Locally Advanced Disease and Clinical Outcomes of Pheochromocytomas and Paragangliomas: Insights from a Multicenter Study.

Abstract

Objective: To evaluate the prognostic significance of locally advanced disease (LAD) in patients with pheochromocytomas and paragangliomas (PPGLs).

Methods: We retrospectively analyzed 389 patients with histopathologically confirmed PPGLs from 19 tertiary centers. LAD was defined as capsular, periadrenal fat, adjacent-organ, or vascular invasion. Persistent/recurrent disease was the composite primary endpoint. The prognostic value of LAD was further assessed after excluding patients with distant metastatic disease at diagnosis, in patients with stage I-II disease, and in combination with Ki-67 labeling index (LI) ≥3%.

Results: LAD was identified in 111 patients (28.5%). Persistent/recurrent disease occurred in 17.1% and 6.1% of patients with and without LAD, respectively (p<0.001), with corresponding 5-year disease-free survival (DFS) rates of 81.8% and 93.4% (log-rank p<0.001). LAD remained independently associated with persistent/recurrent disease in multivariable analysis (HR, 3.64; 95% CI, 1.55-8.52; p=0.003). Its prognostic association persisted after excluding patients with distant metastatic disease at diagnosis. Among patients with stage I-II disease, 5-year DFS was 84.8% and 95.5% with and without LAD, respectively (log-rank p=0.014), and adding LAD to the TNM-only model significantly improved model fit (likelihood-ratio p=0.025). Patients with both LAD and Ki-67 LI ≥3% had a 5-year DFS of 68.5%.

Conclusion: LAD was associated with unfavorable outcomes in PPGLs and provided additional prognostic information beyond TNM stage in stage I-II disease. Combined assessment of local invasiveness and proliferative activity warrants further evaluation for risk stratification.