Pheochromocytomas are tumors of the adrenal medulla that produce, store, and secrete catecholamines. They are usually derived from the adrenal medulla but may develop from chromaffin cells in or about sympathetic ganglia (extraadrenal pheochromocytomas or paragangliomas).
The clinical features are mainly due to the release of catecholamines and, to a lesser extent, to the secretion of other substances. Hypertension is the most common sign, and hypertensive paroxysms or crises, often spectacular and alarming, occur in over half the cases.
PATHOLOGY
Location and Morphology
In adults, approximately 80% of pheochromocytomas are unilateral and sol Solitary lesions inexplicably favor the right side. Although pheochromocytomas may grow to large size (over 3 kg), most weigh less than 100 g and are less than 10 cm in diameter. The tumors are highly vascular, 10% are bilateral, and 10% are extraadrenal.
The tumors are made up of large, polyhedral, pleomorphic chromaffin cells. Less than 10% of these tumors are malignant. As with other endocrine tumors, malignancy cannot be determined from the histologic appearance; tumors that contain large numbers of aneuploid or tetraploid cells, as determined by flow cytometry, are more likely to recur. Local invasion of surrounding tissues or distant metastases indicate malignancy.
Catecholamine Synthesis, Storage, and Release
Pheochromocytomas synthesize and store catecholamines by processes resembling those of the normal adrenal medulla. These tumors are not innervated, and catecholamine release does not result from neural stimulation. Pheochromocytomas also store and secrete a variety of peptides, including endogenous opioids, adrenomedullin, endothelin, erythropoietin, parathyroid hormone-related protein, neuropeptide Y, and chromagranin A. These peptides contribute to the clinical manifestations in selected cases.
Most pheochromocytomas contain and secrete both norepinephrine and epinephrine, and the percentage of norepinephrine is usually greater than in the normal adrenal. Increased production of dopamine and homovanillic acid (HVA) is uncommon with benign lesions but may occur with malignant pheochromocytoma.
FAMILIAL PHEOCHROMOCYTOMA
In approximately 5% of cases, pheochromocytoma is inherited as an autosomal dominant trait either alone or in combination with other abnormalities such as MEN type 2a (Sipple's syndrome) or type 2b (mucosal neuroma syndrome), von Hippel-Lindau's retinal cerebellar hemangioblastomosis, or von Recklinghausen's neurofibromatosis.
A familial syndrome should be suspected in any patient with bilateral pheochromocytomas.
CLINICAL FEATURES
Pheochromocytoma occurs at all ages but is most common in young to midadult life. Most patients come to medical attention as a result of hypertensive crisis, paroxysmal symptoms suggestive of seizure disorder or anxiety attacks, or hypertension that responds poorly to conventional treatment. Most patients have hypertension in association with headaches, excessive sweating, and/or palpitations.
Hypertension Hypertension is the most common manifestation. In approximately 60% of cases the hypertension is sustained, although significant blood pressure lability is usually present, and half of patients with sustained hypertension have distinct crises or paroxysms. The other 40% have blood pressure elevations only during an attack. The hypertension is often severe, occasionally malignant, and may be resistant to treatment with standard antihypertensive drugs.
Paroxysms or Crises The paroxysm or crisis occurs in over half of patients. In an individual patient, the symptoms are often similar with each attack. The paroxysms may be frequent or sporadic, occurring at intervals as long as weeks or months. With time, the paroxysms usually increase in frequency, duration, and severity. The attack usually has a sudden onset. It may last from a few minutes to several hours or longer. Headache, profuse sweating, palpitations, and apprehension, often with a sense of impending doom, are common. Pain in the chest or abdomen may be associated with nausea and vomiting. Either pallor or flushing may occur during the attack. The blood pressure is elevated, often to alarming levels, and the elevation is usually accompanied by tachycardia. The paroxysm may be precipitated by any activity that displaces the abdominal contents. In some cases a particular stimulus may induce an attack in a characteristic fashion, but in others no clearly defined precipitating event can be found. Although anxiety may accompany the attacks, mental or psychological stress does not usually provoke a crisis.
Other Distinctive Clinical Features Symptoms and signs of an increased metabolic rate, such as profuse sweating and mild to moderate weight loss, are common. Orthostatic hypotension is a consequence of diminished plasma volume and blunted sympathetic reflexes. Both these factors predispose the patient with unsuspected pheochromocytoma to hypotension or shock during surgery or trauma. Secretion of the hypotensive peptide adrenomedullin may contribute to the hypotension in some patients.
