Prognostic Features in Surgically Resected Well-Differentiated Pancreatic Neuroendocrine Tumors: An Analysis of 904 Patients with 7882 Person-Years of Follow-Up

Abstract

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.

Keywords: Ki 67; PanNET; Well-differentiated pancreatic neuroendocrine tumor; grade; prognosis; stage; vascular invasion.

Figure 1:

(a) Kaplan-Meier curve for overall survival for the entire cohort. (b) Changes in the hazard ratio for death with increases in tumor size, estimated with restricted cubic splines. The plotted results represent the hazard ratio for different values of the continuous predictor (tumor size), visualizing any non-linear effects captured by the restricted cubic spline. (c) Kaplan-Meier curves for overall survival, separately according to grade. (d) Changes in the hazard ratio for death with increases in Ki-67, estimated with restricted cubic splines. The plotted results represent the hazard ratio for different values of the continuous predictor (Ki-67), visualizing any non-linear effects captured by the restricted cubic spline. (e) Predicted probability [95% CI] of being diagnosed with stage I, II, III, or IV disease (y-axis) by year of surgery grouped into quintiles (x-axis). Probabilities and corresponding odds ratios for the average relative change in the odds of a stage I, II, or III diagnosis compared to stage IV with every increasing quintile of year of surgery, adjusted for age and sex, are estimated from a multinomial regression model.