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Pheochromocytoma

A tumor of chromaffin cells that secrete catecholamines, causing hypertension.

In about 80% of cases, pheochromocytomas are found in the adrenal medulla, but they may also be found in other tissues derived from neural crest cells. Those in the adrenal medulla appear equally in both sexes, are bilateral in 10% of cases (20% in children), and are usually benign (95%). Extra-adrenal tumors are more often malignant (30%). Although pheochromocytomas may occur at any age, the maximum incidence is between the 3rd and 5th decades.

Pathology

Pheochromocytomas vary in size but average only 5 to 6 cm in diameter. They usually 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. The tumor is usually a well-encapsulated nest of chromaffin cells that appear malignant upon microscopic examination. The cells have many bizarre shapes with pyknotic, large, or multiple nuclei. Regardless of the histologic appearance, the tumor may be considered benign if it has not invaded the capsule and if no metastases are found. In addition to the adrenals, tumors may be found in the paraganglia of the sympathetic chain, retroperitoneally along the course of the aorta, in the carotid body, in the organ of Zuckerkandl (at the aortic bifurcation), in the GU system, in the brain, in the pericardial sac, and in dermoid cysts.

Pheochromocytomas are part of the syndrome of familial multiple endocrine neoplasia, type IIA (Sipple's syndrome) and may be associated with medullary thyroid carcinoma and parathyroid adenomas. A type III syndrome has been described, which includes pheochromocytoma, mucosal (oral and ocular) neuromas, and medullary thyroid carcinoma. There is a significant association (10%) with neurofibromatosis (von Recklinghausen disease), and it may be found with hemangiomas, as in von Hippel-Lindau disease.

Symptoms and Signs

The most prominent feature is hypertension, which may be paroxysmal (45%) or persistent (50%) and is rarely absent (5%). About 1/1000 hypertensive patients has a pheochromocytoma. The hypertension is due to secretion of one or more of the catecholamine hormones or precursors: norepinephrine, epinephrine, dopamine, or dopa. Common symptoms and signs are tachycardia, diaphoresis, postural hypotension, tachypnea, flushing, cold and clammy skin, severe headache, angina, palpitation, nausea, vomiting, epigastric pain, visual disturbances, dyspnea, paresthesias, constipation, and a sense of impending doom. Paroxysmal attacks may be provoked by palpation of the tumor, postural changes, abdominal compression or massage, induction of anesthesia, emotional trauma, beta-blockers, and micturition if the tumor is in the bladder.

Physical examination, except for the common finding of hypertension, is usually normal, unless performed during a paroxysmal attack. The severity of retinopathy and cardiomegaly is often less extensive than might be expected for the degree of hypertension present.

Diagnosis

The principal urinary metabolic products of epinephrine and norepinephrine are the metanephrines, vanillylmandelic acid (VMA), and homovanillic acid (HVA). Normal persons excrete only very small amounts of these substances in the urine. Normal values for 24 h are as follows: free epinephrine and norepinephrine < 100 µg (< 582 nmol), total metanephrine < 1.3 mg (< 7.1 µmol), VMA < 10 mg (< 50 µmol), and HVA < 15 mg (< 82.4 µmol). In pheochromocytoma and neuroblastoma, urinary excretion of epinephrine and norepinephrine and of their metabolic products increases intermittently. However, excretion of these compounds may also be elevated in coma, dehydration, or extreme stress states; 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. All of these compounds may be measured in the same urine specimen.

The methods for detection of VMA and metanephrines depend on the conversion to vanillin, the extraction of vanillin into toluene, and the final spectrophotometric determination of vanillin at 360 mµ. Catecholamines (mainly epinephrine and norepinephrine) are measured fluorometrically after extraction and adsorption on alumina gel. Interference from epinephrine-like drugs, antihypertensives (eg, methyldopa), and other drugs that produce fluorescence (eg, tetracycline and quinine) must be considered in the evaluation of abnormal results. High-performance liquid chromatography techniques are also available, as are radioenzymatic procedures, although usually as research tools.

Plasma catecholamine levels are usually valueless unless a blood specimen is obtained during a paroxysm or after administration of a drug such as glucagon, which provokes the release of catecholamines, or clonidine, which lowers catecholamine levels in normal persons (see below).

Because of their hyperkinetic states, these patients may appear hyperthyroid despite being euthyroid. Blood volume is constricted and may falsely elevate Hb and Hct levels. Hyperglycemia, glucosuria, or overt diabetes mellitus may be present, with elevated fasting levels of plasma free fatty acid and glycerol. Plasma insulin levels are inappropriately low for the simultaneously collected plasma glucose levels. After removal of the pheochromocytoma, hypoglycemia may occur, especially if the patient was treated with oral hypoglycemic drugs.

Provocative tests with histamine or tyramine are hazardous and should not be used. Glucagon (0.5 to 1 mg injected rapidly IV) will provoke a rise in BP > 35/25 mm Hg within 2 min in normotensive patients with pheochromocytoma. Phentolamine mesylate must be available to terminate any hypertensive crisis.

