Clinical Information

Pheochromocytomas and paragangliomas (Pheo/PGL) are rare, usually benign, tumors of chromaffin cells in the adrenal medulla or paragangliomas (estimated population prevalence rates of 1 in 200,000 with a yearly incidence rate of 1-2/1000), that are potentially lethal, because they secrete excessive, uncontrolled amounts of catecholamines (dopamine, epinephrine, and norepinephrine) resulting in often severe hypertension and many cardiac abnormalities. A subgroup of these patients will also suffer tumor recurrence and sometimes malignant behavior. Untreated, these tumors have substantial morbidity and mortality.

Key symptoms are episodes of hypertension with palpitations, severe headaches, and sweating (spells). However, some patients might be asymptomatic, have mild symptoms that might be missed, or have sustained hypertension, which is frequently observed in these patients. Finally, due to the high frequency of medical imaging for unrelated ailments, increasing numbers of occult small adrenal tumors are often incidentally discovered, some of which might be Pheo/PGLs.

3-Methoxytyramine (3MT), metanephrine, and normetanephrine are the metabolites of dopamine, epinephrine, and norepinephrine, respectively. These metabolites are further metabolized to vanillylmandelic acid. Pheochromocytoma cells also have the ability to oxymethylate catecholamines into metanephrines, which are secreted into circulation and urine. 3-MT is only elevated in a small proportion of patients with Pheo/PGL. Because of its low levels, testing is performed using only 24-hour urine specimens at this time, while epinephrine, and norepinephrine can be measured in plasma or 24-hour urine specimens.

An early childhood malignancy that arises from immature neuroendocrines in the adrenals, called neuroblastoma, shares many features of Pheo/PGL but has the added threat of a high malignancy rate; however, there are also frequent spontaneous remissions, particular in very young infants. Biochemical testing for neuroblastoma differs from Pheo/PGL because of many specific issues in testing infants and young children, using urine tests rather than blood tests.

For all Pheo/PGL, the preferred initial testing is by plasma metanephrine testing, as it has the highest clinical sensitivity thus facilitating ruling out Pheo/PGL if the test results are within the healthy population reference range. However, in potentially familial cases or monitoring of treated patients, some additional and repeated testing may be required.

Testing for 24-hour urine metanephrine plus urinary catecholamine levels may be used as a confirmatory study in patients with less than a 2-fold elevation in plasma free fractionated catecholamines. This is highly desirable, as the very low population incidence rate of Pheo/PGL (<1:200,000 population per year) will otherwise result in large numbers of unnecessary, costly, and sometimes risky imaging procedures.

Finally, familial Pheo/PGL probably accounts for a higher proportion of cases than previously thought; at least 30% are now believed to be familial. The corollary of this is that about 20 to 30 seemingly sporadic cases are likely familial. Given these statistics, genetic testing for index cases and family members should be considered.

Treatment consists of surgical tumor removal after pharmaceutical alpha-adrenergic blockade, which may be supplemented with beta blockade once the alpha blockade has been established. This preparation is aimed to prevent massive catecholamine surges during surgery.