Clinical Implications of Ki‐67 Index, Grade and Hormonal Changes in Pancreatic Neuroendocrine Tumors: Insights Into Tumor Heterogeneity Based on Primary and Secondary Lesions

ABSTRACT Background Pancreatic neuroendocrine tumors (PanNETs) show heterogeneity, including temporal shifts in proliferation and hormone production; however, their clinical implications remain uncertain. Methods This retrospective study included 114 patients with metastatic or recurrent PanNETs at Kyushu University Hospital. Paired specimens from 46 patients (27 synchronous metastases and 19 recurrences) were evaluated for Ki‐67 index and tumor grade. Proliferation change was defined as grade progression or a ≥ 10% absolute Ki‐67 increase. Hormonal phenotype changes were assessed in all patients. Results In metastases, mean Ki‐67 increased from 12.3% to 16.4% ( p = 0.0043); 22.2% showed a ≥ 10% increase, and 33.3% progressed in grade. In recurrences, Ki‐67 increased from 8.8% to 9.3% ( p = 0.8256); 15.8% showed a ≥ 10% increase, and 21.1% progressed in grade. Median progression‐free survival was 7.8 months in metastases and 17.1 months in recurrences. Median overall survival was significantly longer in the recurrence group (124.8 vs. 32.5 months, p = 0.003). Hormonal transformation occurred in six patients (5.3%), mostly during progressive hepatic disease. Conclusion A subset of PanNETs exhibited increased proliferation of metastases or recurrence without detrimental survival effects, possibly because of timely treatment adjustments. Rebiopsy may be useful for detecting proliferative changes, whereas hormonal shifts highlight tumor heterogeneity and warrant continued clinical and biochemical monitoring.