If a patient with pheochromocytoma is hypertensive, phentolamine 5 mg injected IV will cause a fall in BP > 35/25 mm Hg within 2 min. False-positive results occur in patients with uremia, stroke, and malignant hypertension and in those taking certain drugs, including diuretics, perhaps by decreasing plasma volume, and phenothiazines, perhaps by blocking catecholamine reuptake; phenothiazines can also cause hypertensive crisis. A modification of this test has been developed that takes advantage of catecholamine inhibition of insulin release. An IV infusion of 10% D/W is begun (2 mL/min) 30 min before injection of phentolamine. (Blood is sampled twice for measurement of glucose and insulin before injection.) After phentolamine administration, the BP is measured at 30-sec intervals for 3 min, and blood is again sampled. Pheochromocytoma is present if there is a fall in BP >= 35/25 mm Hg, a fall in glucose > 18 mg/dL (> 1 mmol/L), or a rise in insulin > 13 µU/mL (> 90 pmol/L).

A test using oral clonidine has been described. Forty-eight hours after discontinuing all drugs that act on the sympathetic nervous system, the patient is given 0.3 mg clonidine. Blood is drawn for plasma catecholamine determinations before and 3 h after the administration of clonidine. The normal response is a fall of plasma norepinephrine values to normal (< 400 pg/mL [< 2364 pmol/L]) and a fall of at least 40% from basal values. Patients with pheochromocytoma maintain elevated values.

Attempts to localize tumors by x-ray should be limited to multiple views of the chest and abdomen. CT and MRI may be useful, with and without contrast. Positron emission tomography has also been used successfully. IV pyelography with tomography of the perirenal areas should be used only if the previous modalities are unavailable. Phlebography, aortography, and retroperitoneal gas insufflation are contraindicated, as they may induce a serious or fatal paroxysm. Localization of the tumor's level by repeated sampling of plasma catecholamine concentrations during catheterization of the vena cava has been achieved but is also potentially dangerous. Recently, radiopharmaceuticals have been used to localize pheochromocytomas with nuclear imaging techniques. 131I-metaiodobenzylguanidine (MIBG) is the most studied compound; 0.5 mCi is injected IV and the patient is scanned on days 1, 2, and 3. Normal adrenal tissue rarely picks up this isotope, but 90% of pheochromocytomas do.

Treatment

Surgical removal of the tumor is the treatment of choice. The operation can usually be delayed until the patient is restored to optimal physical condition by the use of a combination of alpha- and beta-blockers (phenoxybenzamine, 40 to 160 mg/day, and propranolol, 30 to 60 mg/day, respectively, po in divided doses). The infusion of trimethaphan camsylate or sodium nitroprusside can be used for hypertensive crises pre- or intraoperatively. When adrenergic-blocking drugs are used, the alpha compounds are usually begun first. When bilateral tumors are documented or suspected (as in a patient with multiple endocrine neoplasia), sufficient hydrocortisone (100 mg IV bid) should be given before and during surgical treatment to avoid glucocorticoid insufficiency.

Metyrosine may be used alone or in combination with an alpha-blocker (phenoxybenzamine); the optimally effective dosage of metyrosine, 1 to 4 g/day in divided doses, should be given for at least 5 to 7 days before the operation. Labetalol, a drug with both alpha- and beta-adrenergic receptor blocking properties, can be given orally, starting at 200 mg/day in divided doses. Rarely, labetalol aggravates hypertension in patients with pheochromocytoma.

An anterior abdominal approach should be used by the surgeon, even if the tumor has been localized in the renal area, so that a search for other pheochromocytomas can be made. BP must be continuously monitored via an intra-arterial catheter, and central venous pressure must be continuously measured to avoid a fall in blood volume. Anesthesia should be induced with a nonarrhythmogenic drug, such as a thiobarbiturate, and continued with enflurane. During surgery, paroxysms of hypertension should be controlled with direct IV injections of phentolamine 1 to 5 mg or nitroprusside infusion (2 to 4 µg/kg/h will usually suffice), and tachyarrhythmias with propranolol 0.5 to 2 mg IV. Ventricular ectopy should be treated with lidocaine, 50 to 100 mg given by rapid IV injection followed by an infusion of 2 to 4 mg/min as required. If a muscle relaxant is needed, pancuronium, which does not release histamine, is the drug of choice. The use of atropine preoperatively should be avoided. One to two units (500 to 1000 mL) of blood should be given before the tumor is removed, in anticipation of probable operative loss. If the BP has been well controlled before the operation, a diet high in salt is recommended to increase blood volume. An infusion of levarterenol 4 to 12 mg/L should be started any time hypotension appears. Some patients whose hypotension responds poorly to levarterenol may benefit by the addition of hydrocortisone 100 mg IV.

Malignant metastatic pheochromocytoma should be treated with alpha- and beta-blockers and with metyrosine. The latter drug inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis. Thus, levels of VMA and BP fall. BP can be controlled even though the tumor growth continues and will eventually cause death. Combination chemotherapy using cyclophosphamide, vincristine, and dacarbazine is the best treatment for metastases. Experimentally, 131I-MIBG has been used to treat large metastases. Radiotherapy may reduce bone pain but is generally ineffective.

From The Merck Manual of Diagnosis and Therapy, Edition 17, edited by Mark H. Beers and Robert Berkow. Copyright 1999 by Merck & Co., Inc., Whitehouse Station, NJ.

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