Gastric Cancer - Deifinition , epidemiology , histological types and molecular genetics and WHO update
Reference - WHO Classificiation of tumors of Digestive system
Rosai and Ackermann
2. ļ±DEFINITION - malignant epithelial neoplasms.
ā¢ Biologically & genetically heterogeneous group of multifactorial
etiologies (environmental and genetic)
ā¢ broad morphological heterogeneity with respect to patterns of
architecture and growth,cell differentiation and histogenesis.
ā¢ Sporadic(90%),Familial (10%) and Hereditary (1%)
ļ±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. ļ±TIME TRENDS-
ā¢ steady decline in incidence and mortality over the last 15 years.
ā¢ absolute incidence rate continues to rise(advancing age)
ā¢ incidence of "tubular" adenocarcinoma has decreased
ā¢ incidence of "diffuse" carcinoma localized to the proximal stomach
has been increasing
ļ±AGE & SEX DISTRIBUTION-
ā¢ >50yrs age ,M=F
ā¢ Young ā hereditary, diffuse type, F>M
ļ±LOCALIZATION -
ā¢ Mc site -antro-pyloric
ā¢ Reporting of Ca of "cardia" is likely to change d/t revision of the TNM
classification of G-E junction (2009)
ā¢ 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. ļ±ETIOLOGY ā
ļ¶ Environmental Factors:
ā¢ Infection by H. pylori
ā¢ Dietā¢ Nitrites derived from nitrates (water, preserved food),Smoked and
salted foods, pickled vegetables, chili peppers
ā¢ Low socioeconomic status
ā¢ Cigarette smoking
ļ¶ Host Factors:
ā¢ Chronic gastritis
ā¢ Partial gastrectomy
ā¢ Gastric adenomas
40% harbor cancer at time of diagnosis
30% have adjacent cancer at time of diagnosis
ā¢ Barrett esophagus
ļ¶ Genetic Factors
ā¢ Slightly increased risk with blood group A
ā¢ Family history of gastric cancer
ā¢ Hereditary non-polyposis colon cancer syndrome
ā¢ Familial gastric carcinoma syndrome (E-cadherin mutation)
5. ļ±Precursor Lesions-
H.Pylori ass. Chronic gastritis Atrophy
A) Gastritis
ā¢ Autoimmune gastritis develops secondary to the development
of autoantibodies to parietal and chief cells and thus affects the
body fundic mucosa.
ā¢ Ass. with the formation of intestinal metaplasia and an
increased risk of developing gastric carcinoma( intestinal type)
Intestinal MetaplasiaNEOPLASIA
6. B) Intestinal Metaplasia
ā¢ 2 main types ā Complete & Incomplete
ā¢ Complete ā IHC expression of MUC2 (intestinal) and decreased
MUC1,MUC5AC & MUC6 (gastric)
ā¢ Incomplete ā Gastric mucins are coexpressed with MUC2
ā¢ positive correlation between degree & extent of incomplete intestinal
metaplasia with risk of progression to carcinoma
ā¢ Spasmolytic polypeptide-expressing metaplasia (SPEM)
ā¢ expression of TFF2 spasmolytic polypeptide is associated with
oxyntic atrophy
ā¢ SPEM ācharacteristically develops in the gastric body and fundus,
share some characteristics with pseudopyloric metaplasia
ā¢ strong association with chronic infection with H pylori and with
gastric adenocarcinoma
ā¢ another pathway to gastric neoplasia .
9. B) For Tumor Staging
ā¢ Screening- Barium meal ,Endoscopy, Serum pepsinogen
ā¢ Tumor Staging ā
Endoscopic USG (T stage)
CT-PET / CT Alone ( N and M stage)
ļ± MACROSCOPY-
ā¢ Borrmann Classification
10.
11. ļ±HISTOPATHOLOGY -
ā¢ various histopathological classification schemes
ā¢ MC used -WHO and Lauren
ā¢ Others - Ming , Nakamura ,Mulligan, Goseki and Carneiro
ļ± Stromal reactions -
ā¢ 4 common stromal responses to invasive gastric carcinoma
a) marked desmoplasia
b) lymphocytic infiltration
c)stromal eosinophilia
d)granulomatous response.
