Gastric Cancer - Deifinition , epidemiology , histological types and molecular genetics and WHO update Reference - WHO Classificiation of tumors of Digestive system Rosai and Ackermann

1. GASTRIC CARCINOMA
Presented by – Dr. Pritika Nehra
Moderator – Dr. Ranjana Solanki
SMS Medical College , Jaipur

2. DEFINITION - malignant epithelial neoplasms.
• Biologically & genetically heterogeneous group of multifactorial
etiologies (environmental and genetic)
• broad morphological heterogeneity with respect to patterns of
architecture and growth,cell differentiation and histogenesis.
• Sporadic(90%),Familial (10%) and Hereditary (1%)
EPIDEMIOLOGY - 7.8% of cancers worldwide
INCIDENCE HIGH INCIDENCE LOW INCIDENCE
Criteria > 60/1lacmales <15/1lacpopulation
Distribution eastern Asia , eastern Europe
and central and Latin America
North America, northern Europe,
Africa and south-eastern Asia
Type of Carcinoma "intestinal " type "diffuse" type
Site of Carcinoma Antrum & pylorus Proximal Stomach (cardia)
Proportion of Early
Gastric Cancer
High Low

3. TIME TRENDS-
• steady decline in incidence and mortality over the last 15 years.
• absolute incidence rate continues to rise(advancing age)
• incidence of "tubular" adenocarcinoma has decreased
• incidence of "diffuse" carcinoma localized to the proximal stomach
has been increasing
AGE & SEX DISTRIBUTION-
• >50yrs age ,M=F
• Young – hereditary, diffuse type, F>M
LOCALIZATION -
• Mc site -antro-pyloric
• Reporting of Ca of "cardia" is likely to change d/t revision of the TNM
classification of G-E junction (2009)
• if the epicentre of tumour is within 5 cm of the oesophagogastric
junction and extends into the distal oesophagus, the tumour should
be staged as an oesophageal carcinoma.

4. ETIOLOGY –
 Environmental Factors:
• Infection by H. pylori
• Diet• Nitrites derived from nitrates (water, preserved food),Smoked and
salted foods, pickled vegetables, chili peppers
• Low socioeconomic status
• Cigarette smoking
 Host Factors:
• Chronic gastritis
• Partial gastrectomy
• Gastric adenomas
40% harbor cancer at time of diagnosis
30% have adjacent cancer at time of diagnosis
• Barrett esophagus
 Genetic Factors
• Slightly increased risk with blood group A
• Family history of gastric cancer
• Hereditary non-polyposis colon cancer syndrome
• Familial gastric carcinoma syndrome (E-cadherin mutation)

5. Precursor Lesions-
H.Pylori ass. Chronic gastritis Atrophy
A) Gastritis
• Autoimmune gastritis develops secondary to the development
of autoantibodies to parietal and chief cells and thus affects the
body fundic mucosa.
• Ass. with the formation of intestinal metaplasia and an
increased risk of developing gastric carcinoma( intestinal type)
Intestinal MetaplasiaNEOPLASIA

6. B) Intestinal Metaplasia
• 2 main types – Complete & Incomplete
• Complete – IHC expression of MUC2 (intestinal) and decreased
MUC1,MUC5AC & MUC6 (gastric)
• Incomplete – Gastric mucins are coexpressed with MUC2
• positive correlation between degree & extent of incomplete intestinal
metaplasia with risk of progression to carcinoma
• Spasmolytic polypeptide-expressing metaplasia (SPEM)
• expression of TFF2 spasmolytic polypeptide is associated with
oxyntic atrophy
• SPEM –characteristically develops in the gastric body and fundus,
share some characteristics with pseudopyloric metaplasia
• strong association with chronic infection with H pylori and with
gastric adenocarcinoma
• another pathway to gastric neoplasia .

8. CLINICAL TOOLS-
A)For Diagnosis
• Endoscopy- sensitive & specific
• Modern video-endoscopy
• Chromoendoscopy

9. B) For Tumor Staging
• Screening- Barium meal ,Endoscopy, Serum pepsinogen
• Tumor Staging –
Endoscopic USG (T stage)
CT-PET / CT Alone ( N and M stage)
 MACROSCOPY-
• Borrmann Classification

11. HISTOPATHOLOGY -
• various histopathological classification schemes
• MC used -WHO and Lauren
• Others - Ming , Nakamura ,Mulligan, Goseki and Carneiro
 Stromal reactions -
• 4 common stromal responses to invasive gastric carcinoma
a) marked desmoplasia
b) lymphocytic infiltration
c)stromal eosinophilia
d)granulomatous response.
• Density of tumor infiltrating lymphocytes - Predictive of regional
lymph-node metastasis with improved outcome
 Grading-
• applies primarily to tubular and papillary carcinomas
• Well , Moderately , Poorly Differentiated
• Low Grade (well & moderately diff.) and High Grade (poorly diff.)

