The only syndrome in this category is produced by pheochromocytomas. Pheochromocytoma is a tumor of the adrenal medulla that frequently secretes epinephrine or norepinephrine. This causes hypertension, which may be continuous (about 30% of patients) or in short episodes (paroxysmal). Although rare, pheochromocytoma is one of the few curable causes of hypertension and so should be considered as a possible etiology in any patient with hypertension of either sudden or recent onset. This is especially true for young or middle-aged persons.

Approximately 90% of pheochromocytomas in adults arise in the adrenal (more often in the right adrenal). Of the 10% that are extraadrenal, the great majority are located in the abdomen, with 1%-2% in the thorax and neck. Extraadrenal abdominal tumors are usually found in the paraaortic sympathetic nerve chain (below the level of the renal artery), but perhaps one third are located in the remnants of the organ of Zuckerkandl (which is situated in the paraaortic region between the origin of the inferior mesenteric artery and the bifurcation of the aorta). About 20% of pheochromocytomas are multiple and about 10% are bilateral. Approximately 5%-10% (range, 3%-14%) of all pheochromocytomas are malignant, but the malignancy rate for extraadrenal abdominal tumors is reported to be about 25%-30%. Although hypertension is the most common significant clinical finding, 10%-20% of pheochromocytomas do not produce hypertension (Table 30-3). Hyperglycemia is reported in about 50% of patients. In one autopsy series of 54 cases, only 25% were diagnosed during life.

Common signs and symptoms of pheochromocytoma

Table 30-3 Common signs and symptoms of pheochromocytoma

About 5% of pheochromocytoma patients have neurofibromatosis, and in 5%-10% the pheochromocytoma is associated with the multiple endocrine neoplasia (MEN) syndrome type II (also known as “IIA,” with medullary carcinoma of the thyroid) or III (also known as “IIB,” with mucosal neuromas). The MEN syndrome pheochromocytomas are bilateral in 50%-95% of cases and multiple in about 70% of cases, whereas nonfamilial (sporadic) pheochromocytomas are usually unilateral and are multiple in about 20% of cases. About 5% of the familial cases are said to be malignant.

In children, extraadrenal pheochromocytomas are more common (30% of cases), more often bilateral (25%-70% of cases), and more often multiple (about 30% of cases) than in adults. About 10%-20% of adrenal or extraadrenal childhood pheochromocytomas are reported to be malignant.

Tests for pheochromocytoma

Regitine test. The first tests for pheochromocytomas were pharmacologic, based on neutralization of epinephrine effects by adrenergic-blocking drugs such as Regitine. After basal blood pressure has been established, 5 mg of Regitine is given intravenously, and the blood pressure is checked every 30 seconds. The result is positive if systolic blood pressure decreases more than 35 mm Hg or diastolic pressure decreases 25 mm Hg or more and remains decreased 3-4 minutes. Laboratory tests have proved much more reliable than the pharmacologic procedures, which yield an appreciable percentage of false positives and negatives.

Clonidine suppression test. Clonidine is a centrally acting alpha-adrenergic agonist that inhibits sympathetic nervous system catecholamine release from postganglionic neurons. The patients should not be on hypertensive medication (if possible) for at least 12 hours before the test. After a baseline blood specimen is obtained, a single 0.3-mg oral dose of clonidine is administered and a second blood specimen is drawn 3 hours later. Most patients without pheochromocytoma had postdose plasma norepinephrine values more than 50% below baseline and plasma catacholamine values less than 500 pg/ml. Most patients with pheochromocytoma showed little change in plasma norepinephrine values between the predose and postdose specimens and had a plasma catacholamine postdose level greater than 500 pg/ml. Apparently, better results are obtained when baseline urine norepinephrine values are greater than 2000 pg/ml (86%-99% sensitivity) than when the baseline value is less than 2000 pg/ml (73%-97% sensitivity). Medication such as tricyclic antidepressants, thiazide diuretics, and beta blockers may interfere with the test.

Catecholamine/vanillylmandelic acid/metanephrine assay. The catecholamines epinephrine and norepinephrine are excreted by the kidney, about 3%-6% free (unchanged), and the remainder as various metabolites. Of these metabolic products, the major portion is vanillylmandelic (vanilmandelic) acid (VMA), and the remainder (about 20%-40%) is compounds known as metanephrines. Therefore, one can measure urinary catecholamines, metanephrines, or VMA. Of these, urine metanephrine assay is considered by many to be the most sensitive and reliable single test. There are also fewer drugs that interfere.

Most investigators report that urine metanephrine assay detects about 95% (range, 77%-100%) of patients with pheochromocytoma. Sensitivity of urine catecholamines is approximately 90%-95% (range, 67%-100%) and that of urine VMA assay is also about 90%-95% (range, 50%-100%). One report indicates that metanephrine excretion is relatively uniform and that a random specimen reported in terms of creatinine excretion can be substituted for the usual 24-hour collection in screening for pheochromocytoma. Methylglucamine x-ray contrast medium is said to produce falsely normal urine metanephrine values for up to 72 hours. One report found that 10%-15% of mildly elevated urine metanephrine values were falsely positive due to medications (such as methyldopa) or other reasons.

