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, because it was thought to be 10% familial, 10% malignant, 10% bilateral, and 10% extra-adrenal.2 However, it has been recently reported that up to 30% of patients with pheochromocytoma and paraganglioma have a hereditary syndrome.9 Paragangliomas alone have an estimated incidence of one in 30,000 individuals.10 When both pheochromocytomas and paragangliomas are grouped together as catecholamine-producing tumors, the estimated incidence is two to eight cases per 1 million people.11 Both pheochromocytomas and paragangliomas occur in equal frequency in men and women. It is uncommon for these tumors to develop in the pediatric population. If present in children, they are commonly multifocal and associated with a hereditary syndrome.

Although it has been reported that pheochromocytomas and paragangliomas are more readily seen in smokers, it is difficult to unequivocally list tobacco as an etiologic agent. However, several known susceptibility genetic mutations have been identified. The more commonly known genes include von Hippel-Lindau (VHL), rearranged during transfection (RET), MEN2, neurofibromatosis type 1 (NF1), and those encoding succinyl dehydrogenase (SDH).9

Genetics

Several familial syndromes are associated with the development of pheochromocytomas and paragangliomas.9 VHL syndrome is an autosomal dominant disorder caused by a mutated tumor suppressor gene located on chromosome 3. The estimated prevalence is one in 35,000 individuals. The organs that may be affected include the brain, eye, ear, kidney, pancreas, prostate, and adrenal gland. Pheochromocytomas have been reported in 20% to 80% of these patients, and paragangliomas have been reported in 10%.12 Typically, the adrenal lesions are bilateral and produce norepinephrine.

In MEN2, a syndrome associated with the RET proto-oncogene located on chromosome 10, approximately 50% of patients develop pheochromocytomas; paragangliomas are uncommon in people with this disorder. The estimated prevalence of this syndrome is also one in 35,000 individuals. The adrenal lesions are typically bilateral and tend to secrete epinephrine. Although extremely atypical, pheochromocytomas have been shown to occur in patients with MEN1, an autosomal disorder caused by mutations in the tumor suppressor gene located on chromosome 11. The prevalence of this disorder is one in 30,000 individuals.

NF1 is an autosomal dominant disorder caused by mutations in the tumor suppressor gene located on chromosome 17. The estimated prevalence is one in 3000 individuals. Both pheochromocytomas and paragangliomas occur in only 2% of these patients.

More recently, familial paraganglioma syndrome has been found to be associated with several mutations in the SDH gene.13 Pathophysiologically, these mutations cause a chronic hypoxic signal in the mitochondrial II complex that leads to cellular proliferation and tumor growth.10 The first germline mutation identified was in the SDH subunit D (SDHD) by Baysal and colleagues in 2000.14 Additional mutations have been discovered in subunits B and C (SDHB and SDHC). When Neumann and colleagues13 evaluated 271 patients with putative nonsyndromic pheochromocytomas and paragangliomas, 12 (4.4%) cases were attributed to SDHB and 11 (4.0%) were attributed to SDHD. The genes encoding SDHB and SDHD are both located on chromosome 1; SDHD is also located on chromosome 11. SDHB mutations are associated with thoracic or abdominal paragangliomas that are more likely to be malignant; pheochromocytomas are rare. SDHD mutations are generally associated with tumors located in the head and neck. SDHD mutations in the tumor suppressor gene on chromosome 11 also are associated with head and neck paragangliomas that are less likely to be malignant but more likely to be multifocal; pheochromocytomas are rare. Interestingly, transmission of the SDH genes is autosomal dominant; however, SDHD has been noted to display maternal imprinting whereby transfer of the gene from the mother leads to a carrier state without pheonotypic expression.15 In SDH-associated disease, if the adrenals are involved, the lesions tend to be bilateral. Other less common syndromes associated with pheochromocytomas and paragangliomas include Carney complex, tuberous sclerosis, Sturge-Weber, and ataxia-telangiectasia.

