Aim: To assess the characteristics and long-term outcome after surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated insulinoma. Methods: Retrospective analysis of prospectively collected data of MEN1 patients with organic hyperinsulinism at a tertiary referral center. Results: Thirteen(17%) of74 patients with MEN1 had organic hyperinsulinism. The median age at diagnosis was 27 (range 9-48) years. In 7 patients insulinoma was the first manifestation of the syndrome. All patients had at least one pancreatic neuroendocrine neoplasm (pNEN) upon imaging, including CT, MRI or endoscopic ultrasonography. Seven patients had solitary lesions upon imaging, 4 patients had one dominant tumor with coexisting multiple small pNENs, and 2 patients had multiple lesions without dominance. Eight patients had limited resections (1 segmental resection, 7 enucleations), 4 subtotal distal pancreatectomies, and 1 patient a partial duodenopancreatectomy. There was no postoperative mortality. Six patients experienced complications, including pancreatic fistula in 5 patients. Pathological examination revealed median three (range 1-14) macro-pNENs sized between 6 and 40 mm, and a total of 14 potentially benign insulinomas were detected in the 13 patients. After median follow-up of 156 months, only 1 patient developed recurrent hyperinsulinism after initial enucleation. Twelve patients developed new pNENs in the pancreatic remnant and 4 patients underwent reoperations (3 for metastatic ZES, 1 for recurrent hyperinsulinism). One of 5 patients with an initial extended pancreatic resection developed insulin-dependent diabetes mellitus. Conclusion: Enucleation and limited resection provide long-term cure forMEN1 insulinoma in patients with solitary or dominant tumors. Subtotal distal pancreatectomy should thus be preserved for patients with multiple pNENs without dominance given the risk of exocrine and endocrine pancreas insufficiency in the mostly young patients.

MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.

Symptomatic or severe manifestations in MEN1 patients rarely occur below the age of 16 years. With regard to psychological burden and cost-effectiveness, routine screening of asymptomatic MEN1 patients should be postponed at least until the age of 16 years.

Background: The aim of this study was to evaluate the efficacy of conservative treatment for nonfunctioning pancreatic neuroendocrine neoplasms (NF-PNEN) ≤2 cm in multiple endocrine neoplasia type 1 (MEN1)-affected patients compared with surgical treatment. Methods: The databases of 4 tertiary referral institutions (San Raffaele Scientific Institute, Milan; Philipps-Universität Marburg, Marburg; University of Padua, Padua; Royal Free Hospital, London) were analyzed. A comparison of conservative management and surgery at initial diagnosis of NF-PNEN ≤2 cm between 1997 and 2013 was performed. Results: Overall, 27 patients (45%) underwent up-front surgery and 33 patients (55%) were followed up after the initial diagnosis. A higher proportion of patients in the surgery group were female (70 vs. 33%, p = 0.004). Patients were mainly operated on in the period 1997-2007 as compared with the period 2008-2013 (n = 17; 63 vs. 37%; p = 0.040). The rate of multifocal tumors was higher in the surgery group (n = 24; 89%) than in the ‘no surgery' group (n = 22; 67%; p = 0.043). After a median follow-up of 126 months, 1 patient deceased due to postoperative complications within 30 days after surgery. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 63, 39, and 10%, respectively. The median PFS was similar in the two groups. Overall, 13 patients (32.5%) were operated on after initial surgical or conservative treatment. The majority of the surgically treated patients had stage 1 (77.5%), T1 (77.5%), and G1 (85%) tumors. Conclusions: NF-PNEN ≤2 cm in MEN1 patients are indolent neoplasms posing a low oncological risk. Surgical treatment of these tumors at initial diagnosis is rarely justified in favor of conservative treatment.

Minimally invasive distal pancreatic resections and enucleations are feasible and safe in MEN1 patients with insulinoma or non-functioning pNENs.