Indications for Total Gastrectomy in CDH1 Mutation Carriers and Outcomes of Risk-Reducing Minimally Invasive and Open Gastrectomies

Question  What is the likelihood of signet ring cell cancer in patients with a germline CDH1 variant who undergo total gastrectomy according to family history?

Findings  In this cohort study of 101 patients who underwent total gastrectomy, signet ring cell cancer was identified in the surgical specimens of 89% of patients with a family history of gastric cancer and 67% of patients lacking family history.

Meaning  Total gastrectomy may be warranted for patients with CDH1 variants and a family history of gastric cancer and may be appropriate for those without a family history.

Importance  CDH1 variants are increasingly identified on commercially available multigene panel tests, calling for data to inform counseling of individuals without a family history of gastric cancer.

Objectives  To assess association between CDH1 variant pathogenicity or family history of gastric or lobular breast cancer and identification of signet ring cell cancer and to describe outcomes of risk-reducing minimally invasive and open total gastrectomy.

Design, Setting, and Participants  This cohort study was performed from January 1, 2006, to January 1, 2020, in 181 patients with CDH1 germline variants from a single institution.

Interventions  Genetic counseling, esophagogastroduodenoscopy, and possible total gastrectomy.

Main Outcomes and Measures  CDH1 variant classification, family cancer history, findings of signet ring cell carcinoma at esophagogastroduodenoscopy and surgery, postoperative events and weight changes, and follow-up.

Results  Of 181 individuals with CDH1 germline variants (mean [SD] age at time of testing, 44 [15] years; 126 [70%] female), 165 harbored a pathogenic or likely pathogenic variant. Of these patients, 101 underwent open (n = 58) or minimally invasive (n = 43) total gastrectomy. Anastomotic leaks that required drainage were infrequent (n = 3), and median long-term weight loss was 20% (interquartile range [IQR], 10%-23%). In those undergoing minimally invasive operations, more lymph nodes were retrieved (median, 28 [IQR, 20-34] vs 15 [IQR, 9-19]; P < .001) and the hospital stay was 1 day shorter (median, 6 [IQR, 5-7] vs 7 [IQR, 6-7] days; P = .04). Signet ring cell cancer was identified in the surgical specimens of 85 of 95 patients (89%) with a family history of gastric cancer and 4 of 6 patients (67%) who lacked a family history. Among the latter 6 patients, 4 had a personal or family history of lobular breast cancer, including 2 with signet ring cell cancer. Of the 16 patients with pathogenic or likely pathogenic CDH1 variants who presented with locally advanced or metastatic gastric cancer, 3 (19%) had no family history of gastric cancer or personal or family history of lobular breast cancer.

Conclusions and Relevance  Total gastrectomy may be warranted for patients with pathogenic or likely pathogenic CDH1 variants and a family history of gastric or lobular breast cancer and may be appropriate for those without a family history. A minimally invasive approach is feasible and may be preferred for selected patients.