Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research

Rebecca C Fitzgerald, Richard Hardwick, David Huntsman, Fatima Carneiro, Parry Guilford, Vanessa Blair, Daniel C Chung, Jeff Norton, Krishnadath Ragunath, J Han Van Krieken, Sarah Dwerryhouse, Carlos Caldas, International Gastric Cancer Linkage Consortium, William Allum, Stephen Attwood, Vanessa Blair, Nicola Bradshaw, Carole Brewer, Carlos Caldas, Fatima Carneiro, Annemieke Cats, Amanda Charlton, Daniel C Chung, Trevor Cole, Gianni Corso, Jean Crabtree, Huw Dorkins, Sarah Downing, Jason Dunn, Sarah Dwerryhouse, Peter Fairclough, Rebecca Fitzgerald, James Going, Samantha Grimes, Parry Guilford, Mike Hallissey, Nina Hallowell, Richard Hardwick, Nicoline Hoogerbrugge, Laetitia Huiart, David Huntsman, Gisela Keller, Ann Kershaw, Ajith Kumar, Laurence Lovat, Ken McColl, Shane McKee, Jeffrey Norton, Maria O'Donovan, Carla Oliveira, Sylvianne Olschwang, Bijendra P Patel, Joan Paterson, Corrado Pedrazzani, Paul Pharoah, Krish Ragunath, Franco Roviello, Vicki Save, Siobhan Sengupta, Raquel Seruca, Manish A Shah, Hubert Stein, Nicola C Van Grieken, J Han van Krieken, Matthew Wallis, Debrah Wirtzfeld, Rebecca C Fitzgerald, Richard Hardwick, David Huntsman, Fatima Carneiro, Parry Guilford, Vanessa Blair, Daniel C Chung, Jeff Norton, Krishnadath Ragunath, J Han Van Krieken, Sarah Dwerryhouse, Carlos Caldas, International Gastric Cancer Linkage Consortium, William Allum, Stephen Attwood, Vanessa Blair, Nicola Bradshaw, Carole Brewer, Carlos Caldas, Fatima Carneiro, Annemieke Cats, Amanda Charlton, Daniel C Chung, Trevor Cole, Gianni Corso, Jean Crabtree, Huw Dorkins, Sarah Downing, Jason Dunn, Sarah Dwerryhouse, Peter Fairclough, Rebecca Fitzgerald, James Going, Samantha Grimes, Parry Guilford, Mike Hallissey, Nina Hallowell, Richard Hardwick, Nicoline Hoogerbrugge, Laetitia Huiart, David Huntsman, Gisela Keller, Ann Kershaw, Ajith Kumar, Laurence Lovat, Ken McColl, Shane McKee, Jeffrey Norton, Maria O'Donovan, Carla Oliveira, Sylvianne Olschwang, Bijendra P Patel, Joan Paterson, Corrado Pedrazzani, Paul Pharoah, Krish Ragunath, Franco Roviello, Vicki Save, Siobhan Sengupta, Raquel Seruca, Manish A Shah, Hubert Stein, Nicola C Van Grieken, J Han van Krieken, Matthew Wallis, Debrah Wirtzfeld

Abstract

25-30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

Conflict of interest statement

Competing interests: None.

Figures

Figure 1
Figure 1
Algorithm for management starting from clinical criteria, genetic testing, role of endoscopy and gastrectomy. EGD, oesophagogastroduodenoscopy; MLPA, multiplex ligation dependent probe amplification.
Figure 2
Figure 2
Germline deletions in CDH1. The CDH1 and CDH3 genes are shown in grey with the exons for CDH1 indicated. The red areas indicate five deletions detected by multiplex ligation dependent probe amplification.
Figure 3
Figure 3
(A) In situ signet ring cell carcinoma: gland with intact basement membrane lined by signet ring cells, with hyperchromatic and depolarised nuclei. (B) Pagetoid spread of signet ring cells below the preserved epithelium of one gland (arrow heads). (C) Focus of invasive intramucosal carcinoma T1a, constituted by signet ring cells (arrows), in the lamina propria.
Figure 4
Figure 4
(A) Foveolar hyperplasia (between arrows); in comparison to normal epithelium (below) cells are globoid (rounded with abundant cytoplasm). (B) Vacuolisation of the cytoplasm of superficial and foveolar cells. (C) Granulomatous reaction at the periphery of a disrupted gland.
Figure 5
Figure 5
An example of a gastrectomy specimen processed for pathology.

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