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There are currently no reliable markers associated with aggressive behavior in well-differentiated and moderately differentiated pancreatic neuroendocrine tumors. We aimed to determine whether expression of ubiquitin carboxyl-terminal hydrolase L1 in conjunction with Ki67 can identify metastatic potential of well-differentiated and moderately differentiated pancreatic neuroendocrine tumors from fine-needle aspiration samples obtained by endoscopic ultrasound.Retrospective review of 48 patients with well-differentiated and moderately differentiated pancreatic neuroendocrine tumors diagnosed by endoscopic ultrasound fine-needle aspiration at a single center identified 35 biopsy samples with adequate material for analysis. Ubiquitin carboxyl-terminal esterase L1 immunocytochemistry of primary pancreatic neuroendocrine tumors was performed along with Ki67 staining and scored semiquantitatively. The combination of ubiquitin carboxyl-terminal esterase L1 score ≤4 (weak) and Ki67 ≥3% (high) was considered a positive test for predicting tumors associated with metastases.Weak ubiquitin carboxyl-terminal hydrolase L1 staining had 80% sensitivity, 65% specificity, 63% positive predictive value, and 81% negative predictive value to identify primary tumors associated with metastatic disease. The combination of weak ubiquitin carboxyl-terminal hydrolase L1 staining and high Ki67 staining increased the test specificity to 95%. On multivariable analysis, combined positive test of weak ubiquitin carboxyl-terminal esterase L1 staining and high Ki67 staining was an independent predictor of metastatic disease (P = .047).Ubiquitin carboxyl-terminal hydrolase L1 is a novel biomarker for identifying malignant potential of primary well-differentiated and moderately differentiated pancreatic neuroendocrine tumors and in combination with Ki67 is an independent predictor of development of metastatic disease.