Original ArticlesAn Integrative Morphomolecular Classification System of Gastric Carcinoma With Distinct Clinical OutcomesTsai, Jia-Huei MD, PhD*,†; Jeng, Yung-Ming MD, PhD*,†; Chen, Kuo-Hsing MD‡,§,∥; Lee, Chia-Hsiang MSc*; Yuan, Chang-Tsu MD*; Liau, Jau-Yu MD, PhD*,†Author Information Departments of *Pathology ‡Oncology, National Taiwan University Hospital †Graduate Institute of Pathology ∥Graduate Institute of Oncology, College of Medicine, National Taiwan University §National Taiwan University Cancer Center, Taipei City, Taiwan Supported by grant 108-2320-B-002-062 from the Ministry of Science and Technology, Republic of China. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Jau-Yu Liau, MD, PhD, Department of Pathology, National Taiwan University Hospital, 7 Chung-Shun South Road, Taipei 10002, Taiwan (e-mail: [email protected]). The American Journal of Surgical Pathology: August 2020 - Volume 44 - Issue 8 - p 1017-1030 doi: 10.1097/PAS.0000000000001521 Buy SDC Metrics 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.