Although the metanephrine excretion test is slowly gaining preference, VMA and catecholamine assay are still widely used. All three methods have detection rates within 5%-10% of one another. A small but significant percentage of pheochromocytomas are missed by any of the three tests (fewer by metanephrine excretion), especially if the tumor secretes intermittently. The VMA test has one definite advantage in that certain screening methods are technically more simple than catecholamine or metanephrine assay and therefore are more readily available in smaller laboratories. The VMA screening methods are apt to produce more false positive results, however, so that abnormal values (or normal results in patients with strong suspicion for pheochromocytoma) should be confirmed by some other procedure.

Catecholamine production and plasma catecholamine levels may be increased after severe exercise (although mild exercise has no appreciable effect), by emotional stress, and by smoking. Uremia interferes with assay methods based on fluorescence. Other diseases or conditions that may increase plasma or urine catecholamines or urine catecholamine metabolites are hypothyroidism, diuretic therapy, heavy alcohol intake, hypoglycemia, hypoxia, severe acidosis, Cushing’s syndrome, myocardial infarction, hemolytic anemia, and occasionally lymphoma or severe renal disease. In addition, bananas, coffee, and various other foods as well as certain medications may produce falsely elevated results. These foods or medications produce appreciable numbers of false-positive results in some of the standard screening techniques for VMA. An abnormal result with the “screening” VMA techniques should be confirmed by some other VMA method. Although other VMA methods or methods for metanephrine and catecholamine assay are more reliable, they too may be affected by certain foods or medications, so it is best to check with individual laboratories for details on substances that affect their particular test method. Reports differ on whether some patients with essential hypertension may have elevated serum or urine catecholamine or catecholamine metabolite results; and if so, how often it occurs and what percentage are due to conditions known to elevate catecholamines, or to medications, or to unknown causes.

Some investigators use urine fractionated catecholamines (epinephrine and norepinephrine, sometimes also dopamine) by high-pressure liquid chromatography as a confirmatory test for pheochromocytoma. It is said that about 50%-70% of pheochromocytomas produce epinephrine, about 75%-85% produce norepinephrine, and about 95% produce one or the other.

Plasma catecholamine assay. Several investigators report better sensitivity in pheochromocytoma with plasma catecholamine assay than with the particular urine metabolite assays they were using. Another advantage is the simplicity of a single blood specimen versus 24-hour collection. However, upright posture and stress can greatly affect plasma catecholamine levels, even the stress of venipuncture, so it is best to draw the specimen in the early morning before the patient rises. Even then, some advocate placement of an indwelling venous catheter or heparinized scalp vein apparatus with an interval of 30 minutes between insertion of the catheter and withdrawal of the blood specimen. One investigator reported that plasma catecholamine values decreased rapidly if the red blood cells (RBCs) were not removed within 5 minutes after obtaining the specimen. Placing the specimen on ice was helpful but only partially retarded RBC catecholamine uptake. Plasma catecholamine assay detection rate in pheochromocytomas is about 90% (literature range, 53%-100%). Failure to detect the tumor in some instances is due to intermittent tumor secretion. Urine collection has the advantage of averaging the 24-hour excretion.

Tumor localization methods. Once pheochromocytoma is strongly suspected by results of biochemical testing, certain procedures have been useful in localizing the tumor. Intravenous pyelography with nephrotomography is reported to have an accuracy of about 70% in detecting adrenal pheochromocytoma. CT has been reported to detect 85%-95% (range, 84%-over 95%) of pheochromocytomas, including some in extraadrenal locations. Consensus now is that CT (or magnetic resonance imaging [MRI]) is the best single localization test (better than ultrasound). Radioactive mIBG has been used to locate pheochromocytomas and other neural tumors with sensitivity of about 85%. However, this procedure is only available in a very few nuclear medicine centers. Angiographic procedures are reported to detect 60%-84% of pheochromocytomas; but angiography is somewhat controversial because it is invasive, because it yields about 10% false negative results in adrenal tumors, and because some investigators believe that the incidence of tumor bilaterality warrants exploration of both sides of the abdomen regardless of angiographic findings.

Miscellaneous procedures. Serum chromogranin A (CgA), a substance produced in the adrenal medulla and some other endocrine and neuroendocrine tissues and tumors, has been used in diagnosis of pheochromocytoma. CgA is not affected by posture, venipuncture, and many medications that interfere with catecholamine assay; in one series CGA detected 86% of pheochromocytomas.

Deoxyribonucleic acid (DNA) analysis by flow cytometry in small numbers of patients suggest that pheochromocytomas with diploid ploidy are most often (but not always) benign, whereas those that are aneuploid are most often (but not always) malignant.

Serum neuron-specific enolase (NSE) in small numbers of patients suggest that pheochromocytomas with normal NSE levels are usually benign, but those with elevated values are often malignant.