Gastric Cancer - Pathology Seminar

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 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 Metaplasia NEOPLASIA

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 .

7. CLINICAL TOOLS- A)For Diagnosis Endoscopy- sensitive & specific Modern video-endoscopy C hromoendoscopy

8. 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

9. 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.)

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

11. 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

12. 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

13. WHO Classification of Tumors of Stomach

14. 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

15. 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 .

16. 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.

17. 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.

18. 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.

19. 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.

20. 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

21. 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.

22. 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 .

23. 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

24. 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.

25. 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

26. 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

27. 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

28. 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 .

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

30. 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

31. 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