PHEOCHROMOCYTOMA
INTRODUCTION
Pheochromocytomas 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). Related tumors that secrete catecholamines and produce similar clinical syndromes include chemodectomas derived from the carotid body and ganglioneuromas derived from the postganglionic sympathetic neurons.
The clinical features are due predominantly 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.
Pheochromocytoma occurs in approximately 0.1% of the hypertensive population but is, nevertheless, an important correctable cause of high blood pressure. Indeed, it is usually curable if diagnosed and treated, but it may be fatal if undiagnosed or mistreated. Postmortem series indicate that most pheochromocytomas are unsuspected clinically, even when the tumor is related to the fatal outcome.
PATHOLOGY
Location and Morphology In adults, approximately 80% of pheochromocytomas are unilateral and solitary, 10% are bilateral, and 10% are extraadrenal. In children, a fourth of tumors are bilateral, and an additional fourth are extraadrenal. Solitary lesions inexplicably favor the right side. Although pheochromocytomas may grow to large size (>3 kg), most weigh <100 g and are <10 cm in diameter. Pheochromocytomas are highly vascular.
The tumors are made up of large, polyhedral, pleomorphic chromaffin cells. Fewer than 10% of these tumors are malignant. As with several 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.
EXTRAADRENAL PHEOCHROMOCYTOMAS Extraadrenal pheochromocytomas usually weigh 20 to 40 g and are <5 cm in diameter. Most are located within the abdomen in association with the celiac, superior mesenteric, and inferior mesenteric ganglia. Approximately 10% are in the thorax, 1% are within the urinary bladder, and <3% are in the neck, usually in association with the sympathetic ganglia or the extracranial branches of the ninth or tenth cranial nerves.
Catecholamine Synthesis, Storage, and Release Pheochromocytomas synthesize and store catecholamines by processes resembling those of the normal adrenal medulla. Little is known about the mechanisms of catecholamine release from pheochromocytomas, but changes in blood flow and necrosis within the tumor may be the cause in some instances. 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, as noted below.
EPINEPHRINE, NOREPINEPHRINE, AND DOPAMINE Most pheochromocytomas produce both norepinephrine and epinephrine, and the percentage of norepinephrine is usually greater than in the normal adrenal. Most extraadrenal pheochromocytomas secrete norepinephrine exclusively. Rarely, pheochromocytomas produce epinephrine alone, particularly in association with multiple endocrine neoplasia (MEN). Although epinephrine-producing tumors may cause a preponderance of metabolic and beta-re 333h721d ceptor effects, in general the major catecholamine secreted cannot be predicted from the clinical presentation. Increased production of dopamine and homovanillic acid (HVA) is uncommon with benign lesions but may occur with malignant pheochromocytoma.
FAMILIAL PHEOCHROMOCYTOMA
Pheochromocytoma may be inherited as an autosomal dominant trait either alone or in combination with other abnormalities such as MEN1 type 2A (Sipple's syndrome) or type 2B (mucosal neuroma syndrome) (Chap. 330), von Hippel-Lindau's (VHL) retinal cerebellar hemangioblastomosis, or von Recklinghausen's neurofibromatosis (type 1) and in association with paragangliomas of the neck. Recent evidence suggests that 25% of patients with pheochromocytoma may have an inherited form of the disease. Features that suggest familial disease include bilaterality, multicentricity (within the adrenal and at diverse sites), and age of onset <30 years.
GENETIC CONSIDERATIONS
MEN 2 The MEN1 2A and 2B syndromes are associated with abnormalities in the RET protooncogene located in pericentromeric region of chromosome 10 (Chap. 330). These mutations result in the constitutive activation of the receptor tyrosine kinase, causing adrenal medullary chromaffin cell and thyroid parafollicular C cell hyperplasia and rendering the cells susceptible to malignant transformation. The RET mutations are located in the extracellular domain in MEN 2A and in the intracellular portion of the receptor in families with the MEN 2B syndrome. Mutations at specific sites in the RET protooncogene are highly predictive of pheochromocytoma. Pheochromocytomas in MEN 2 are multicentric and bilateral but not extraadrenal. Individuals at risk for MEN 2A and 2B should be screened periodically for pheochromocytoma by assay of a 24-h urine sample for catecholamines, including measurement of epinephrine. Pheochromocytoma should be excluded or removed before thyroid or parathyroid surgery.
