Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk

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Abstract

Hereditary diffuse gastric cancer (HDGC) is caused by germline E-cadherin (CDH1) mutations in 25-40% of tested families. Management options for asymptomatic mutation carriers are fraught, since endoscopic surveillance can miss cancer foci and prophylactic gastrectomy has profound clinical sequelae. The aims of this study were to evaluate the impact of current surveillance practices on pre-operative diagnosis and to characterize the microscopic lesions in gastrectomy specimens to better inform clinical practice. Histological assessment and mapping of endoscopic surveillance and gastrectomy specimens were performed for eight asymptomatic CDH1 mutation carriers. E-cadherin expression and proliferation were analysed and evidence of epithelial-mesenchymal transition (EMT) was sought by immunohistochemistry for vimentin and cytokeratin 8/18. Four of eight patients had lesions detected at endoscopic surveillance. A median of 20.5 (range 0-66) signet ring foci were identified per gastrectomy (including in situ lesions and pagetoid spread). Foci were predominantly identified in the fundus and body (90% endoscopic biopsies and 85% in gastrectomy). The likelihood of detecting foci pre-operatively was positively correlated with the number of biopsies taken and the number of lesions in the gastrectomy specimen. E-cadherin expression in gastrectomy specimens was reduced or absent in all of the foci compared with the intervening gastric tissue, suggesting that these lesions are polyclonal. The foci had a low proliferative index (<2%) and there was no evidence for EMT. Multiple endoscopic biopsy sampling of the gastric mucosa increases the yield of microscopic cancer foci. The low proliferative index and lack of EMT suggests that these foci may represent an indolent stage of HDGC.

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