ArticleFrontiers in surgery2026
Hereditary diffuse gastric cancer: between underdiagnosis and overtreatment: a case series.
Article in Frontiers in surgery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Hereditary Diffuse Gastric Cancer (HDGC) is a rare but highly penetrant autosomal dominant cancer predisposition syndrome, most commonly associated with germline pathogenic variants in the CDH1 gene. Early diagnosis remains challenging due to the absence of specific clinical or endoscopic features in early disease stages. Methods: We present a case series describing a cluster of advanced diffuse gastric cancer (DGC) cases in a single Italian family. Clinical, genetic, and surgical data were collected and analyzed, including pedigree reconstruction, genetic testing, and risk-reducing interventions. Results: Two male siblings developed advanced signet ring cell gastric carcinoma at ages 41 and 44, both with rapid disease progression and fatal outcomes. Their family history revealed two sisters who had died from gastric cancer at a young age. Genetic counseling identified a CDH1 c.1792C>T pathogenic variant in affected family members. Two young, asymptomatic female carriers (aged 18 and 22) underwent prophylactic total gastrectomy in accordance with international guidelines. Subsequently, another male sibling died at the age of 30 due to gastric cancer. This familial cluster demonstrated high phenotypic penetrance and highlighted the impact of genetic testing on clinical management. In addition, we discuss the evolving landscape of risk stratification and the balance between prophylactic total gastrectomy and structured endoscopic surveillance. Conclusion: This case series underscores the clinical heterogeneity of HDGC and the critical role of timely genetic testing, family history assessment, and early prophylactic gastrectomy in high-risk carriers. A multidisciplinary approach integrating clinical genetics, surgery, and endoscopic expertise is essential to optimize risk-reducing strategies and outcomes in HDGC.
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