VHL In the VHL2 syndrome, mutation of one copy of the VHL tumor-suppressor gene is associated with the development of tumors characteristic of the syndrome, including pheochromocytomas. Loss of function of the VHL tumor-suppressor gene promotes tumor formation by mechanisms that are incompletely understood but may involve alterations in mRNA transcript elongation. In the VHL syndrome, the frequency of pheochromocytoma varies considerably but may be as high as 60% in some kindreds. As in the MEN1 2 syndromes, certain VHL mutations are highly associated with the development of pheochromocytoma. Of further interest is the recent finding that the VHL mutation has been identified in some kindreds with familial pheochromocytoma as the sole manifestation without other clinical evidence of the VHL syndrome. Missense mutations, as opposed to deletions, insertions, or nonsense mutations, appear to be more commonly associated with pheochromocytoma, which may be adrenal, extraadrenal, or multifocal. A high incidence of germ-line VHL mutations in patients with thoracic extraadrenal pheochromocytomas has also been reported.
Familial Paraganglioma Syndromes Mutations in the genes encoding succinate dehydrogenase subunit B (SDHB) and subunit D (SDHD) may occur in kindreds with inherited paraganglioma, usually located in the head or neck (glomus tumors) or carotid body. Paraganglioma in these syndromes are distinct from extraadrenal pheochromocytomas, which are also commonly referred to as paragangliomas. Adrenal or extraadrenal pheochromocytomas are often inherited in association with these paragangliomas.
Neurofibromatosis Type I Mutations in the NF-I gene predispose to the development of pheochromocytoma, although the association is not very common. It has been estimated that 1% of patients with pheochromocytoma have an NF-I mutation. Pheochromocytomas may occur in patients with minor clinical manifestations of neurofibromatosis such as a few cafe au lait spots, vertebral abnormalities, or kyphoscoliosis.
Nonsyndromic Familial Pheochromocytoma Patients presenting with a solitary adrenal pheochromocytoma, negative family history, and no evidence of associated disease may still have an inherited form of the disease. This is most common with the SDHB3 and SDHD4 mutations but also occurs with alterations in the VHL2 gene.
Screening for Genetic Disease Genetic screening for the RET mutation is available and of established utility in the evaluation of families for the MEN1 2 syndromes. Genetic tests for the SDH, NF-I, and VHL2 mutations are not yet generally available. Screening in these kindreds therefore is dependent on a vigorous search for the associated diseases and a complete evaluation of family history.
CLINICAL FEATURES
Pheochromocytoma occurs at all ages but is most common in young to midadult life. Some series show a slight female preponderance. 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. Less commonly, unexplained hypotension or shock in association with surgery or trauma will suggest the diagnosis. Aberrant reactions to medications such as opioids or tricyclic antidepressants may bring the patient to clinical attention. In most patients the hypertension is associated with other symptoms, such as 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 have all 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 may require treatment with insulin and disappears after removal of the tumor.
HEMATOCRIT An elevated hematocrit may be 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. Ectopic production of adrenocorticotropic hormone and vasoactive intestinal peptide have been documented in association with the characteristic manifestations of inappropriate secretion of these hormones (Chap. 317).
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.
Adverse Drug Interactions Severe and occasionally fatal paroxysms have been induced by opiates, histamine, adrenocorticotropin, saralasin, and glucagon. These agents appear to release catecholamines directly from the tumor. Indirect-acting sympathomimetic amines, including methyldopa (when administered intravenously), may increase blood pressure by releasing catecholamines from the augmented stores within nerve endings. Drugs that block neuronal uptake of catecholamines, such as tricyclic antidepressants, may enhance the physiologic effects of circulating catecholamines. Indeed, all medications should be considered carefully and administered cautiously in patients with known or suspected pheochromocytoma.
DIAGNOSIS
The diagnosis is established by the demonstration of increased production 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 (as noted below) 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 >1480 nmol (250 ug) per day are obtained. Measurement of epinephrine is often of value, since increased epinephrine excretion [>275 nmol (50 ug) per 24 h] is usually due to an adrenal lesion and may be the only abnormality in cases associated with MEN1 2. 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 may also 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 VMA5 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. In addition, a- and ß-adrenergic receptor blocking agents may elevate plasma catecholamines by impairing clearance.