12. LAUREN CLASSIFICATION
C ) Mixed - approximately equal quantities of intestinal and diffuse
components
D ) Indeterminate -Undifferentiated tumours.

13. Intestinal Type (53%)-
• wide range in the degree of differentiation, correlates inversely with
tumor size
• better differentiated tumors-columnar and mucin secreting ,stimulate
a complete-type intestinal metaplasia, ciliated
• Poorly differentiated variants -solid pattern.
• Variable mucin production
• stroma infiltrated
by neutrophils
or histiocytes

14. Diffuse-type (23%)-
• linitis plastica , currently as signet ring adenoca
• prepyloric area. Pyloric obstruction often
• Microscopically, a diffuse growth of malignant cells
• associated with extensive fibrosis
and inflammation
• most tumor cells grow individually
or in linear arrays
• Intracytoplasmic mucin,
signet ring cell appearance
• Pools of extracellular mucin may
present

15. WHO Classification of Tumors of Stomach

16. WHO CLASSIFICATION-
• Tubular
• Papillary
• Mucinous
• Poorly cohesive
(including signet ring cell type)
• Mixed carcinomas
• Rare variants: (5%)
Adenosquamous carcinoma
Carcinoma with lymphoid stroma
Choriocarcinoma
Embryonal carcinoma
Endodermal sinus tumor
Hepatoid carcinoma
Malignant rhabdoid tumor
Mixed adeno-neuroendocrine Ca
Mucoepidermoid carcinoma
Oncocytic adenocarcinoma
Paneth cell carcinoma
Parietal cell carcinoma
Undifferentiated carcinoma

17. TUBULAR ADENOCARCINOMA –
• dilated or slit-like,branching tubules
• columnar, cuboidal. or flat tumor cells
• nuclear atypia - low- to high-grade
• Poorly differentiated variant - solid carcinoma.
• Variants – Clear cell , carcinoma with lymphoid stroma,
medullary carcinoma or lymphoepithelioma-like carcinoma .
• Variable desmoplasia.

18. PAPILLARY ADENOCARCINOMA -
• well-differentiated exophytic carcinoma with elongated finger-like
processes
• cylindrical or cuboidal cells supported by fibrovascular connective
tissue cores,maintained polarity
• Tubular (papillotubular) differentiation.
• Variable cellular atypia and mitotic index.
• Sharply demarcated edges invading the tumour
• may be infiltrated by acute and chronic inflammatory cells.

19.  Mucinous adenocarcinoma -
• Malignant epithelium
• extracellular mucinous pools.
• > 50% extracellular mucin.
Poorly cohesive carcinomas,
including signet ring cell ca
and other variants-
• Signet-ring cell type –central optically clear, globoid droplet of
cytoplasmic mucin with an eccentrically placed nucleus.
• may form a lace-like gland or delicate microtrabecular pattern in
the mucosa or marked desmoplasia in deeper levels of the
stomach wall.

20. • Other variants - tumours composed of neoplastic cells resembling
histiocytes or lymphocytes;
• others have deeply eosinophilic cytoplasm;
• some poorly cohesive cells may show irregular, bizarre nuclei.
• A mixture of the different cell types can be present. including few
signet-ring cells.

21. MIXED CARCINOMA-
• mixture of discrete morphologically
identifiable glandular & poorly-
cohesive cellular histological
components.
• Any discrete histological component
should be reported
• signet-ringcomponent is associated
with a poor prognosis.
• Clonal ,somatic mutation in the
E-cadherin gene ( COH1),
restricted to the signet-ring/poorly-cohesive component.

22. SO-CALLED EARLY CARCINOMA-
• carcinoma confined to the mucosa or/and submucosa ,regardless of
the LN status
• measure 2-5 cm ,located on the lesser curvature,around the angulus
• If untreated,progress over a few months to several years
• Tubular(50%) and papillary (30%) variants
• usually depressed or ulcerated

24. TUMOR SPREAD & STAGING-
• Intestinal type – haematogenously to the liver.
• Diffuse cancers–serosal & LVI & LN metastasis .
• Invade duodenum (submucosal & subserosal routes)
• Ca penetrates the serosa - peritoneal implants
• Krukenberg tumour- transperitoneal or haematogenous
• Nodal dissection for detection & removal of metastatic
disease and appropriate staging.
• Accuracy of pathological staging - proportional to the no.
of regional LNs examined & their anatomical location in
relation to the neoplasm.