Patients with pheochromocytoma and paraganglioma often present with hypertension that is of new onset, episodic, and persistent or refractory to standard pharmacologic agents. Additionally, more common signs and symptoms include headache, palpitations, and diaphoresis. Other findings may include anxiety, tremor, pallor, flushing, tachycardia, postural hypotension, visual disturbances, heat intolerance, fever, nausea, vomiting, abdominal pain, constipation, polyuria, hematuria (related to a paraganglioma of the bladder), polydypsia, hyperglycemia, and hypercalcemia.16 Patients with pheochromocytomas may be asymptomatic even in the setting of extremely large tumors (50 g) because of their tendency for cystic degeneration (Figure 15-1). It is essential to note that malignant catecholamine-producing tumors have a clinical presentation identical to their benign counterparts. The most common metastatic sites are regional lymph nodes, bone, liver, and lung.17 In the majority of cases, however, pheochromocytoma and paraganglioma are benign tumors. The malignancy rate is approximately 5% to 10% and 15% to 35%, respectively. According to the WHO, malignancy is defined by the presence of metastatic disease rather than by local invasion.1 There is no single histologic feature, including capsular or vascular invasion or cytologic atypia, that solely identifies metastatic potential.1 Other scoring systems have been used, including those developed by Linnoila and coworkers18 in 1990, Thompson19 in 2002, and Kimura and coworkers20 in 2005; however, they have not been routinely implemented.

Pheochromocytomas may present as adrenal incidentalomas. Most that are serendipitously discovered in this way are smaller than 3 cm. The incidence of pheochromocytomas among patients who have adrenal incidentalomas is reported to be between 1.5% and 11%.21 A recent multicenter study involving nearly 100 patients who had pheochromocytomas or paragangliomas reported that 40% of tumors were found incidentally.22 In some cases, pheochromocytomas and paragangliomas are not associated with hypertension. One theory has included the desensitization of catecholamine receptors over time because of constant and chronic exposure that then leads to disruption of normal circadian variation in blood pressure.23 In fact, the same authors have reported that up to 40% of patients with pheochromocytoma are asymptomatic and are considered “subclinical.”23

Biochemical Tests

When a pheochromocytoma or paraganglioma is suspected, it is imperative that functional biochemical studies be performed before any radiologic imaging is done. The diagnosis of this entity is essential because if not identified, it could result in catastrophic consequences such as sudden death or stroke. Testing patients for excessive production of catecholamines should be the initial step in the differential diagnosis. Unfortunately, some of these tests, whether performed via blood or urine sampling, are plagued by false-positive results. Confounding factors include interfering substances and patient comorbidities that lead to inaccuracies. Specifically, levodopa, pseudoephedrine, amphetamines, reserpine, acetaminophen, ethanol, prochlorperazine, tricyclic antidepressants, labetalol, and methylglucamine from iodine-containing contrast media should be avoided when doing an evaluation. Disorders such as acute myocardial infarction, acute stroke, severe congestive heart failure, acute clonidine withdrawal, and acute alcohol withdrawal may also cause falsely elevated catecholamine levels.24

A comprehensive multicenter cohort study involving 214 patients with and 644 patients without pheochromocytoma was performed.25 The investigators compared the sensitivities and specificities of plasma-free metanephrines, plasma catecholamines, urinary fractionated metanephrines, urinary catecholamines, urinary total metanephrines, and vanillylmandelic acid. They reported that plasma-free metanephrine testing was the best initial test for patients being evaluated for pheochromocytoma. Sensitivities ranged from 97% to 99%, and specificities ranged from 82% to 96%. The false-negative plasma-free metanephrine rate was 1.4%, indicating that the probability of missing a pheochromocytoma with this test is extremely rare.25

In patients at low risk for pheochromocytoma or paraganglioma, others recommend urinary total catecholamines and metanephrines as the initial diagnostic test of choice, with plasma levels reserved for patients with a strong family history.26 It is important to note that in general, whereas pheochromocytomas secrete epinephrine, paragangliomas primarily secrete norepinephrine. Phenylethanolamine N-methyltransferase, an enzyme primarily located in the adrenal gland, converts norepinephrine to epinephrine; therefore, patients with extra-adrenal paragangliomas tend to have higher levels of normetanephrine. Tumors associated with VHL produce mostly norepinephrine, and tumors associated with MEN2 produce both epinephrine and norepinephrine. In malignant disease, dopamine is often preferentially secreted because of alterations in catecholamine synthesis. Because pheochromocytomas and paragangliomas are neuroendocrine tumors, serum chromogranin A may also be used as a tumor marker.27 It may be falsely elevated in patients with renal insufficiency, however. The sensitivity is 86%; and the specificity can be as high as 98% when combined with an elevated plasma catecholamine level in patients with normal renal function (patients with creatinine clearance at least 80 mL/min).28