The adrenal medulla and extra-adrenal paraganglia: then and now

The past 25 years have witnessed revolutionary changes in the care of patients with pheochromocytomas and extra-adrenal paragangliomas. Germline mutations of at least 13 genes are now associated with tumor development, a greater degree of hereditary susceptibility than for any other human neoplasm. Somatic mutations, either of the same genes or of several additional ones with closely related functions, are also increasingly recognized. Clinicians are now aware of the genetic implications of a pheochromocytoma or paraganglioma. All patients are therefore offered genetic testing and receive lifelong surveillance. Almost all of the mutated genes have well-described correlations with clinical and biochemical phenotypes. Tumors arising in patients with mutations of the SDHB gene have at least a 30 % chance of metastasizing and typically produce norepinephrine and/or dopamine. Assay of plasma-free metanephrines serves as a highly sensitive and specific biochemical screen for the presence of catecholamine-producing tumors, and the dopamine metabolite methoxytyramine serves as a useful marker for detecting minimally functional tumors or their metastases. New functional imaging techniques provide highly sensitive tumor localization. In addition to differential diagnosis, pathologists play new roles in helping to identify hereditary disease and guiding the sequence of genetic testing.