Gastric cancer: immunohistochemical classification of molecular subtypes and their association with clinicopathological characteristics

Abstract

Gastric cancer is traditionally divided into intestinal and diffuse histological subtypes, but recent molecular analyses have led to novel classification proposals based on genomic alterations. While the intestinal- and diffuse-type tumours are distinguishable from each other at the molecular level, intestinal-type tumours have more diverse molecular profile. The technology required for comprehensive molecular analysis is expensive and not applicable for routine clinical diagnostics. In this study, we have used immunohistochemistry and in situ hybridisation in molecular classification of gastric adenocarcinomas with an emphasis on the intestinal subtype. A tissue microarray consisting of 244 gastric adenocarcinomas was constructed, and the tumours were divided into four subgroups based on the presence of Epstein-Barr virus, TP53 aberrations and microsatellite instability. The intestinal- and diffuse-type tumours were separately examined. The distribution of EGFR and HER2 gene amplifications was studied in the intestinal-type tumours. Epstein-Barr virus positive intestinal-type tumours were more common in male patients (p = 0.035) and most often found in the gastric corpus (p = 0.011). The majority of the intestinal-type tumours with TP53 aberrations were proximally located (p = 0.010). All tumours with microsatellite instability showed intestinal-type histology (p = 0.017) and were associated with increased overall survival both in the univariate (p = 0.040) and multivariate analysis (p = 0.015). In conclusion, this study shows that gastric adenocarcinomas can be classified into biologically and clinically different subgroups by using a simple method also applicable for clinical diagnostics.

Keywords: Gastric cancer; Immunohistochemistry; In situ hybridisation; Molecular classification.

Fig. 1

Classification of adenocarcinomas of the stomach, gastro-oesophageal junction and distal oesophagus based on immunohistochemistry and in situ hybridisation. a Examples of EBER in situ hybridisation and MLH1, TP53 and E-cadherin immunohistochemistry in eight oesophagogastric adenocarcinomas. (a) EBV positive, (b) TP53 aberration, (c) MLH1 mutated, (d) E-cadherin wild-type, (e) EBV negative, (f) TP53 wild-type, (g) MLH1 wild-type and (h) E-cadherin aberration. b The classification of the intestinal- and diffuse-type adenocarcinomas of the stomach, gastro-oesophageal junction and distal oesophagus according to the immunohistochemical data and in situ hybridisation. c Distribution of the four molecular subtypes of intestinal-type oesophagogastric adenocarcinomas in different anatomical locations. ^aImmunohistochemical data available for 238 (EBV, MSI, TP53) or 232 tumours (E-cadherin). ^bIncluding one tumour (2%) with co-amplification EGFR and HER2. ^cIncluding five tumours (5%) with co-amplification of EGFR and HER2. EBV Epstein-Barr virus, GOJ gastro-oesophageal junction, MSS microsatellite-stable, MSI microsatellite-instable, wt wild-type, aberr aberration, amp amplification