Subjects

To examine the predictive features associated with shorter overall and disease-specific survival, we retrospectively reviewed a consecutive cohort of patients with malignant PPGL evaluated at the Mayo Clinic (Rochester) between 1 January 1960 and 30 September 2016. The study was approved by the Institutional Review Board of the Mayo Clinic. The Mayo Clinic PPGL database was reviewed to identify patients with malignant PPGL. Of 3280 patients, 272 (8.3%) had malignant disease. Diagnosis was confirmed by reviewing clinical, histopathological, and biochemical data. PGL was categorized according to the location of the primary tumor. Patients with both PHEO and PGL were included in the PGL group. Malignant disease was defined in accordance with the 2004 World Health Organization criteria (17). Synchronous metastatic disease was defined as the presence of distant metastases at the time or within 3 months of the primary tumor diagnosis. Patients who developed metastatic disease ≥3 months after the diagnosis of the primary tumor were defined to have metachronous metastases. Patients were characterized to have a genetic mutation predisposing to PPGL if they had a documented genetic testing for major PPGL susceptibility genes, familial history of genetic mutation, or presence of at least two National Institutes of Health criteria for diagnosing NF1 syndrome.

All PPGL tumors were defined as functional when urine or plasma-fractionated catecholamines or fractionated or total metanephrines were elevated above the upper limit of respective reference ranges. The reference intervals for plasma concentrations were established at the Mayo Clinic (18). The tumors were considered nonfunctional when the levels of plasma or urine metanephrines/catecholamines remained within the reference ranges. Tumors hypersecreting primarily epinephrine/metanephrine or norepinephrine/normetanephrine were termed adrenergic and noradrenergic, respectively. We separately evaluated for dopamine hypersecretion in all tumors and termed them dopaminergic. To investigate whether the time period of diagnosis played a role in baseline characteristics and outcomes of patients with malignant PPGL, we analyzed the variables based on year of diagnosis using the following arbitrary time intervals: 1960 to 1990 and 1991 to 2016. Additionally, for more detailed evaluation of prognostic factors for disease progression, we identified the patients with at least 5 years of follow-up from the primary tumor diagnosis, unless preceded by death due to malignant PPGL, and divided the cohort into two groups: patients with rapidly progressive disease who died of malignant PPGL within 5 years of the primary tumor diagnosis, and patients with indolent disease with at least 5-year disease survival. Patients with <5 years of follow-up, or those who died of other causes within 5 years of primary tumor diagnosis, were excluded from this analysis.