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.
PLASMA METANEPHRINES Measurement of free (unconjugated) total plasma metanephrines, fractionated into normetanephrine and metanephrine, is a highly sensitive technique for the diagnosis of pheochromocytoma. Questions of specificity, particularly among the elderly, as well as the availability of high-quality assays need to be addressed before plasma metanephrines replace the 24-h urinary measurement of free catecholamines and metanephrines as the screening test of choice.
Pharmacologic Tests Reliable methods for the measurement of catecholamines and catecholamine metabolites in urine have rendered obsolete both the provocative and adrenolytic tests, which are nonspecific and entail considerable risk. A modified version of the adrenolytic test may be of some use, however, as a therapeutic trial in a patient in hypertensive crisis with features suggestive of pheochromocytoma. A positive response to phentolamine (5-mg bolus following a test dose of 0.5 mg) is a reduction in blood pressure of at least 35/25 mmHg after 2 min that persists for 10 to 15 min. The pharmacologic response is never diagnostic, and biochemical confirmation is essential. Provocative tests in normotensive patients are potentially dangerous and rarely indicated. However, a glucagon provocative test may be of use in patients with paroxysmal hypertension and nondiagnostic basal catecholamine levels. Glucagon has a negligible effect on blood pressure or plasma catecholamine levels in normal or hypertensive subjects. In patients with pheochromocytoma, on the other hand, glucagon may increase both blood pressure and circulating catecholamine levels. The elevation in plasma catecholamine concentration, moreover, may occur without a blood pressure response. It must be emphasized, however, that life-threatening pressor crises have occurred after administration of glucagon to patients with pheochromocytoma, so the test should never be performed casually. Careful continuous monitoring of the blood pressure is required, intravenous access must be adequate, and phentolamine must be at hand to terminate the test if a significant pressor reaction ensues.
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. 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 this diagnosis.
TREATMENT
Preoperative Management The induction of stable a-adrenergic blockade provides the foundation for successful surgical treatment. Once the diagnosis is established, the patient should be placed on phenoxybenzamine to induce a long-lasting, noncompetitive a-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 may be necessary. Phenoxybenzamine should be administered for at least 10 to 14 days prior to surgery. Over this time, the combination of a-receptor blockade and a liberal salt intake will restore the contracted plasma volume to normal. Before adequate a-adrenergic blockade with phenoxybenzamine is achieved, paroxysms may be treated with oral prazosin or intravenous phentolamine. Selective a1 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 reduce blood pressure in patients with pheochromocytoma. Nitroprusside may also be useful in the treatment of pressor crises.
ß-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-mediated vasodilation in skeletal muscle. Beta blockade is usually initiated when tachycardia develops during the induction of a-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 Once pheochromocytoma is diagnosed, localization should be undertaken while the patient is being prepared for surgery. Computed tomography (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 or positron emission tomography (PET) scanning with 18F dopa is useful in identifying extraadrenal tumors. Abdominal aortography (once a-adrenergic blockade is complete) or venous sampling at different levels of the inferior and superior vena cava in search of catecholamine gradients has been useful in the past but are rarely necessary now. An additional localization technique involves a radionuclide scintiscan after administration of the radiopharmaceutical [131I]metaiodobenzylguanidine (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 but is less useful at localizing extraadrenal pheochromocytomas than MRI or PET. Percutaneous fine-needle aspiration of chromaffin tumors is contraindicated; indeed, pheochromocytoma should be considered before 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. Surgical mortality is <2 or 3%. Extensive experience with the laparoscopic approach over the past decade has demonstrated that in experienced hands pheochromocytoma can be safely and efficiently removed by this technique.
Monitoring during the surgical procedure should include continuous recording of arterial pressure and central venous pressure as well as electrocardiography; in the presence of cardiac disease or if congestive failure has been present, pulmonary capillary wedge pressure should be monitored. 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.
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 is occasionally of some benefit. Use of 131I-MIBG6 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 >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 usually <50%, although long-term survival is occasionally noted.
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
|
