Evolving concepts in pheochromocytoma and paraganglioma

Purpose of review The pheochromocytoma field has recently undergone a paradigm shift. This review will highlight some of these novel findings, including their impact on our understanding of the disease biology and influence on clinical management. Recent findings Identification of novel susceptibility loci and recognition of a high rate of germline mutations in pheochromocytomas indicate that their genetic diversity is broader and more complex than previously estimated. Further, increased risk of tumor malignancy and aggressiveness in certain patients with succinate dehydrogenase subunit B (SDHB) mutations suggest that they may have prognostic value as predictors of pheochromocytoma behavior. Finally, discovery of a shared activation of the hypoxic response in pheochromocytomas with mutations in VHL and SDH genes and uncovering of a common JunB-mediated apoptosis defect in the major hereditary groups of pheochromocytoma have provided a mechanistic basis for the clinical similarities between these distinct syndromes. Summary The notion that 'sporadic'-appearing tumors may in fact be components of one of multiple hereditary syndromes has a major impact on surveillance and follow-up of patients and their at-risk family members. Likewise, the ability to predict tumor malignancy has the potential to improve the prognosis of these patients. Importantly, insights into the biology of pheochromocytomas have provided clues on pathway interactions in cancers and have laid the ground for generation of new hypotheses on the cell-of-origin of these tumors. Pheochromocytomas have therefore emerged as key models for understanding cancer biology and for paving the way for future designer treatment in this and other cancers.