Chapter 15

Pheochromocytomas and paragangliomas, otherwise referred to as extra-adrenal pheochromocytomas, are rare neuroendocrine tumors that originate from neural crest cells of the autonomic nervous system.1 They secrete catecholamines in variable amounts (e.g., those of the head and neck produce less than those located within the abdomen).1 Sympathetic paraganglia are intimately associated with the adrenal medulla and organ of Zuckerkandl, and parasympathetic paraganglia are associated with the carotid bodies.2 Neural crest tumors that arise from the adrenal medulla are referred to as pheochromocytomas, and those that occur extra-adrenally are called paragangliomas. In 2004, the World Health Organization (WHO) clarified the definition of pheochromocytomas as tumors that arise in the adrenal medulla and that are derived from chromaffin cells of neural crest origin.3 Pheochromocytomas were first described in 1886 by Felix Fränkel.4 Evidence suggests that the patient described, Ms. Minna Roll, had bilateral adrenal lesions and multiple endocrine neoplasia type 2 (MEN2). This is based on genetic analyses performed in 2007.5

The term pheochromocytoma was first coined in 1912 by Ludwig Pick. This was based on the dark color these tumors turned when exposed to chromaffin salts.4 In 1926, Cesar Roux was the first to successfully remove a pheochromocytoma.4 The term paraganglioma was first used by Drs. Alezais and Peyron of Marseilles in 1908.4 Biochemically, only pheochromocytomas and paragangliomas of the organ of Zuckerkandl secrete epinephrine because the enzyme phenyl ethanolamine N-methyl transferase is only present in the adrenal medulla and organ of Zuckerkandl. The organ of Zuckerkandl, also know as the para-aortic bodies, is located at the bifurcation of the aorta or origin of the inferior mesenteric artery. First described by Emil Zuckerkandl in 1901, it is the most common site for paragangliomas.3

Although generally described together, pheochromocytomas and paragangliomas should be kept distinct because they exhibit several differences. Pheochromocytomas tend to have a lower rate of malignancy (10%), an adrenergic phenotype, and a higher propensity to be associated with hereditary syndromes. Paragangliomas contain neurosecretory granules; however, only 1% to 3% have clinical evidence of oversecretion. In addition, paragangliomas are predominantly located in the abdomen (85%) and rarely (3%) in the head and neck. When found in the abdomen, 15% to 35% of paragangliomas are malignant.6 When discovered in the head and neck region, they are likely to be carotid body tumors. These tumors are characterized clinically as painless masses that are laterally mobile but vertically fixed (Fontaine's sign). They tend to cause cranial nerve palsy via mass effect. Patients with pheochromocytomas and paragangliomas should always be managed surgically, if possible.6

Both pheochromocytomas and paragangliomas are rare but may cause hypertension. The estimated prevalence of pheochromocytomas is as high as 0.05%.7 However, the incidence of pheochromocytomas is less than 0.5% in patients with hypertensive symptoms and as high as 4% in patients with adrenal incidentalomas.8 Pheochromocytoma was once called the 10% tumor, ...

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