Integrating the Ki67 proliferation index into risk-adapted management of medullary thyroid carcinoma: evidence from the first large retrospective chinese cohort

Background: To evaluate the clinical implications of the Ki67 proliferation index in medullary thyroid carcinoma (MTC), focusing on its association with lateral lymph node metastasis (LLNM) and disease-free survival (DFS) to refine risk-adapted management. Methods: A retrospective cohort of 148 consecutive patients who underwent initial thyroidectomy for MTC (2008-2024) was analyzed. Patients were stratified by Ki67 index according to IMTCGS criteria (< 5% vs. ≥ 5%). Comprehensive clinicopathological and lymph node data were collected. The primary endpoints were associations between Ki67 index and nodal metastatic burden, as well as postoperative DFS. Multivariate logistic and Cox regression models were used to identify independent predictors of LLNM and DFS. Results: Among the 148 patients, 37 exhibited high Ki67 expression (≥ 5%). Elevated Ki67 was significantly associated with aggressive clinicopathological features, including higher preoperative calcitonin levels, larger tumors, advanced T-stage, and higher rates of LLNM. Furthermore, Spearman analysis revealed a positive correlation between the Ki67 index and lymph node metastatic burden. Kaplan-Meier survival analysis demonstrated that high Ki67 (≥ 5%) predicted significantly worse DFS (HR = 3.389, P = 0.003) and distant metastasis-free survival ( HR = 4.958, P = 0.018). Further stratification revealed that patients with Ki67 ≥ 20% exhibited the worst DFS (HR = 5.589, 95% CI: 1.135-27.522) compared to the < 5% baseline. Multivariate analysis confirmed Ki67 ≥ 5% as an independent predictor for worse DFS (HR = 2.60, P = 0.029), and this association remained significant in patients with regional disease (P = 0.021). Conclusions: The Ki67 index positively correlates with lymph node metastatic burden and provides critical prognostic value for MTC. An index ≥ 5% independently predicts inferior DFS, particularly in regional disease, while an index ≥ 20% identifies patients requiring intensive surveillance. Integrating Ki67 evaluation facilitates optimal risk stratification, though adopting the complete IMTCGS remains recommended.