Stratification of G2 pancreatic neuroendocrine tumors using a Ten Percent Ki-67 index cut-off based on clinicopathological and molecular analyses

Pancreatic neuroendocrine tumors (PanNETs) often have low malignancy, but some develop distant metastasis or recurrence. This study aimed to investigate the prognostic utility of a Ki-67 index 10% cut-off using clinicopathological and multiomics analyses. Eighty-seven resected PanNETs were classified as G1, G2-low, G2-high, and G3 according to the World Health Organization classification, incorporating a 10% Ki-67 threshold. These groups comprised 29 (33%), 33 (38%), 16 (18%), and 9 (10%) patients, respectively. Comprehensive analyses evaluated tumor characteristics and mutation profiles across the groups. Significant differences in tumor size, recurrence, and overall survival were observed between the G2-low and G2-high groups. Genomic profiling of 19 samples revealed that the G3 (4 patients) and G2-high (6 patients) groups showed greater tumor mutation burdens and more driver gene mutations than the G2-low (6 patients) and G1 (3 patients) groups. Gene expression profiling revealed distinct patterns between the G3/G2-high and G2-low/G1 groups, with the oncogene SERPINA1 significantly upregulated in the G3/G2-high group. The multiomics approach identified key genes, emphasizing the significance of the Ki-67 index 10% cut-off in predicting tumor behavior. The findings support using the Ki-67 index of 10% as a critical threshold for stratifying PanNETs and guiding prognosis and treatment.