title: Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future.
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.
authors: Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands.
authors: Rachel S
authors: RS
authors: van der Post
authors: Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.|Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal.
authors: Irene
authors: I
authors: Gullo
authors: Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.|Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.
authors: Carla
authors: C
authors: Oliveira
authors: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY, 10065, USA.
authors: Laura H
authors: LH
authors: Tang
authors: GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Centre, Peter Debyelaan 25, Maastricht, 6229 HX, The Netherlands.
authors: Heike I
authors: HI
authors: Grabsch
authors: Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0QQ, UK.
authors: Maria
authors: M
authors: O'Donovan
authors: MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, 197, Biomedical Campus, Cambridge, CB2 0XZ, UK.
authors: Rebecca C
authors: RC
authors: Fitzgerald
authors: Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands.
authors: Han
authors: H
authors: van Krieken
authors: Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. fcarneiro@ipatimup.pt.|Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. fcarneiro@ipatimup.pt.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal. fcarneiro@ipatimup.pt.
authors: Fátima
authors: F
authors: Carneiro
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D035843:Biomedical Research / Q000379:methods* / Q000639:trends; D005544:Forecasting; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D009154:Mutation; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor
keywords: CDH1; CTNNA1; E-cadherin; Gastric cancer; Hereditary; Immunohistochemistry; Signet-ring cell; Stomach