A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine products in blood or urine. Imaging tests, especially CT or MRI, help localize tumors. Treatment involves removal of the tumor when possible. Drug therapy for control of BP includes alpha-blockade, usually combined with beta-blockade.
(See also Overview of Adrenal Function.)
The catecholamines secreted include norepinephrine, epinephrine, dopamine, and dopa in varying proportions. About 90% of pheochromocytomas are in the adrenal medulla, but they may also be located in other tissues derived from neural crest cells. Possible sites include the following:
Pheochromocytomas in the adrenal medulla occur equally in both sexes, are bilateral in 10% of cases (20% in children), and are malignant in < 10%. Of extra-adrenal tumors, 30% are malignant. Although pheochromocytomas occur at any age, peak incidence is between the 20s and 40s. About 25 to 30% are now thought to be due to germline mutations.
Pheochromocytomas vary in size but average 5 to 6 cm in diameter. They weigh 50 to 200 g, but tumors weighing several kilograms have been reported. Rarely, they are large enough to be palpated or cause symptoms due to pressure or obstruction. Regardless of the histologic appearance, the tumor is considered benign if it has not invaded the capsule and no metastases are found, although exceptions occur. In general, larger tumors are more likely to be malignant.
Pheochromocytomas may be part of the syndrome of familial multiple endocrine neoplasia (MEN) types 2A and 2B, in which other endocrine tumors (parathyroid or medullary carcinoma of the thyroid) coexist or develop subsequently. Pheochromocytoma develops in 1% of patients with neurofibromatosis (von Recklinghausen disease) and may occur with hemangioblastomas and renal cell carcinoma, as in von Hippel-Lindau disease. Familial pheochromocytomas and carotid body tumors may be due to mutations of the enzyme succinate dehydrogenase as well as of the genes responsible for other more recently described signaling molecules.
Hypertension, which is paroxysmal in 45% of patients, is prominent. About 1/1000 hypertensive patients has a pheochromocytoma. Common symptoms and signs are
Paroxysmal attacks may be provoked by palpation of the tumor, postural changes, abdominal compression or massage, induction of anesthesia, emotional trauma, unopposed beta-blockade (which paradoxically increases BP by blocking beta-mediated vasodilation), or micturition (if the tumor is in the bladder). In elderly patients, severe weight loss with persistent hypertension is suggestive of pheochromocytoma.
Physical examination, except for the presence of hypertension, is usually normal unless done during a paroxysmal attack. Retinopathy and cardiomegaly are often less severe than might be expected for the degree of hypertension, but a specific catecholamine cardiomyopathy can occur.
Pheochromocytoma is suspected in patients with typical symptoms or particularly sudden, severe, or intermittent unexplained hypertension. Diagnosis involves demonstrating high levels of catecholamine products in the serum or urine.
Plasma free metanephrine is up to 99% sensitive. This test has superior sensitivity to measurement of circulating epinephrine and norepinephrine because plasma metanephrines are elevated continuously, unlike epinephrine and norepinephrine, which are secreted intermittently. Grossly elevated plasma norepinephrine renders the diagnosis highly probable.
Urinary metanephrine is slightly less specific than plasma free metanephrine, but sensitivity is about 95%. Two or 3 normal results while the patient is hypertensive render the diagnosis extremely unlikely. Measurement of urinary norepinephrine and epinephrine is nearly as accurate. The principal urinary metabolic products of epinephrine and norepinephrine are the metanephrines, vanillylmandelic acid (VMA) and homovanillic acid (HVA). Healthy people excrete only very small amounts of these substances. Normal values for 24 h are as follows:
In pheochromocytoma, increased urinary excretion of epinephrine and norepinephrine and their metabolic products is intermittent. Elevated excretion of these compounds may also occur in other disorders (eg, neuroblastoma, coma, dehydration, sleep apnea) or extreme stress; in patients being treated with rauwolfia alkaloids, methyldopa, or catecholamines; or after ingestion of foods containing large quantities of vanilla (especially if renal insufficiency is present).
Blood volume is constricted and may falsely elevate Hb and Hct levels. Hyperglycemia, glycosuria, or overt diabetes mellitus may be present, with elevated fasting levels of plasma free fatty acid and glycerol. Plasma insulin level is inappropriately low for the plasma glucose. After removal of the pheochromocytoma, hypoglycemia may occur, especially in patients treated with oral antihyperglycemics.
Provocative tests with histamine or tyramine are hazardous and should not be used. Glucagon 0.5 to 1 mg injected rapidly IV provokes a rise in BP of > 35/25 mm Hg within 2 min in normotensive patients with pheochromocytoma but is now generally unnecessary. Phentolamine mesylate must be available to terminate any hypertensive crisis.