Cardiac Manifestations Sinus tachycardia, sinus bradycardia, supraventricular arrhythmias, and ventricular premature contractions all have been noted. Angina and acute myocardial infarction may occur even in the absence of coronary artery disease. A catecholamine-induced increase in myocardial oxygen consumption and, perhaps, coronary spasm may play a role in these ischemic events. Electrocardiographic changes, including nonspecific ST-T wave changes, prominent U waves, left ventricular strain patterns, and right and left bundle branch blocks may be present in the absence of demonstrable ischemia or infarction. Cardiomyopathy, either congestive with myocarditis and myocardial fibrosis or hypertrophic with concentric or asymmetric hypertrophy, may be associated with heart failure and cardiac arrhythmias. Multiorgan system failure with noncardiogenic pulmonary edema may be the presenting manifestation. Elevated levels of amylase originating from damaged pulmonary endothelium and abdominal pain may suggest acute pancreatitis, although serum lipase levels are normal.
Carbohydrate Intolerance Over half of patients have impaired carbohydrate tolerance due to suppression of insulin and stimulation of hepatic glucose output. The impaired glucose tolerance rarely requires treatment with insulin and disappears after removal of the tumor.
Hematocrit The elevated hematocrit is secondary to diminished plasma volume. Rarely, production of erythropoietin by the tumor may cause a true erythrocytosis
Other Manifestations Hypercalcemia has been attributed to the ectopic secretion of parathyroid hormone-related protein. Fever and an elevated erythrocyte sedimentation rate have been reported in association with the production of interleukin 6. Elevated temperature more commonly reflects catecholamine-mediated increases in metabolic rate and diminished heat dissipation secondary to vasoconstriction. Polyuria is an occasional finding, and rhabdomyolysis with myoglobinuric renal failure may result from extreme vasoconstriction with muscle ischemia.
Pheochromocytoma of the Urinary Bladder Pheochromocytoma in the wall of the urinary bladder may result in typical paroxysms in relation to micturition. The location in the bladder wall is responsible for the occurrence of symptoms while the tumors are quite small, and, consequently, catecholamine excretion may be normal or minimally elevated. Hematuria is present in over half of patients, and the tumor can often be visualized at cystoscopy.
DIAGNOSIS
The diagnosis is established by the demonstration of increased excretion of catecholamines or catecholamine metabolites. The diagnosis can usually be made by the analysis of a single 24-h urine sample, provided the patient is hypertensive or symptomatic at the time of collection.
Biochemical Tests
The assays employed include those for vanillylmandelic acid (VMA), the metanephrines, and unconjugated or "free" catecholamines. The VMA assay is both less sensitive and less specific than assays of metanephrines or catecholamines. Accuracy of diagnosis is improved when two of three determinations are employed.
The following considerations apply to all the urinary tests:
(1) Despite claims for the adequacy of determinations made on random urine samples, analysis of a full 24-h urine sample is preferable. Creatinine should also be determined to assess the adequacy of collection.
(2) Where possible, the collection should be made when the patient is at rest, on no medication, and without recent exposure to radiographic contrast media. When it is not practical to discontinue all medications, drugs known specifically to interfere with these assays should be avoided.
(3) The urine should be acidified and refrigerated during and after collection.
(4) With high-quality assays, dietary restrictions are minimal and should be specified by the laboratory performing the analyses.
(5) Although most patients with pheochromocytoma excrete increased amounts of catecholamines and catecholamine metabolites at all times, the yield is increased in patients with paroxysmal hypertension if a 24-h urine collection is initiated during a crisis.
Free Catecholamines
The upper limit of normal for total urinary catecholamines is between 590 and 885 nmol (100 and 150 ug) per 24 h. In most patients with pheochromocytoma, values in excess of 1480 nmol (250 ug) per day are obtained. Measurement of epinephrine is often of value, since increased epinephrine excretion [over 275 nmol (50 ug) per 24 h] is usually due to an adrenal lesion and may be the only abnormality in cases associated with MEN. False-positive increases in catecholamine excretion result from exogenous catecholamines and related drugs such as methyldopa, levodopa, labetalol, and sympathomimetic amines, which may elevate catecholamine excretion for up to 2 weeks. Endogenous catecholamines from stimulation of the sympathoadrenal system also may increase urinary catecholamine excretion. Relevant clinical situations that cause such increases include hypoglycemia, strenuous exertion, central nervous system disease with increased intracranial pressure, severe hypoxia, and clonidine withdrawal.
Metanephrines and VMA
In most laboratories, the upper limit of normal is 7 umol (1.3 mg) of total metanephrines and 35 umol (7.0 mg) of VMA excretion per 24 h. In most patients with pheochromocytoma, the increase in these urinary metabolites is considerable, often to more than three times the normal range. Metanephrine excretion is increased by exogenous and endogenous catecholamines and by treatment with monoamine oxidase inhibitors; propranolol may cause a spurious increase in metanephrine excretion, since a propranolol metabolite interferes in the commonly used spectrophotometric assay. VMA is less affected by endogenous and exogenous catecholamines but is spuriously increased by a variety of drugs, including carbidopa. VMA excretion is decreased by monoamine oxidase inhibitors.
