Research ArticlesThree Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine DifferentiationSpeck, Olga MD, PhD*; Tang, Weihua MD, PhD*; Morgan, Douglas R. MD, MPH†; Kuan, Pei Fen PhD‡; Meyers, Michael O. MD§; Dominguez, Ricardo L. MD∥; Martinez, Enrique MD¶; Gulley, Margaret L. MD*Author Information Departments of *Pathology and Laboratory Medicine ‡Biostatistics, Lineberger Comprehensive Cancer Center †Department of Medicine, Division of Gastroenterology, University of North Carolina, Chapel Hill, NC 27599-7080 §Department of Surgical Oncology, Lineberger Comprehensive Cancer Center ∥Department of Medicine, Hospital de Occidente, Santa Rosa de Copan ¶Department of Gastroenterology, Hospital Evangelico, Siguatepeque, Honduras Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.appliedimmunohist.com. Supported by the University of North Carolina Department of Pathology and Laboratory Medicine, the University Cancer Research Fund, the Alliance for Clinical Trials in Oncology (NCI U10 CA031946), a Clinical Translational Science Award (NIH U54 RR024383), an award for Innovative Technologies for Molecular Analysis of Cancer (NCI R21 CA155543), and the Western Honduras Gastric Cancer Initiative (NCI CA125588, D.R.M.). The authors declare no conflict of interest. Reprints: Margaret L. Gulley, MD, Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, 913 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525 (e-mail: [email protected]). Received November 4, 2013 Accepted June 21, 2014 Applied Immunohistochemistry & Molecular Morphology: October 2015 - Volume 23 - Issue 9 - p 633-645 doi: 10.1097/PAI.0000000000000122 Buy SDC Metrics Abstract Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features. Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.