Redefining the Ki-67 index stratification for low-grade pancreatic neuroendocrine tumors: improving its prognostic value for recurrence of disease

Abstract

Objective: Ki-67 is an established prognostic marker for recurrence after resection of pancreatic neuroendocrine tumors (PanNETs), which groups tumors into 3-categories of low, intermediate, and high grade (<3%, 3–20%, and >20%). Given that most resected PanNETs are <3%, our aim was to further stratify this group to more accurately predict recurrence of disease. Methods: Ki-67 index was re-reviewed and scored by pathologists blinded to all other clinicopathologic variables using tissue microarray blocks made in triplicate for patients who underwent curative-intent resection of non-metastatic PanNETs at a single institution from 2000–2013. Primary outcome was recurrence-free survival (RFS). Results: Of 113 PanNETs resected, 83 had tissue available for analysis. Ki-67 was <3% in 72 (87%), 3–20% in 11 (13%), and >20% in 0 tumors. All tumors were well-differentiated. Considering only <3%, tumors were further stratified by Ki-67 into A: <1% (n=43), B: 1–1.99% (n=23), and C: 2–2.99% (n=6). Compared to group A, groups B and C more frequently had advanced T-stage tumors (T3: 44 and 67% vs 12%; p=0.003) and lymphovascular invasion (50 and 83% vs 23%; p=0.007). Group B and C had a similar 1- and 3-yr RFS, both less than group A (Figure 1A). After combining groups B and C, a Ki-67 of 1–2.99% was associated with decreased RFS compared to group A (<1%) (Figure 1B). This persisted on multivariable analysis (HR: 10.3; 95% CI: 1.3–83.2; p=0.03), controlling for tumor size >2 cm, margin-positivity, LN-involvement, and advanced T-stage. Conclusion: PanNETs with a Ki-67 of 1–2.99% have distinct biologic behavior and earlier recurrence of disease compared to those <1%. This new stratification scheme, if externally validated, should be incorporated in future grading systems.