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.
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.
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.
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, -blockers, and
micturition if the tumor is in the bladder.
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.
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
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.
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.
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.
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.
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 - and -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
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 -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 -
and -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.
metastatic pheochromocytoma should be treated with -
and -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.
The Merck Manual of Diagnosis and
Therapy, Edition 17, edited by Mark H. Beers and Robert Berkow.
Copyright 1999 by Merck & Co., Inc., Whitehouse
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