Pheochromocytomas and extra-adrenal paragangliomas are rare tumors arising from neural crest tissue that develops into sympathetic and parasympathetic paraganglia throughout the body.
The most recent World Health Organization classification utilizes the term pheochromocytoma exclusively for tumors arising from the adrenal medulla, and the term extra-adrenal paraganglioma for similar tumors that arise from other locations.
Incidence and Mortality
The incidence of pheochromocytoma is 2 to 8 per million persons per year.[2,3] Pheochromocytoma is present in 0.1% to 1% of patients with hypertension,[4,5,6] and it is present in approximately 5% of patients with incidentally discovered adrenal masses. The peak incidence occurs in the third to fifth decades of life; the average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases. The incidence is equal between males and females.
Pheochromocytomas and extra-adrenal paragangliomas arise from neural crest tissue. Neural crest tissue develops into sympathetic and parasympathetic paraganglia.
Sympathetic paraganglia include the following:
- The adrenal medulla.
- The organ of Zuckerkandl near the aortic bifurcation.
- Other paraganglia along the distribution of the sympathetic nervous system.
Parasympathetic paraganglia include the following:
- The carotid body.
- Other paraganglia along the cervical and thoracic branches of the vagus and glossopharyngeal nerves.
No known environmental, dietary, or lifestyle risk factors have been linked to the development of pheochromocytoma.
Hereditary Predisposition Syndromes
Of all pheochromocytomas and extra-adrenal paragangliomas, 25% occur in the setting of a hereditary syndrome.[8,9,10] Major genetic syndromes that have been identified as carrying an increased risk of pheochromocytoma are included in Table 1.
Table 1. Major Genetic Syndromes That Carry an Increased Risk of Pheochromocytoma
|Genetic Syndrome or Condition||Affected Gene||Comment|
|Multiple endocrine neoplasia type 2A and 2B||RET||(Refer to thePheochromocytoma section in the PDQ summary on theGenetics of Medullary Thyroid Cancerfor more information.)|
|von Hippel-Lindau disease||VHL|| |
|Neurofibromatosis type 1||NF1|| |
|Hereditary Paraganglioma Syndrome||SDHD||Formerly referred to as familial pheochromocytoma-paraganglioma syndrome type 1|
|SDHAF2(SDH5)||Formerly referred to as familial pheochromocytoma-paraganglioma syndrome type 2|
|SDHC||Formerly referred to as familial pheochromocytoma-paraganglioma syndrome type 3|
|SDHB||Formerly referred to as familial pheochromocytoma-paraganglioma syndrome type 4|
Pheochromocytomas and extra-adrenal paragangliomas can also occur in the following two other very rare syndromes:
- The Carney triad of extra-adrenal paraganglioma, gastrointestinal stromal tumor (GIST), and pulmonary chondroma.
- The Carney-Stratakis dyad of paraganglioma and GIST.
Other genetic causes of pheochromocytoma and paraganglioma are being studied. For example, truncating germline mutations in the transmembrane-encoding gene TMEM127 on chromosome 2q11 have been shown to be present in approximately 30% of affected patients with familial disease and in about 3% of patients with apparently sporadic pheochromocytomas without a known genetic cause.TMEM127 is a negative regulator of mammalian target of rapamycin (mTOR) effector proteins.