Pancreatic neuroendocrine tumors: a multicenter international evaluation of grading, staging and outcomes

Background: Predicting the outcomes of pancreatic neuroendocrine tumors (PNETs) has been complicated by rarity, staging systems, and variable biology. Tumor activity (Ki67) and mitoses have emerged as a grading based on international consensus, however adequate validation has been limited to small, single institution series. We sought to validate the WHO grading of PNETs in a large, multi-center, international cohort. Materials and methods: PNETs undergoing surgery from 1996-2016 were collected from eight major referral centers on three continents were collected. A total of 696 patients were identified. We excluded patients with diagnosed genetic syndromes predisposing to PNET, and those with incomplete staging. Preoperative characteristics, operative, pathologic, staging, and patient survival data and outcomes were collected. Data were analyzed using R and compared on the basis of overall survival. Results: Median follow-up was 36.4 months (range 1-192); median age was 59yrs and 50.6% female; 40.5% of procedures involved the head; 57.7% tail; 36.7% had N1 or M1 disease. Metastatic disease, LN positivity, lymphovascular invasion, WHO G3 tumors, R1 resection, and necrosis on path specimen were associated-with worse odds of survival. On multivariate analysis, LVI and necrosis on final pathology were associated with worse survival. Overall survival was worse in WHO G3 tumors, however no difference between G1 & G2 at current WHO values were identified. Conclusions: In a large international cohort of resected PNETs with robust follow-up, survival differences between G1 & G2 tumors was not seen. G3 tumors had poor survival, similar to poorly differentiated neuroendocrine carcinomas.