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

  • Rachel S. van der Post
  • Irene Gullo
  • Carla Oliveira
  • Laura H. Tang
  • Heike I. Grabsch
  • Maria O’Donovan
  • Rebecca C. Fitzgerald
  • Han van Krieken
  • Fátima CarneiroEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 908)

Abstract

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.

Keywords

Hereditary Gastric cancer Signet-ring cell Stomach E-cadherin Immunohistochemistry CDH1 CTNNA1 

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Rachel S. van der Post
    • 1
  • Irene Gullo
    • 2
    • 3
    • 4
  • Carla Oliveira
    • 2
    • 3
  • Laura H. Tang
    • 5
  • Heike I. Grabsch
    • 6
  • Maria O’Donovan
    • 7
  • Rebecca C. Fitzgerald
    • 8
  • Han van Krieken
    • 1
  • Fátima Carneiro
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of PathologyRadboud University Medical CentreNijmegenThe Netherlands
  2. 2.Department of PathologyCentro Hospitalar de São JoãoPortoPortugal
  3. 3.Department of Pathology and OncologyFaculdade de Medicina da Universidade do Porto (FMUP)PortoPortugal
  4. 4.Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
  5. 5.Department of PathologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  6. 6.GROW School of Oncology and Developmental Biology and Department of PathologyMaastricht University Medical CentreMaastrichtThe Netherlands
  7. 7.Department of HistopathologyCambridge University Hospitals NHS TrustCambridgeUK
  8. 8.MRC Cancer Unit, Hutchison-MRC Research CentreUniversity of CambridgeCambridgeUK

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