Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Rachel S. van der Post, Irine Gullo, Carla Oliveira, Laura H. Tang, Heike Grabsch, Maria O’Donovan, Rebecca C. Fitzgerald, Han van Krieken, Fátima Carneiro*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterAcademic


Familial clustering is seen in 10?% of gastric cancer cases and approximately 1-3?% of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis. Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterized by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT?>?1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.
Original languageEnglish
Title of host publicationStem Cells, Pre-neoplasia, and Early Cancer of the Upper Gastrointestinal Tract
EditorsMarnix Jansen, Nicholas A. Wright
Number of pages21
ISBN (Electronic)978-3-319-41388-4
ISBN (Print)978-3-319-41386-0
Publication statusPublished - 2016

Publication series

SeriesAdvances in Experimental Medicine and Biology


  • CDH1
  • RISK
  • P53


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