Despite evidence of different malignant potentials, postoperative follow-up assessment is similar for G1 and G2 pancreatic neuroendocrine tumors (panNETs)

Non-functional pancreatic neuroendocrine tumours (NF-pNETs) are rare neoplasms, often detected incidentally. The prognosis varies and is largely dependent on the Ki-67 proliferation index, presence of a genetic syndrome, lymph node involvement, and tumour size ^1–4. Resection of pancreatic lesions is associated with significant morbidity, and may include long-term complications such as new-onset diabetes and exocrine pancreatic insufficiency ^{5, 6}. Clearly, the potential survival benefit obtained with surgery needs to outweigh the morbidity associated with pancreatic surgery. This explains the current controversy regarding small (2 cm or less) asymptomatic NF-pNETs, for which some advocate surgery and others suggest a conservative approach ^7–11.

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.

Resection for pancreatic neuroendocrine tumours (PNET) is suggested to be associated with an increased risk of a post-operative pancreatic fistula (POPF). The aim of this study was to describe morbidity after resections for PNET, focusing on POPF. Outcomes were compared with resections for other lesions. Patients undergoing an elective pancreatic resection during a 12-year period were retrospectively analysed. Morbidity was defined according to the International Study Group of Pancreatic Surgery (ISGPS) definitions. Eighty-eight out of 832 patients (10.6%) underwent a resection for PNET. Atypical pancreatic resections (enucleation and central pancreatectomy) and distal pancreatectomies were more frequently performed for PNET. The POPF rate was 22.7% in patients operated for PNET compared with 17.2% in other patients (P = 0.200). In univariate analysis, body mass index (BMI), pancreatic duct diameter, somatostatin analogue administration, type of resection and type of pathology were associated with a POPF. In multivariate analysis, BMI, a pancreatic duct diameter <3 mm and central pancreatectomy remained independent risk factors [odds ratio (OR) 1.93, 95% confidence interval (CI) 1.22-3.07 and OR 3.04, 95% CI 1.05-8.82, respectively]. High rates of POPF were found in patients operated for PNET. However, this was mainly owing to the fact that atypical resections, known to be associated with a higher fistula rate, were performed more frequently in these patients.

Background: Large population‐based studies give insight into the prognosis and treatment outcomes of patients with pancreatic neuroendocrine tumors (pNETs). Therefore, we provide an overview of the treatment and related survival of pNET in the Netherlands.Methods: Patients diagnosed with pNET between 2008 and 2013 from the Netherlands Cancer Registry were included. Patient, tumors and treatment characteristics were reported. Survival analyses with log‐rank testing were performed to compare survival.Results: In total, 611 patients were included. Median follow‐up was 25.7 months, and all‐cause mortality was 42%. Higher tumor grade and TNM stage were significantly associated with worse survival in both the overall and metastasized population. The effect of distant metastases on survival was more significant in lower tumor stages (T1–3 p < 0.05, T4 p = 0.074). Resection of the primary tumor was performed in 255 (42%) patients. Patients who underwent surgery had the highest 5‐year survival (86%) compared to PRRT (33%), chemotherapy (21%), targeted therapy and somatostatin analogs (24%) (all p < 0.001). Patients with T1M0 tumors (n = 115) showed favorable survival after surgical resection (N = 95) compared to no therapy (N = 20, p = 0.008). Resection also improved survival significantly in patients with metastases compared to other treatments (all p > 0.05). Without surgery, PRRT showed the best survival curves in patients with distant metastases. Grade 3 tumors and surgical resection were independently associated with survival (HR 7.23 and 0.12, respectively).Conclusion: Surgical resection shows favorable outcome for all pNET tumors, including indolent tumors and tumors with distant metastases. Prospective trials should be initiated to confirm these results.