Plasma Catecholamines
Measurement of plasma catecholamines has a limited application. The care required in obtaining basal levels and the satisfactory results with urinary determinations make measurement of plasma catecholamines unnecessary in most cases. Plasma catecholamine levels are affected by the same drugs and physiologic perturbations that increase urinary catecholamine excretion.
When the clinical features suggest pheochromocytoma and the urinary assay results are borderline, measurement of plasma catecholamines may be worthwhile. Markedly elevated basal levels of total catecholamines support the diagnosis, although approximately one-third of patients with pheochromocytoma have normal or slightly elevated basal values. The usefulness of plasma catecholamine determinations may be increased by agents that suppress sympathetic nervous system activity. Clonidine and ganglionic blocking agents reduce plasma catecholamine levels in normal subjects and in patients with essential hypertension. These drugs have little effect on catecholamine levels in patients with pheochromocytoma. In patients with elevated or borderline basal catecholamine values, failure to suppress plasma or urinary levels with clonidine supports the diagnosis of pheochromocytoma.
DIFFERENTIAL DIAGNOSIS
Since the manifestations of pheochromocytoma can be protean; the diagnosis must be considered and excluded in many patients with suggestive clinical features.
- In patients with essential hypertension and "hyperadrenergic" features such as tachycardia, sweating, and increased cardiac output, and in patients with anxiety attacks associated with blood pressure elevations, analysis of a 24-h urine collection is usually decisive in excluding the diagnosis. Repeated determinations on urine collected during attacks may be necessary, however, before the diagnosis can be excluded with certainty. The clonidine suppression and glucagon stimulation tests may be helpful in excluding the diagnosis in difficult cases.
- Pressor crises associated with clonidine withdrawal and the use of cocaine or monoamine oxidase inhibitors may mimic the paroxysms of pheochromocytoma.
- Factitious crises may be produced by self-administration of sympathomimetic amines in psychiatrically disturbed patients.
- Intracranial lesions, particularly posterior fossa tumors or subarachnoid hemorrhage, may cause hypertension and increased excretion of catecholamines or catecholamine metabolites. While this is most common in patients with an obvious neurologic catastrophe, the possibility of subarachnoid or intracranial hemorrhage secondary to pheochromocytoma should be considered.
- Diencephalic or autonomic epilepsy may be associated with paroxysmal spells, hypertension, and increased plasma catecholamine levels. This rare entity may be difficult to distinguish from pheochromocytoma, but an aura, an abnormal electroencephalogram, and a beneficial response to anticonvulsant medications will often suggest the proper diagnosis.
- Related tumors that secrete catecholamines and produce similar clinical syndromes should be carefully ruled out. These include chemodectomas derived from the carotid body and ganglioneuromas derived from the postganglionic sympathetic neurons.
TREATMENT
Preoperative Management
The induction of stable alpha-adrenergic blockade is the basis of preoperative management and provides the foundation for successful surgical treatment. Once the diagnosis is established, the patient should be placed on phenoxybenzamine to induce a long-lived, noncompetitive alpha-receptor blockade. The usual initial dose is 10 mg every 12 h with increments of 10 to 20 mg added every few days until the blood pressure is controlled and the paroxysms disappear. Because of the long duration of action, the therapeutic effects are cumulative, and the optimal dose must be achieved gradually with careful monitoring of supine and upright blood pressures. Most patients require between 40 and 80 mg phenoxybenzamine per day, although 200 mg or more may be necessary. Phenoxybenzamine should be administered for at least 10 to 14 days prior to surgery. Over this time, the combination of alpha-receptor blockade and a liberal salt intake will restore the contracted plasma volume to normal. Before adequate alpha-adrenergic blockade with phenoxybenzamine is achieved, paroxysms may be treated with oral prazosin or noncompetitive intravenous phentolamine. Selective alpha1 antagonists have been employed for preoperative preparation, but their role in preparative management should be limited to the treatment of individual paroxysms. They may be useful as antihypertensive agents in patients with suspected pheochromocytoma while workup is in progress, since they are usually better tolerated than phenoxybenzamine and will prevent serious pressor crises if pheochromocytoma is present.
Nitroprusside, calcium channel blocking agents, and possibly angiotensin-converting enzyme inhibitors also reduce blood pressure in patients with pheochromocytoma. Nitroprusside may also be useful in the treatment of pressor crises.
Beta-Adrenergic receptor blocking agents should be given only after alpha blockade has been induced, since administration of such agents by themselves may cause a paradoxic increase in blood pressure by antagonizing beta 2-mediated vasodilation in skeletal muscle. Beta blockade is usually initiated when tachycardia develops during the induction of alpha-adrenergic blockade. Low doses often suffice, and a reasonable starting dose is 10 mg propranolol three to four times per day, increased as needed to control the pulse rate. Beta blockade is effective for catecholamine-induced arrhythmias, particularly those potentiated by anesthetic agents.
