Prognostic significance of Ki-67 in assessing the risk of progression, relapse or metastasis in pheochromocytomas and paragangliomas

Abstract

Introduction: Since the Fourth edition of the WHO classification, PPGLs have been recognized for their metastatic potential, though no clear features can accurately predict this behavior. The prognostic value of Ki-67 in assessing the risk of progression, relapse, or metastasis in PPGLs remains debated. Methods: This cohort study included 501 patients diagnosed with PPGLs at the First Hospital of Jilin University between 2000 and 2022, with clinical data, treatment details, pathological indicators, and germline gene test results collected. Bulk sequencing was performed on formalin-fixed paraffin-embedded (FFPE) primary tumor samples from 87 patients. Progression-free survival (PFS) was analyzed using multivariable Cox regression. Results: Among the 119 enrolled patients with PPGLs, the average age was 45.7 ± 14.0 years, and the median follow-up time was 46 months. A significant finding was the high expression of CDK1, a gene known to be significantly associated with the metastatic risk of PPGLs, in samples with Ki-67 ≥ 3% (p < 0.0001). More importantly, patients with PPGLs and a Ki-67 level ≥ 3% had a 3.59-fold higher risk of progression, relapse or metastasis compared to those with Ki-67 < 3% (HR = 4.59, 95% CI: 1.06–11.95), after adjusting for all confounding factors. In the composite model, the addition of Ki-67 enhanced the predictive ability of the combined model of SDHB, primary site, tumor size, and invade neighboring tissue (AUC = 0.888, 95% CI: 0.808–0.967 vs. AUC = 0.874, 95% CI: 0.783–0.965). Conclusion: A Ki-67 level ≥ 3% is associated with an increased risk of progression, relapse or metastasis in patients with PPGLs.