Screening tests are preferred to provocative tests. The general approach is to measure plasma or urinary metanephrines as a screening test and to avoid provocative tests. In patients with elevated plasma catecholamines, a suppression test using oral clonidine or IV pentolinium can be used but is rarely necessary.
Imaging tests to localize tumors are usually done in patients with abnormal screening results. Tests should include CT and MRI of the chest and abdomen with and without contrast. With isotonic contrast media, no adrenoceptor blockade is necessary. FDG-PET has also been used successfully, especially in patients with succinate dehydrogenase mutations.
Repeated sampling of plasma catecholamine concentrations during catheterization of the vena cava with sampling at different locations, including the adrenal veins, can help localize the tumor: there will be a step up in norepinephrine level in a vein draining the tumor. Adrenal vein norepinephrine:epinephrine ratios may help in the hunt for a small adrenal source, but determining these ratios is now rarely necessary.
Radiopharmaceuticals with nuclear imaging techniques can also help localize pheochromocytomas. MIBG is the most used compound; 0.5 mCi 123I-MIBG is injected IV, and the patient is scanned on days 1, 2, and 3. Normal adrenal tissue rarely picks up this isotope, but 85% of pheochromocytomas do. The imaging is usually positive only when the lesion is large enough to be obvious on CT or MRI, but it can help confirm that a mass is likely to be the source of the catecholamines. 131I-MIBG is a less sensitive alternative.
Signs of an associated genetic disorder (eg, café-au-lait patches in neurofibromatosis) should be sought. Patients should be screened for MEN with a serum calcitonin measurement and any other tests as directed by clinical findings. Many centers routinely do genetic testing, especially when pheochromocytoma involves the sympathetic paraganglia.
Surgical removal is the treatment of choice. The operation is usually delayed until hypertension is controlled by a combination of alpha-blockers and beta-blockers (usually phenoxybenzamine 20 to 40 mg po tid and propranolol 20 to 40 mg po tid). Beta-blockers should not be used until adequate alpha-blockade has been achieved. Some alpha-blockers, such as doxazosin, may be equally effective but better tolerated.
The most effective and safest preoperative alpha-blockade is phenoxybenzamine 0.5 mg/kg IV in 0.9% saline over 2 h on each of the 3 days before the operation, but oral phenoxybenzamine is usually very effective as long as 7 to 14 days are available for volume equilibration. Nitroprusside can be infused for hypertensive crises preoperatively or intraoperatively. When bilateral tumors are documented or suspected (as in a patient with MEN), sufficient hydrocortisone (100 mg IV bid) given before and during surgery avoids acute glucocorticoid insufficiency due to bilateral adrenalectomy.
Most pheochromocytomas can be removed laparoscopically. BP must be continuously monitored via an intra-arterial catheter, and volume status is closely monitored. Anesthesia should be induced with a nonarrhythmogenic drug (eg, a thiobarbiturate) and continued with an inhaled drug (eg, enflurane, isoflurane). During surgery, paroxysms of hypertension should be controlled with injections of phentolamine 1 to 5 mg IV or nitroprusside infusion (2 to 4 mcg/kg/min), and tachyarrhythmias should be controlled with propranolol 0.5 to 2 mg IV. If a muscle relaxant is needed, drugs that do not release histamine are preferred. Atropine should not be used preoperatively.
Preoperative blood transfusion (1 to 2 units) may be given before the tumor is removed in anticipation of blood loss. If BP has been well controlled before surgery, a diet high in salt is recommended to increase blood volume. An infusion of norepinephrine 4 to 12 mg/L in a dextrose-containing solution may be considered if hypotension develops. Some patients whose hypotension responds poorly to norepinephrine may benefit from hydrocortisone 100 mg IV, but adequate fluid replacement is usually all that is required.
Malignant metastatic pheochromocytoma should be treated with alpha-blockers and beta-blockers. The tumor may be indolent and survival long-lasting. However, even with rapid tumor growth, BP can be controlled. 131I-MIBG can help relieve symptoms in patients with residual disease. Metyrosine, a tyrosine hydroxylase inhibitor, may be used to decrease catecholamine production in patients whose BP is difficult to control. Radiation therapy may reduce bone pain. Chemotherapy is rarely effective, but the most common regimen tried is the combination of cyclophosphamide, vincristine, and dacarbazine. Recent data have shown some promising results with the chemotherapy agent temozolomide and targeted therapy with sunitinib.
Hypertension may be constant or episodic.
Diagnosis involves demonstrating high levels of catecholamine products (typically metanephrine) in the serum or urine.
Tumors should be localized with imaging tests, sometimes using radiolabeled compounds.
A combination of alpha-blockers and beta-blockers are given pending tumor removal.