ā¢ Density of tumor infiltrating lymphocytes - Predictive of regional
lymph-node metastasis with improved outcome
ļ± Grading-
ā¢ applies primarily to tubular and papillary carcinomas
ā¢ Well , Moderately , Poorly Differentiated
ā¢ 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. ļ¶Intestinal Type (53%)-
ā¢ wide range in the degree of differentiation, correlates inversely with
tumor size
ā¢ better differentiated tumors-columnar and mucin secreting ,stimulate
a complete-type intestinal metaplasia, ciliated
ā¢ Poorly differentiated variants -solid pattern.
ā¢ Variable mucin production
ā¢ stroma infiltrated
by neutrophils
or histiocytes
14. ļ¶Diffuse-type (23%)-
ā¢ linitis plastica , currently as signet ring adenoca
ā¢ prepyloric area. Pyloric obstruction often
ā¢ Microscopically, a diffuse growth of malignant cells
ā¢ associated with extensive fibrosis
and inflammation
ā¢ most tumor cells grow individually
or in linear arrays
ā¢ Intracytoplasmic mucin,
signet ring cell appearance
ā¢ Pools of extracellular mucin may
present
17. ļ±TUBULAR ADENOCARCINOMA ā
ā¢ dilated or slit-like,branching tubules
ā¢ columnar, cuboidal. or flat tumor cells
ā¢ nuclear atypia - low- to high-grade
ā¢ Poorly differentiated variant - solid carcinoma.
ā¢ Variants ā Clear cell , carcinoma with lymphoid stroma,
medullary carcinoma or lymphoepithelioma-like carcinoma .
ā¢ Variable desmoplasia.
18. ļ±PAPILLARY ADENOCARCINOMA -
ā¢ well-differentiated exophytic carcinoma with elongated finger-like
processes
ā¢ cylindrical or cuboidal cells supported by fibrovascular connective
tissue cores,maintained polarity
ā¢ Tubular (papillotubular) differentiation.
ā¢ Variable cellular atypia and mitotic index.
ā¢ Sharply demarcated edges invading the tumour
ā¢ may be infiltrated by acute and chronic inflammatory cells.
19. ļ± Mucinous adenocarcinoma -
ā¢ Malignant epithelium
ā¢ extracellular mucinous pools.
ā¢ > 50% extracellular mucin.
ļ±Poorly cohesive carcinomas,
including signet ring cell ca
and other variants-
ā¢ Signet-ring cell type ācentral optically clear, globoid droplet of
cytoplasmic mucin with an eccentrically placed nucleus.
ā¢ may form a lace-like gland or delicate microtrabecular pattern in
the mucosa or marked desmoplasia in deeper levels of the
stomach wall.
20. ā¢ Other variants - tumours composed of neoplastic cells resembling
histiocytes or lymphocytes;
ā¢ others have deeply eosinophilic cytoplasm;
ā¢ some poorly cohesive cells may show irregular, bizarre nuclei.
ā¢ A mixture of the different cell types can be present. including few
signet-ring cells.
21. ļ±MIXED CARCINOMA-
ā¢ mixture of discrete morphologically
identifiable glandular & poorly-
cohesive cellular histological
components.
ā¢ Any discrete histological component
should be reported
ā¢ signet-ringcomponent is associated
with a poor prognosis.
ā¢ Clonal ,somatic mutation in the
E-cadherin gene ( COH1),
restricted to the signet-ring/poorly-cohesive component.
22. ļ±SO-CALLED EARLY CARCINOMA-
ā¢ carcinoma confined to the mucosa or/and submucosa ,regardless of
the LN status
ā¢ measure 2-5 cm ,located on the lesser curvature,around the angulus
ā¢ If untreated,progress over a few months to several years
ā¢ Tubular(50%) and papillary (30%) variants
ā¢ usually depressed or ulcerated
23.
24. ļ±TUMOR SPREAD & STAGING-
ā¢ Intestinal type ā haematogenously to the liver.
ā¢ Diffuse cancersāserosal & LVI & LN metastasis .
ā¢ Invade duodenum (submucosal & subserosal routes)
ā¢ Ca penetrates the serosa - peritoneal implants
ā¢ Krukenberg tumour- transperitoneal or haematogenous
ā¢ Nodal dissection for detection & removal of metastatic
disease and appropriate staging.
