The Paradox of Grade 2 Pancreatic Neuroendocrine Tumors: G2a/G2b Subdivision in Patients With and Without Liver Metastases: A Retrospective Single-Center Analysis.

BACKGROUND

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous, with grade 2 (G2) tumors encompassing a broad Ki-67 proliferation range from 3% to 20%. Subdividing G2 into G2a (Ki-67 3-10%) and G2b (Ki-67 10-20%) may improve prognostic stratification of patients undergoing pancreatic resection for non-metastatic disease, but the clinical significance after cytoreductive hepatectomy remains unexplored.

METHODS

This retrospective single-center analysis included 676 of 1077 well-differentiated PNETs treated between 2000 and 2022. Of these, 578 had initially non-metastatic disease, and 98 presented with synchronous hepatic metastases. From the non-metastatic cohort, 37 patients experienced metachronous metastases. In total, 135 patients underwent cytoreductive hepatectomy for neuroendocrine liver metastases. Tumors were graded as G1 (Ki-67 ≤2.99%), G2a (Ki-67 3-9.99%), G2b (Ki-67 10-19.99%), and G3 (Ki-67 ≥20%).

RESULTS

G2b tumors were larger, more frequently node-positive, and more likely to have vascular invasion and a higher stage than the G2a tumors (p < 0.001). Recurrence-free survival (RFS) was worse for G2b versus G2a tumors (5.5 vs 11.5 years; 5 year RFS, 47.7% vs 84.0%; p < 0.001). Conversely, patients undergoing hepatectomy for neuroendocrine tumor liver metastases (NETLM) showed no significant difference in progression-free survival (PFS) (5-year PFS, 10.9% vs 15.3%; p = 0.584) or overall-survival (12.5 vs 15.5 years; p = 0.056). After hepatectomy, the largest hepatic lesion size emerged as a stronger prognostic determinant than primary tumor grading (hazard ratio [HR], 1.077; 95% CI, 1.016-1.141; p = 0.013).

CONCLUSION

Subclassification into G2a and G2b categories based on a 10% Ki-67 threshold significantly improves prognostic stratification for non-metastatic PNETs but loses relevance once liver metastases develop. In metastatic disease, hepatic tumor burden surpasses tumor grading in prognostic value, highlighting the necessity for dynamic, burden-focused management strategies.