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Paraganglioma and pheochromocytoma: Management of malignant disease

Sally E Carty, MD, FACS
William F Young, Jr, MD, MSc
Aymen Elfiky, MD, MPH
Section Editors
Jay S Loeffler, MD
André Lacroix, MD
Deputy Editor
Sadhna R Vora, MD


Pheochromocytomas and paragangliomas are catecholamine-secreting neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla (in the case of pheochromocytomas) and from neuroendocrine cells of the extra-adrenal autonomic paraganglia (in the case of paragangliomas). While pheochromocytomas/paragangliomas share overlapping characteristics that span histopathology, epidemiology, and even molecular pathobiology, they also have many differences in terms of their clinical behavior, aggressiveness and metastatic potential, biochemical findings, and association with inherited genetic syndromes.

Although some paragangliomas, particularly those arising in the skull base and neck, do not present with symptoms of catecholamine excess, intratumoral metabolism of catecholamines to metanephrines (norepinephrine to normetanephrine, and epinephrine to metanephrine, respectively) occurs independently of catecholamine release. As a result, biochemical testing is indicated in every patient with a paraganglioma even if he or she does not present with a clinical picture of catecholamine hypersecretion. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Diagnosis'.)

Paragangliomas and pheochromocytomas are indistinguishable at the cellular level, and catecholamine-secreting paragangliomas often present clinically like pheochromocytomas with hypertension, episodic headache, sweating, tremor, and forceful palpitations. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for associated neoplasms, risk for malignancy, and genetic testing.

The study of familial pheochromocytoma syndromes has been very important in understanding the pathogenic mechanisms involved in both familial as well as sporadic forms. Several susceptibility genes have been established as playing a central role in the pathogenesis of both pheochromocytomas and paragangliomas [1]. At present, 11 different genes have been implicated in the pathogenesis of these tumors: some of these represent inherited conditions (mutations in the von Hippel-Lindau [VHL] tumor suppressor gene, the rearranged during transfection [RET] proto-oncogene, the neurofibromatosis type 1 [NF1] tumor suppressor gene, genes encoding for the four subunits [A, B, C, and D] of the succinate dehydrogenase [SDH] complex, and a gene encoding the enzyme responsible for flavination of the SDHA subunit [SDHAF2]), while others are somatic mutations that have not been demonstrated to be linked to an inherited syndrome (mutations in the genes TMEM127 and MAX, and HIF2A). Genetic studies suggest that other genes may be involved in the pathogenesis of these tumors and investigations are underway to uncover novel mutations in apparently "sporadic" cases. Genetic testing is recommended for all patients with a paraganglioma and in selected patients with pheochromocytoma. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Hereditary syndromes' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Molecular pathogenesis' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Indications for genetic testing' and "Pheochromocytoma in genetic disorders", section on 'Suggested approach'.)

Most pheochromocytomas/paragangliomas are benign. At least 10 percent of pheochromocytomas are malignant (as defined by the presence of metastases), while a larger proportion of paragangliomas (up to 25 percent) are malignant. Malignancy rates are highest for paragangliomas that arise in the setting of an inherited mutation in the B subunit of the succinate dehydrogenase gene (SDHB). (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH gene mutations'.)


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