The diagnosis is based on documentation of catecholamine excess by biochemical testing and localization of the tumor by imaging. These two criteria are of equal importance, although measurement of catecholamines or metanephrines (their methylated metabolites) is traditionally the first step in diagnosis.
Pheochromocytomas and paragangliomas synthesize and store catecholamines, which include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. Elevated plasma and urinary levels of catecholamines and metanephrines form the cornerstone of diagnosis. The characteristic fluctuations in the hormonal activity of tumors results in considerable variation in serial catecholamine measurements. However, most tumors continuously leak O-methylated metabolites, which are detected by measurement of metanephrines.
Catecholamines and metanephrines can be measured by different methods, including high-performance liquid chromatography, enzyme-linked immunosorbent assay, and liquid chromatography/mass spectrometry. When pheochromocytoma is suspected on clinical grounds (i.e., when values are three times the upper limit of normal), this diagnosis is highly likely regardless of the assay used. However, as summarized in Table 9-2, the sensitivity and specificity of available biochemical tests vary greatly, and these differences are important in assessing patients with borderline elevations of different compounds. Urinary tests for metanephrines (total or fractionated) and catecholamines are widely available and are used commonly for initial evaluation. Among these tests, those for the fractionated metanephrines and catecholamines are the most sensitive. Plasma tests are more convenient and include measurements of catecholamines and metanephrines. Measurements of plasma metanephrine are the most sensitive and are less susceptible to false-positive elevations from stress, including venipuncture. Although the incidence of false-positive test results has been reduced by the introduction of newer assays, physiologic stress responses and medications that increase catecholamine levels still can confound testing. Because the tumors are relatively rare, borderline elevations are likely to represent false-positive results. In this circumstance, it is important to exclude dietary or drug-related factors (withdrawal of levodopa or use of sympathomimetics, diuretics, tricyclic antidepressants, alpha and beta blockers) that might cause false-positive results and then to repeat testing or perform a clonidine suppression test (i.e., the measurement of plasma normetanephrine 3 h after oral administration of 300 μg of clonidine). Other pharmacologic tests, such as the phentolamine test and the glucagon provocation test, are of relatively low sensitivity and are not recommended.
TABLE 9-2Biochemical and Imaging Methods Used for Diagnosis of Pheochromocytoma and Paraganglioma ||Download (.pdf) TABLE 9-2 Biochemical and Imaging Methods Used for Diagnosis of Pheochromocytoma and Paraganglioma
|DIAGNOSTIC METHOD ||SENSITIVITY ||SPECIFICITY |
|24-h urinary tests || || |
| Catecholamines ||+++ ||+++ |
| Fractionated metanephrines ||++++ ||++ |
| Total metanephrines ||+++ ||++++ |
|Plasma tests || || |
| Catecholamines ||+++ ||++ |
| Free metanephrines ||++++ ||+++ |
|Imaging || || |
| CT ||++++ ||+++ |
| MRI ||++++ ||+++ |
|MIBG scintigraphy ||+++ ||++++ |
|Somatostatin receptor scintigraphya ||++ ||++ |
|18Fluoro-DOPA PET/CT ||+++ ||++++ |
A variety of methods have been used to localize pheochromocytomas and paragangliomas (Table 9-2). CT and MRI are similar in sensitivity and should be performed with contrast. T2-weighted MRI with gadolinium contrast is optimal for detecting pheochromocytomas and is somewhat better than CT for imaging extraadrenal pheochromocytomas and paragangliomas. About 5% of adrenal incidentalomas, which usually are detected by CT or MRI, prove to be pheochromocytomas upon endocrinologic evaluation.
Tumors also can be localized by procedures using radioactive tracers, including 131I- or 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 111In-somatostatin analogue scintigraphy, 18F-DOPA positron emission tomography (PET), or 18F-fluorodeoxyglucose (FDG) PET. Because these agents exhibit selective uptake in paragangliomas, nuclear imaging is particularly useful in the hereditary syndromes.
When the possibility of a pheochromocytoma is being entertained, other disorders to consider include essential hypertension, anxiety attacks, use of cocaine or amphetamines, mastocytosis or carcinoid syndrome (usually without hypertension), intracranial lesions, clonidine withdrawal, autonomic epilepsy, and factitious crises (usually from use of sympathomimetic amines). When an asymptomatic adrenal mass is identified, likely diagnoses other than pheochromocytoma include a nonfunctioning adrenal adenoma, an aldosteronoma, and a cortisol-producing adenoma (Cushing’s syndrome).
Complete tumor removal, the ultimate therapeutic goal, can be achieved by partial or total adrenalectomy. It is important to preserve the normal adrenal cortex, particularly in hereditary disorders in which bilateral pheochromocytomas are most likely. Preoperative preparation of the patient is important. Before surgery, blood pressure should be consistently below 160/90 mmHg. Classically, blood pressure has been controlled by α-adrenergic blockers (oral phenoxybenzamine, 0.5–4 mg/kg of body weight). Because patients are volume-constricted, liberal salt intake and hydration are necessary to avoid severe orthostasis. Oral prazosin or intravenous phentolamine can be used to manage paroxysms while adequate alpha blockade is awaited. Beta blockers (e.g., 10 mg of propranolol three or four times per day) can then be added. Other antihypertensives, such as calcium channel blockers or angiotensin-converting enzyme inhibitors, have also been used effectively.
Surgery should be performed by teams of surgeons and anesthesiologists with experience in the management of pheochromocytomas. Blood pressure can be labile during surgery, particularly at the outset of intubation or when the tumor is manipulated. Nitroprusside infusion is useful for intraoperative hypertensive crises, and hypotension usually responds to volume infusion.
Minimally invasive techniques (laparoscopy or retroperitoneoscopy) have become the standard approaches in pheochromocytoma surgery. They are associated with fewer complications, a faster recovery, and optimal cosmetic results. Extra-adrenal abdominal and most thoracic pheochromocytomas also can also be removed endoscopically. Postoperatively, catecholamine normalization should be documented. An adrenocorticotropic hormone test should be used to exclude cortisol deficiency when bilateral adrenal cortex–sparing surgery has been performed.