Association between genotype and long-term risk of reintervention and distant metastases in patients with multiple endocrine neoplasia type 1-associated duodenopancreatic neuroendocrine tumors.

BACKGROUND

Duodenal and pancreatic neuroendocrine tumors are the leading cause of mortality in multiple endocrine neoplasia type 1, due to distant metastasis. Although surgery is the cornerstone of management, patients may require reintervention for disease progression or hormone-related morbidity. The clinical and genetic determinants of reintervention and long-term oncologic outcomes after index duodenal and pancreatic neuroendocrine tumor surgery in multiple endocrine neoplasia type 1 remain unclear.

METHODS

We retrospectively analyzed patients with genetically confirmed multiple endocrine neoplasia type 1 and duodenal and pancreatic neuroendocrine tumors evaluated at our institution from 1985 to 2024. Reintervention was defined as any subsequent surgical or locoregional therapy. Kaplan-Meier methods and multivariable Cox proportional hazards models were used to evaluate predictors of reintervention-free survival and distant metastasis-free survival, focusing on truncating versus nontruncating MEN1 variants.

RESULTS

Among 153 patients with multiple endocrine neoplasia type 1, 94 (61%) underwent surgical resection for duodenal and pancreatic neuroendocrine tumors at a median age of 40 (interquartile range, 28-49) years. After a median follow-up of 16.4 years, 25 patients (27%) required reintervention, with 45 total procedures performed. Truncating multiple endocrine neoplasia type 1 variants were significantly more common among patients undergoing reintervention (88.0% vs 63.8%; P = .024). On multivariable analysis, truncating genotype was independently associated with reintervention (hazard ratio, 3.82; 95% confidence interval, 1.25-16.68; P = .036). Among 84 patients without metastases at surgery, 24 (28.6%) developed distant metastases during follow-up; truncating genotype independently predicted shorter distant metastasis-free survival (hazard ratio, 5.55; 95% confidence interval, 1.56-35.40; P = .024). Notably, 37.5% of patients who developed metastases had a largest resected tumor ≤2 cm.

CONCLUSION

Over a quarter of patients undergoing surgery for multiple endocrine neoplasia type 1-associated duodenal and pancreatic neuroendocrine tumors require reintervention for progressive disease, and truncating MEN1 variants confer a nearly 4-fold higher risk of reintervention and >5-fold higher risk of distant metastatic progression during follow-up. Our findings underscore the limitations of size-based surgical algorithms and suggest that germline genotype may provide complementary prognostic information to refine postoperative risk stratification and surveillance strategies.