Preoperative Localization of the Tumor
Surgical removal of pheochromocytoma is facilitated if the location of the tumor or tumors can be established preoperatively. Once pheochromocytoma is diagnosed, localization should be undertaken while the patient is being prepared for surgery.
CT or magnetic resonance imaging (MRI) of the adrenals is usually successful in identifying intraadrenal lesions. Extraadrenal tumors within the chest can frequently be identified by conventional chest films or CT. MRI is useful in identifying extraadrenal tumors in the abdomen. If these studies are negative, abdominal aortography (once alpha-adrenergic blockade is complete) may identify extraadrenal pheochromocytomas in the abdomen, since these lesions are often supplied by a large aberrant artery.
If aortography, CT, and MRI fail to localize the lesion, venous sampling at different levels of the inferior and superior vena cava may reveal catecholamine gradients in the region drained by the tumor; this area may then be restudied by selective angiography or scanning by CT or MRI.
An additional localization technique involves a radionuclide scintiscan after administration of the radiopharmaceutical [I131] meta-iodo-benzyl-guanidine (MIBG). This agent is concentrated by the amine uptake process and produces an external scintigraphic image at the site of the tumor. This type of scanning may be useful in characterizing lesions discovered by CT when biochemical confirmation is indeterminate, as well as in localizing extraadrenal pheochromocytomas.
Percutaneous fine-needle aspiration of chromaffin tumors is contraindicated; indeed, pheochromocytoma should be considered before any adrenal lesions are aspirated.
Surgery
Surgical treatment of pheochromocytoma is best performed in centers with experience in the preoperative, anesthetic, and intraoperative management of pheochromocytoma.
- Monitoring during the surgical procedure should include continuous recording of arterial pressure and central venous pressure as well as electrocardiography.
- Adequate fluid replacement is crucial.
- Intraoperative hypotension responds better to volume replacement than to vasoconstrictors.
- Hypertension and cardiac arrhythmias are most likely during induction of anesthesia, intubation, and manipulation of the tumor.
- Intravenous phentolamine is usually sufficient to control the blood pressure, but nitroprusside may be required.
- Propranolol may be given in the treatment of tachycardia or ventricular ectopy.
Special situations
Pheochromocytoma in Pregnancy Spontaneous labor and vaginal delivery in unprepared patients are usually disastrous for mother and fetus. In early pregnancy, the patient should be prepared with phenoxybenzamine, and the tumor should be removed as soon as the diagnosis is confirmed. The pregnancy need not be terminated, but the operative procedure itself may result in spontaneous abortion. In the third trimester, treatment with adrenergic blocking agents should be undertaken; when the fetus is of sufficient size, cesarean section may be followed by extirpation of the tumor. Although the safety of adrenergic blocking drugs in pregnancy is not established, these agents have been administered in several cases without obvious adverse effect. Antepartum diagnosis and treatment lowers the maternal death rate to that approaching nonpregnant pheochromocytoma patients; fetal death rate, however, remains elevated.
Unresectable and Malignant Tumors In cases of metastatic or locally invasive tumor in patients with intercurrent illness that precludes surgery, long-term medical management is required. When the manifestations cannot be adequately controlled by adrenergic blocking agents, the concomitant administration of metyrosine may be required. This agent inhibits tyrosine hydroxylase, diminishes catecholamine production by the tumor, and often simplifies chronic management. Malignant pheochromocytoma frequently recurs in the retroperitoneum, and it metastasizes most commonly to bone and lung. Although these malignant tumors are resistant to radiotherapy, combination chemotherapy has had limited success in controlling them. Use of 131I-MIBG has had limited success in the treatment of malignant pheochromocytoma, due to poor uptake of the radioligand.
PROGNOSIS AND FOLLOW-UP
The 5-year survival rate after surgery is usually over 95%, the recurrence rate is 10%. After successful surgery, catecholamine excretion returns to normal in about 2 weeks and should be measured to ensure complete tumor removal. Catecholamine excretion should be assessed at the reappearance of suggestive symptoms or yearly if the patient remains asymptomatic. For malignant pheochromocytoma, the 5-year survival rate is 50%.
Complete removal cures the hypertension in approximately three-fourths of patients. In the remainder, hypertension recurs but is usually well controlled by standard antihypertensive agents. In this group, either underlying essential hypertension or irreversible vascular damage induced by catecholamines may cause the persistence of the hypertension.
REFERENCES
Harrison’s Principles of Internal medicine – 15th and 16th ed
http://www.harrisonsonline.com/
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