Redefining the Ki-67 Index Stratification for Low-Grade Pancreatic Neuroendocrine Tumors: Improving Its Prognostic Value for Recurrence of Disease

• Published in: Annals of surgical oncology Vol. 25; no. 1; pp. 290 - 298
• Main Authors: Lopez-Aguiar, Alexandra G., Ethun, Cecilia G., Postlewait, Lauren M., Zhelnin, Kristen, Krasinskas, Alyssa, El-Rayes, Bassel F., Russell, Maria C., Sarmiento, Juan M., Kooby, David A., Staley, Charles A., Maithel, Shishir K., Cardona, Kenneth
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 2018; Springer Nature B.V
• Subjects: Adult; Aged; Disease-Free Survival; Female; Humans; Ki-67 Antigen - metabolism; Lymph nodes; Male; Medicine; Medicine & Public Health; Metastases; Middle Aged; Mitotic Index; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Recurrence, Local - metabolism; Neoplasm Staging; Neuroendocrine tumors; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Neuroendocrine Tumors - surgery; Oncology; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - surgery; Pancreatic Tumors; Predictive Value of Tests; Retrospective Studies; Surgery; Surgical Oncology; Tumors; PanNETs; Stratification Scheme; Predict Disease Recurrence; Well-differentiated PanNETs; Pancreatic Neuroendocrine Tumors
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/s10434-017-6140-8

Background The Ki-67 index is an established prognostic marker for recurrence after resection of pancreatic neuroendocrine tumors (PanNETs) that groups tumors into three categories: low grade (< 3%), intermediate grade (3–20%), and high grade (> 20%). Given that the majority of resected PanNETs have a Ki-67 less than 3%, this study aimed to stratify this group further to predict disease recurrence more accurately. Methods The Ki-67 index was pathologically re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables using tissue microarray blocks made in triplicate. All patients who underwent curative-intent resection of non-metastatic PanNETs at a single institution from 2000 to 2013 were included in the study. The primary outcome was recurrence-free survival (RFS). Results Of 113 patients with well-differentiated PanNETs resected, 83 had tissue available for pathologic re-review. The Ki-67 index was lower than 3% for 72 tumors (87%) and between 3 and 20% for 11 tumors (13%). Considering only Ki-67 less than 3%, the tumors were further stratified by Ki-67 into three groups: group A (< 1%, n  = 43), group B (1–1.99%, n  = 23), and group C (2–2.99%, n  = 6). Compared with group A, groups B and C more frequently had advanced T stage (T3: 44% and 67% vs 12%; p  = 0.003) and lymphovascular invasion (50% and 83% vs 23%; p  = 0.007). Groups B and C had similar 1- and 3-year RFS, both less than group A. After combining groups B and C, a Ki-67 of 1–2.99% was associated with decreased RFS compared with group A (< 1%). This persisted in the multivariable analysis (hazard ratio [HR] 8.6; 95% confidence interval [CI] 1.0–70.7; p  = 0.045), with control used for tumor size, margin-positivity, lymph node involvement, and advanced T stage. Conclusions PanNETs with a Ki-67 of 1–2.99% exhibit distinct biologic behavior and earlier disease recurrence than those with a Ki-67 lower than 1%. This new stratification scheme, if externally validated, should be incorporated into future grading systems to guide both surveillance protocols and treatment strategies.