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Key Points Question Is cortical-sparing adrenalectomy associated with increased pheochromocytoma-specific morbidity and mortality for patients with bilateral pheochromocytomas compared with total adrenalectomy? Findings In this cohort study of 625 patients with bilateral pheochromocytomas, most had hereditary syndromes, but 36% initially presented with unilateral pheochromocytoma. Bilateral total adrenalectomy resulted in a high rate of adverse effects from glucocorticoid replacement therapy, whereas cortical-sparing surgery was not associated with a worse outcome. Meaning These findings suggest that cortical-sparing surgery may be the preferred approach for patients at risk for, or diagnosed with, bilateral pheochromocytomas, especially those harboring a germline mutation in one of the known predisposition genes.

The adrenal medulla is composed predominantly of chromaffin cells producing and secreting the catecholamines dopamine, norepinephrine, and epinephrine. Catecholamine biosynthesis and secretion is a complex and tightly controlled physiologic process. The pathways involved have been extensively studied, and various elements of the underlying molecular machinery have been identified. In this review, we provide a detailed description of the route from stimulus to secretion of catecholamines by the normal adrenal chromaffin cell compared to chromaffin tumor cells in pheochromocytomas. Pheochromocytomas are adrenomedullary tumors that are characterized by uncontrolled synthesis and secretion of catecholamines. This uncontrolled secretion can be partly explained by perturbations of the molecular catecholamine secretory machinery in pheochromocytoma cells. Chromaffin cell tumors also include sympathetic paragangliomas originating in sympathetic ganglia. Pheochromocytomas and paragangliomas are usually locally confined tumors, but about 15% do metastasize to distant locations. Histopathological examination currently poorly predicts future biologic behavior, thus long term postoperative follow-up is required. Therefore, there is an unmet need for prognostic biomarkers. Clearer understanding of the cellular mechanisms involved in the secretory characteristics of pheochromocytomas and sympathetic paragangliomas may offer one approach for the discovery of novel prognostic biomarkers for improved therapeutic targeting and monitoring of treatment or disease progression.