Simple SummaryPheochromocytoma and sympathetic paraganglioma (PHEO/sPGL) are rare and mainly sporadic tumors arising from chromaffin cells, for which hereditary variants occur in about one-third of cases. The discrimination between benign and malignant lesions is extremely challenging in PHEO/sPGL and the prognosis is indeterminate. The study aimed to analyze the long-term outcomes of PHEO/sPGL in a cohort of 170 patients. The results demonstrated that new tumor recurrence occurred more frequently with hereditary variants, even though new tumors also reoccurred with sporadic variants. Moreover, even if the risk of metastatic recurrence was higher with malignant variants at diagnosis, the risk also occurred with apparently benign cases. This suggests that lifelong follow-up is required for PHEO/sPGL, even in sporadic and apparently benign cases.AbstractBackground: The prognosis of pheochromocytoma and sympathetic paraganglioma (PHEO/sPGL) is difficult to predict at the time of diagnosis and long-term follow-up data are scarce, especially for apparently benign and sporadic variants. The aim of the study was to analyze the long-term outcomes in PHEO/sPGL patients. Methods: A monocentric series of 170 patients who underwent surgery for PHEO/sPGL was analyzed. Results: The study cohort included 91 female and 79 males with a median age of 48 years (range 6–83). The majority of PHEO/sPGL cases were considered apparently benign at the time of diagnosis; evident malignant behavior was found in 5% of cases. The overall 10-year risk of recurrence was 13%, but it rose up to 33% at 30 years. The risk of new tumor recurrence was higher in patients with hereditary tumors, but the risk was still significant in patients with apparently sporadic variants (20-year risk: 38% vs. 6.5%, respectively;p< 0.0001). The risk of metastatic recurrence was higher in patients with locally aggressive tumors at diagnosis, but the risk was present also in apparently benign variants (5-year risk: 100% vs. 1%, respectively;p< 0.0001). Conclusions: Lifelong follow-up is required not only for hereditary PHEO/sPGL but also for apparently benign and sporadic tumors at diagnosis because of the risk of long-term recurrent disease.