Importance The clinical behavior of well-differentiated pancreatic neuroendocrine tumors (PanNETs) is difficult to predict.

Objective To define more accurately prognosticators for patients with a surgically resected PanNET.

Design The pathology and Ki-67 immunolabeling index of PanNETs resected from 904 patients was correlated with patient outcome.

Setting Academic tertiary care hospital.

Participants Consecutive patients who had a PanNET resected between 1985 and 2025.

Results The mean patient age at surgery was 56.6 years (SD 14.0), 477 were male (52.8%), and 7882 person-years of follow-up were obtained (mean 8.8 years, SD 6.5). The 10-year survival was 81% (95% CI: 77,86%) for patients with G1 PanNETs (Ki-67 <3%), 68% (95% CI: 61,76%) for patients with G2a PanNETs (Ki-67 3-<10%), 44% (95% CI: 29,66%) for patients with G2b PanNETs (Ki-67 of 10%-≤20%), and 23% (95% CI: 8,61%) for patients with G3 PanNETs. Metastases (HR 4.7, p <0.0001), vascular invasion (HR 3.0, p <0.0001), tumor size ≥ 2 cm (HR 2.88, p <0.0001), perineural invasion (HR 2.42, p<0.0001), and positive margins (HR 2.18, p <0.0001) were associated with worse overall survival. Insulinoma (HR 0.34, p=3e-04), sclerosing variant (HR 0.47, p=0.05), and cystic variant (HR 0.61, p=0.05) were associated with improved overall survival. T stage and N stage were all statistically significant classifiers of overall survival. Similar associations were found with respect to disease relapse. There was a significant (P<0.001) increase in the proportion of patients diagnosed with stage I vs stage IV disease over time.

Conclusions and relevance This study supports the classification of PanNETs into four grades (G1, G2a, G2b, and G3) based on Ki-67 labeling, which allows a more accurate prognostic assessments of patients.

Question Does subdividing grade 2 well-differentiated pancreatic neuroendocrine tumors (PanNETs) into grade 2a (Ki-67 3-<10%), and grade 2b (Ki-67 10%-≤20%) improve patient prognostication after surgery?

Findings In this single-institution cohort study of 904 adults, patients with grade 2a and patients with grade 2b PanNETs had distinct outcomes. Furthermore, the magnitude of the risk associated with metastases, perineural invasion, positive margins, tumor size, vascular invasion, sclerosing variant and cystic variant was refined.

Meaning This study supports classifying PanNETs into four grades (G1, G2a, G2b, and G3), and provides a basis for accurate prognostic assessments of patients.

The authors have declared no competing interest.

This study was funded by Stringer Foundation, and Doug and Julie Ostrover.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Johns Hopkins University Institutional Review Board.

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All data produced in the present study are available upon reasonable request to the authors.