These symptoms are often paroxysmal, although sustained hypertension in between paroxysmal episodes occurs in 50% to 60% of patients with pheochromocytoma. Symptoms of catecholamine excess can be spontaneous or induced by a variety of events, including the following:
- Strenuous physical exertion.
- Labor and delivery.
- Anesthesia induction.
- Surgery or other invasive procedures, including direct instrumentation of the tumor (e.g., fine-needle aspiration).
- Foods high in tyramine (e.g., red wine, chocolate, and cheese).
- Urination (e.g., bladder wall tumor, which is rare).
Episodes of hypertension can be variable in frequency, severity, and duration and are often extremely difficult to manage medically. Hypertensive crisis can lead to cardiac arrhythmias, myocardial infarction, and even death.
Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines and usually present as a neck mass with symptoms related to compression or are incidentally discovered on an imaging study performed for an unrelated reason. In addition, approximately half of patients with pheochromocytoma are asymptomatic because their neoplasms are discovered in the presymptomatic state by either abdominal imaging for other reasons (e.g., adrenal incidentalomas) or genetic testing in at-risk family members.[20,21,22,23]
The diagnosis of pheochromocytoma is established by biochemical testing to document excess catecholamine secretion. Controversy exists as to the optimal single test to make the diagnosis. Measurement of plasma-free fractionated metanephrines (e.g., metanephrine and normetanephrine) has a high sensitivity (97%-99%) but a relatively low specificity (85%).
A 24-hour urine collection for catecholamines (e.g., epinephrine, norepinephrine, and dopamine) and fractionated metanephrines (e.g., metanephrine and normetanephrine) has a relatively low sensitivity (77%-90%) but a high specificity (98%). Pretest probability is also important. The specificity of plasma-free fractionated metanephrines is 82% in patients tested for sporadic pheochromocytoma versus 96% in patients tested for hereditary pheochromocytoma.[24,25]
Measurement of plasma-free fractionated metanephrines appears to be an ideal case detection test for patients at higher baseline risk of pheochromocytoma. Examples of these patients might include the following:
- Patients with an incidentally discovered adrenal mass.
- Patients with a family history of pheochromocytoma.
- Patients with a known inherited predisposition to pheochromocytoma.
The test is associated with a relatively high false-positive rate in patients with a lower baseline risk of pheochromocytoma.
In general, it is reasonable to use measurement of plasma-free fractionated metanephrines for initial case detection, which is followed by 24-hour measurement of urine-fractionated metanephrines and catecholamines for confirmation. Test results can be difficult to interpret because of the false-positive results. False-positive results can be caused by any of the following:[19,24]
- Common medications (e.g., tricyclic antidepressants).
- Physical or emotional stress.
- Inappropriately low reference ranges based on normal laboratory data rather than clinical data sets.
A mildly elevated catecholamine or metanephrine level is usually the result of assay interference caused by drugs or other factors. Patients with symptomatic pheochromocytoma almost always have increases in catecholamines or metanephrines two to three times higher than the upper limits of reference ranges. Provocative testing (e.g., using glucagon) can be dangerous, adds no value to other current testing methods, and is not recommended.