distal
gastrectomy
 Assessing malignant potential of gastric gastrointestinal stromal
tumors of different sizes and mitotic activity

• Benign (No Tumor-Related Mortality)

– No larger than 2 cm, no more than 5 mitoses/50 HPF
• Probably Benign (<3% With Progressive Disease)
– >2 cm but ≤5 cm; no more than 5 mitoses/50 HPF
• Uncertain or Low Malignant Potential
– No larger than 2 cm; >5 mitoses/50 HPF
• Low to Moderate Malignant Potential (12%–15% Tumor-Related
Mortality)
– >10 cm; no more than 5 mitoses/HPF
– >2 cm but ≤5 cm; >5 mitoses/50 HPF
• High Malignant Potential (49%-86% Tumor-Related Mortality)
– >5 cm but ≤10 cm; >5 mitoses/50 HPF
– >10 cm; >5 mitoses/50 HPF
Gastric neuroendocrine tumors