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

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.