25. • MODIFICATIONS IN STAGING-
1) Subdivision of T1 into mucosal & submucosal depth
of invasion.
2) T2a and T2b were separated into T2(muscularis
propria) and T3 (subserosa);
3) T3 and T 4 were changed to T4a(penetrates serosa)
and T 4b (invades adjacent structures), respectively
4) T, N, and M categories almost identical to those for
the oesophagus except that N3 (metastasis in 7 or
more regional lymph nodes) is divided into N3a (7-
15 nodes) and N3b (> 16 nodes) for gastric ca only .

27. GENETIC SUSCEPTIBILITY-
• Familial diffuse gastric cancer - AD inheritance ,germline mutation of
the E-cadherin gene
• Hereditary diffuse gastric cancer, newly introduced
• Dominantly inherited cancer predisposition syndromes - FAP and
Lynch syndrome, Li-Fraumeni syndrome with germline mutation of
TP53
• Peutz-Jeghers with frameshift mutations in STK 11 gene develop
aggressive gastric cancer
• Carriers of mutations in MSH2- increased risk
• Finally, susceptibility to carcinogens and their precursors varies
among individuals. Ex- polymorphisms of genes encoding for
glutathione S-transferase enzymes (known to metabolize tobacco
related carcinogens) and N-acetyltransferase 1

28. MOLECULAR PATHOLOGY-
• characterized by genetic and epigenetic changes
that affect oncogenes, tumour suppressor genes,
and DNA mismatch repair (MMR).
• deregulation of cellular proliferation, adhesion,
differentiation, signal transduction, telomerase
activity, and DNA repair has been reported.
• Different genetic pathways have been described for
various histological types of gastric cancer.

29. Promoter methylation, acetylation & Demethylation-
• Aberrant CpG island promotor methylation of several genes
• CDKN2A (p16) gene hypermethylation – 12-30% cases ,
reduced expression – depth of invasion and metastasis.
• Hypermethylation with reduced expression of the RARB
gene -60-65% of "intestinal" carcinomas
• Hypermethylation of RUNX3 - 45-65% of cancers
• Aberrant acetylation is frequently detected in H3 and H4
histone genes
• Demethylation of MAGE - advanced adenocarcinoma
SNCG- LN metastasis

30. Microsatellite instability (MSI)-
• defects in the MMR system responsible for the
correction of mismatches that occur during DNA
replication.
• In gastric cancer. MSI is mainly caused by epigenetic
silencing (promoter methylation) of the MLH1 gene
• observed in 5-10% "diffuse" carcinomas
15-40% "intestinal" carcinomas.
• Gastric carcinomas with a High MSI-antral
location,"intestinal" phenotype and expanding
growth pattern.
• MSI High tumors - better prognosis than MSl-low

31. • Molecular profiling of gastric cancer has been
performed using gene expression or DNA
sequencing, but has not led to a clear biologic
classification scheme.
• study by The Cancer Genome Atlas (TCGA) -
developed a robust molecular classification of
gastric cancer

32. Molecular subtypes:
A)Tumours Positive For Epstein–barr Virus,
• Recurrent PIK3CA mutations
• extreme DNA hypermethylation
• amplification of JAK2, CD274 (also known as PD-L1)
and PDCD1LG2 (also known as PD-L2);
B)Microsatellite unstable tumours
• elevated mutation rates
• mutations of genes encoding targetable oncogenic signalling
proteins
C)Genomically stable tumours
• diffuse histological variant
• mutations of RHOA or fusions involving RHO-family GTPase-
activating proteins
D)Tumours with chromosomal instability - MC
• marked aneuploidy
• focal amplification of receptor tyrosine kinases.

33. Identification of these subtypes provides a roadmap for
patient stratification and trials of targeted therapies.

34. HEREDITARY DIFFUSE GASTRIC CANCER-
• Autosomal dominant cancer susceptibility syndrome
• Characterized by signet ring cell (diffuse) gastric cancer & lobular
breast cancer
• Germline mutations of E-Cadherin (CDH-1 ) gene
Developmental Model:
• Mild non atrophic gastritis
• Insitu signet ring cell carcinoma
• Pagetoid spread of signet ring cells
• Invasive Carcinoma

37. • Diagnosis of HOGC offers the opportunity for pre-
symptomatic genetic screening for at-risk family
members and life-saving cancer risk-reduction
surgery for carriers of CDH1 mutations.
• Through the study of prophylactic gastrectomy
specimens, it has provided a unique window to
study the earliest stage of diffuse gastric cancer