(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, known as paragangliomas, 30% are malignant. Although pheochromocytomas occur at any age, peak incidence is between the 20s and 40s. Nearly 50% are 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 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 in genes encoding the enzyme succinate dehydrogenase or other 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 blood pressure by blocking beta-mediated vasodilation), or micturition (if the tumor is in the bladder). In older 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. However, cardiac and cerebrovascular events are more frequent in patients with pheochromocytomas than in others with similar blood-pressure levels.
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 hours 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)
Patients being treated with rauwolfia alkaloids, methyldopa, monoamine oxidase inhibitors, or catecholamines
Ingestion of foods containing large quantities of VMA
Blood volume is constricted and may falsely elevate hemoglobin and hematocrit 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 blood pressure of > 35/25 mm Hg within 2 minutes 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. Fluorodeoxyglucose (FDG)-PET has also been used successfully, especially in patients with succinate dehydrogenase mutations, but Gallium-68 dotatate PET scanning is proving to be more useful.
During catheterization of the vena cava, repeated sampling of plasma catecholamine concentrations 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. Radionuclide imaging is rapidly advancing and increasingly I-123 MIBG is being replaced by Gallium-68 dotatate PET scanning.
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 the 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 orally 3 times a day and propranolol 20 to 40 mg orally 3 times a day). One should aim for blood pressure of < 130/80 mmHg; some suggest the target should also include achieving a certain postural drop in pressure, but this is not essential. Re-equilibration of the cardiovascular system requires about 10 to 14 days, after which one can assume that the blockade is effective. 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. Nitroprusside can be infused for hypertensive crises preoperatively or intraoperatively.
When bilateral tumors are documented or suspected (as in a patient with multiple endocrine neoplasia [MEN]), sufficient hydrocortisone (100 mg IV twice a day) given before and during surgery avoids acute glucocorticoid insufficiency due to bilateral adrenalectomy.
Most pheochromocytomas can be removed laparoscopically. Blood pressure 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/minute), 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 blood pressure 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, blood pressure can be controlled. I-131 MIBG or more recently lutetium-177 dotatate can help relieve symptoms in patients with residual disease. Metyrosine, a tyrosine hydroxylase inhibitor, may be used to decrease catecholamine production in patients whose blood pressure is difficult to control. Radiation therapy may reduce bone pain due to metastases. 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 plasma free metanephrines in the serum or 24-hour metanephrines in the 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.