An Integrative Morphomolecular Classification System of Gastric Carcinoma With Distinct Clinical Outcomes

Am J Surg Pathol. 2020 Aug;44(8):1017-1030. doi: 10.1097/PAS.0000000000001521.

Abstract

A robust morphomolecular classification system for gastric carcinoma is required. A 4-tier morphologic classification is proposed, including diffuse, intestinal, tubular, and lymphoid types. A tissue microarray for mismatch repair immunohistochemistry and Epstein-Barr virus (EBV) in situ hybridization were performed in 329 gastric carcinomas. DNA flow cytometry was used to detect aneuploidy in formalin-fixed paraffin-embedded samples. Lymphoid histology was the third most common histologic pattern at our institute and strongly associated with EBV infection and PMS2/MLH1-deficiency (both P<0.001). HER2 overexpression and SATB2 expression more frequently occurred in intestinal histology (both P<0.001). Loss of ARID1A expression was strikingly associated with lymphoid histology (P<0.001) and negative E-cadherin expression was correlated with diffuse histology (P=0.001). Programmed death-ligand 1 expression was most frequently present in lymphoid-type gastric carcinoma than other histologic subtypes and correlated with the molecular features of PMS2/MLH1-deficiency and EBV infection (all P<0.001). Aneuploidy was detected in 53% of gastric carcinomas and was highly correlated with intestinal type and the least with the lymphoid type (P<0.001). Notably, lymphoid-type gastric carcinoma showed the best outcome, whereas tubular type showed the worst survival rate (P<0.001). We integrated aneuploidy with morphologic patterns to propose a morphomolecular classification scheme, which served as a successful and independent prognostic factor in multivariate 5-year disease-free survival analysis (P<0.001). Overall, we describe an integrated morphomolecular classification system for gastric carcinomas to effectively predict patient outcomes. This system is cost-effective and reliable and can help select target therapeutics and facilitate clinical management.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemistry*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenocarcinoma / virology
  • Adult
  • Aged
  • Aged, 80 and over
  • Aneuploidy
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics*
  • DNA Mismatch Repair
  • Disease-Free Survival
  • Female
  • Herpesvirus 4, Human / genetics
  • Humans
  • Male
  • Matrix Attachment Region Binding Proteins / analysis
  • Microsatellite Instability
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2 / analysis
  • MutL Protein Homolog 1 / analysis
  • Neoplasm Staging
  • Receptor, ErbB-2 / analysis
  • Risk Factors
  • Stomach Neoplasms / chemistry*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / virology
  • Taiwan
  • Time Factors
  • Transcription Factors / analysis
  • Young Adult

Substances

  • Biomarkers, Tumor
  • MLH1 protein, human
  • Matrix Attachment Region Binding Proteins
  • SATB2 protein, human
  • Transcription Factors
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1