ā¢ Accuracy of pathological staging - proportional to the no.
of regional LNs examined & their anatomical location in
relation to the neoplasm.
25. ā¢ 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 .
26.
27. ļ±GENETIC SUSCEPTIBILITY-
ā¢ Familial diffuse gastric cancer - AD inheritance ,germline mutation of
the E-cadherin gene
ā¢ Hereditary diffuse gastric cancer, newly introduced
ā¢ Dominantly inherited cancer predisposition syndromes - FAP and
Lynch syndrome, Li-Fraumeni syndrome with germline mutation of
TP53
ā¢ Peutz-Jeghers with frameshift mutations in STK 11 gene develop
aggressive gastric cancer
ā¢ Carriers of mutations in MSH2- increased risk
ā¢ 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. ļ±MOLECULAR PATHOLOGY-
ā¢ characterized by genetic and epigenetic changes
that affect oncogenes, tumour suppressor genes,
and DNA mismatch repair (MMR).
ā¢ deregulation of cellular proliferation, adhesion,
differentiation, signal transduction, telomerase
activity, and DNA repair has been reported.
ā¢ Different genetic pathways have been described for
various histological types of gastric cancer.
29. ļ¶Promoter methylation, acetylation & Demethylation-
ā¢ Aberrant CpG island promotor methylation of several genes
ā¢ CDKN2A (p16) gene hypermethylation ā 12-30% cases ,
reduced expression ā depth of invasion and metastasis.
ā¢ Hypermethylation with reduced expression of the RARB
gene -60-65% of "intestinal" carcinomas
ā¢ Hypermethylation of RUNX3 - 45-65% of cancers
ā¢ Aberrant acetylation is frequently detected in H3 and H4
histone genes
ā¢ Demethylation of MAGE - advanced adenocarcinoma
SNCG- LN metastasis
30. ļ¶Microsatellite instability (MSI)-
ā¢ defects in the MMR system responsible for the
correction of mismatches that occur during DNA
replication.
ā¢ In gastric cancer. MSI is mainly caused by epigenetic
silencing (promoter methylation) of the MLH1 gene
ā¢ observed in 5-10% "diffuse" carcinomas
15-40% "intestinal" carcinomas.
ā¢ Gastric carcinomas with a High MSI-antral
location,"intestinal" phenotype and expanding
growth pattern.
ā¢ MSI High tumors - better prognosis than MSl-low
31. ā¢ Molecular profiling of gastric cancer has been
performed using gene expression or DNA
sequencing, but has not led to a clear biologic
classification scheme.
ā¢ study by The Cancer Genome Atlas (TCGA) -
developed a robust molecular classification of
gastric cancer
32. ļ±Molecular subtypes:
A)Tumours Positive For Epsteinābarr Virus,
ā¢ Recurrent PIK3CA mutations
ā¢ extreme DNA hypermethylation
ā¢ amplification of JAK2, CD274 (also known as PD-L1)
and PDCD1LG2 (also known as PD-L2);
B)Microsatellite unstable tumours
ā¢ elevated mutation rates
ā¢ mutations of genes encoding targetable oncogenic signalling
proteins
C)Genomically stable tumours
ā¢ diffuse histological variant
ā¢ mutations of RHOA or fusions involving RHO-family GTPase-
activating proteins
D)Tumours with chromosomal instability - MC
ā¢ marked aneuploidy
ā¢ focal amplification of receptor tyrosine kinases.
33. Identification of these subtypes provides a roadmap for
patient stratification and trials of targeted therapies.
34. ļ±HEREDITARY DIFFUSE GASTRIC CANCER-
ā¢ Autosomal dominant cancer susceptibility syndrome
ā¢ Characterized by signet ring cell (diffuse) gastric cancer & lobular
breast cancer
ā¢ Germline mutations of E-Cadherin (CDH-1 ) gene
ļ¶Developmental Model:
ā¢ Mild non atrophic gastritis
ā¢ Insitu signet ring cell carcinoma
ā¢ Pagetoid spread of signet ring cells
ā¢ Invasive Carcinoma
35.
36.
37. ā¢ 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.
ā¢ Through the study of prophylactic gastrectomy
specimens, it has provided a unique window to
study the earliest stage of diffuse gastric cancer