Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.

van der Post RS1, Vogelaar IP2, Carneiro F3, Guilford P4, Huntsman D5, Hoogerbrugge N2, Caldas C6, Schreiber KE7, Hardwick RH8, Ausems MG9, Bardram L10, Benusiglio PR11, Bisseling TM12, Blair V13, Bleiker E14, Boussioutas A15, Cats A16, Coit D17, DeGregorio L18, Figueiredo J19, Ford JM20, Heijkoop E21,Hermens R22, Humar B23, Kaurah P24, Keller G25, Lai J7, Ligtenberg MJ26, O'Donovan M27, Oliveira C28, Pinheiro H19, Ragunath K29, Rasenberg E30,Richardson S31, Roviello F32, Schackert H33, Seruca R28, Taylor A34, Ter Huurne A35, Tischkowitz M36, Joe ST20, van Dijck B35, van Grieken NC37, van Hillegersberg R38, van Sandick JW39, Vehof R40, van Krieken JH1, Fitzgerald RC41.

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Abstract

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

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