Pheochromocytoma

Abstract

Pheochromocytoma, a relatively rare (<0.05% of hypertensives), catecholamine‐secreting tumor, is almost always lethal unless recognized and appropriately treated. Clinical and biochemical manifestations are mainly caused by excess circulating catecholamines and hypertension. Manifestations mimic many conditions, which may result in erroneous diagnoses and improper treatment. Sustained or paroxysmal hypertension associated with headaches, sweating, or palpitations, occurs in 95% of patients, but at least 5% are normotensive. All patients with manifestations of hypercatecholaminemia or coexisting neoplasms should be investigated for pheochromocytoma. Plasma free metanephrines and fractionated urinary metanephrines are the most sensitive (≊100%) chemical tests for diagnosing sporadic and familial pheochromocytomas; plasma and urinary catecholamines and total metanephrines are fairly sensitive for identifying sporadic cases but are less sensitive for familial tumors. The clonidine suppression test helps exclude other conditions that may elevate plasma and urinary catecholamines and their metabolites. Magnetic resonance imaging is more sensitive than computed tomography for localizing pheochromocytomas; iodine‐131‐metaiodobenzylguanidine (¹³¹I‐MIBG) tumor uptake confers specificity. Surgical resection is successful in 90% of cases, but 10% of tumors are malignant. Pheochromocytomas <5 cm in diameter can be removed laparoscopically; larger tumors should be removed by open surgery. Drug treatment prior to and during surgery is mandatory; drug treatment, chemotherapy, and radiation therapy are used to treat malignant lesions.

The key to diagnosing pheochromocytoma is first to think of it! Since this deceptive tumor poses great risk of death or severe complications, early diagnosis and prompt treatment of this “pharmacologic bomb” are crucial. The peril of missing the diagnosis is strikingly revealed by a Mayo Clinic report of 54 autopsied patients whose pheochromocytomas contributed to 55% of deaths and was not suspected in 75% of cases! ¹

Fortunately, pheochromocytomas can be successfully removed in 90% of cases, and a diagnosis should be established in almost all cases with current diagnostic modalities. However, because of its many manifestations, it may mimic a large variety of conditions. This can challenge the physician's acumen and sometimes result in an erroneous diagnosis. No tumor or disease is capable of causing more diversified manifestations than pheochromocytoma. ²

About 85% of pheochromocytomas occur in the adrenal medulla, whereas up to 18% have been reported in extra‐adrenal locations, ³ e.g., the organ of Zuckerkandl (at the bifurcation of the aorta), the urinary bladder (<1%), and paraganglionic chromaffin cells, which are found in association with sympathetic nerves in the abdomen and pelvis. Occasionally, tumors occur in the chest (<2%) and neck (<0.1%) and, rarely, in other locations, e.g., the base of the skull, middle ear, and spermatic cord. Extra‐adrenal pheochromocytomas (paragangliomas) are more frequent in children (30%) than adults (15%).

Pheochromocytoma is a relatively rare tumor, occurring in fewer than 0.05% of patients with diastolic hypertension. About 45% of tumors cause only paroxysmal hypertension, and a small percentage of patients remain normotensive. Tumors occur at any age, but most often in the 4th and 5th decades.

PATHOPHYSIOLOGY ²

Pheochromocytoma is a catecholamine‐secreting tumor that can cause severe morbidity and/or lethal complications (e.g., cerebrovascular and/or cardiovascular) from effects of excess circulating catecholamines and hypertension. Tumors usually secrete norepinephrine and epinephrine, but predominantly norepinephrine; some secrete only norepinephrine or epinephrine, and very rarely dopa and dopamine are secreted. It is not known why some pheochromocytomas secrete catecholamines intermittently and cause paroxysmal hypertension, while others cause sustained hypertension by constantly secreting catecholamines. Hypovolemia occurs in the majority of patients, primarily those with sustained hypertension, and this may contribute to orthostatic hypotension in some patients with this tumor.

About 10% of pheochromocytomas are malignant (evident from metastases or invasion of adjacent tissues). Malignancy occurs in 30%–40% of extra‐adrenal pheochromocytomas, i.e., three to 15 times more commonly than in adrenal tumors (2.4%–11%); however, one cannot differentiate benign from malignant tumors by histopathology.

Many substances, mostly peptides, have been identified in some pheochromocytomas; these include a potent vasodilator, vasoactive intestinal peptide; adrenocorticotropic hormone; neuropeptide Y (a potent vasoconstrictor); atrial natriuretic factor; growth hormone‐releasing factor; somatostatin; parathyroid hormone‐related peptides; calcitonin; serotonin; and others. Some of these substances may be released into the circulation and cause physiologic and/or pharmacologic effects with diverse manifestations and syndromes.

CLINICAL PRESENTATION ²

Because it secretes catecholamines, often episodically, pheochromocytoma frequently presents dramatically and explosively with numerous and diverse manifestations that mimic many diseases. Of great diagnostic importance is the presence of sustained or paroxysmal hypertension. Manifestations or “attacks” suggesting hypercatecholaminemia without hypertension are highly atypical. Rarely, hypertension will be absent; this is most common when pheochromocytoma is familial.

One or more symptomatic attacks occur weekly in 75% of patients; attacks may occur several times daily or only every few months. Attacks occur abruptly and subside slowly; they last less than 1 hour in 80% of patients, but may last less than 1 minute or persist for 1 week. They may be precipitated by palpation of the tumor, postural changes, exertion, anxiety, trauma, pain, ingestion of foods or beverages containing tyramine (certain cheeses, beers, and wines), use of certain drugs (histamine, glucagon, tyramine, phenothiazine, metoclopramide, adrenocorticotropic hormone), intubation, induction of anesthesia, operative chemotherpay manipulation, and micturition or bladder distention (with bladder tumors).

The symptoms and signs of pheochromocytoma (Table I) are mainly due to hypercatecholaminemia and hypertension. Headaches occur in any part of the head; they may be mild but are usually severe and throbbing (especially during paroxysmal hypertension) and are often accompanied by nausea and vomiting. Generalized sweating (sometimes drenching) and palpitations with tachycardia (or reflex bradycardia) occur frequently. Acute anxiety with fear of death is often experienced. Since most patients with hypertension have few symptoms, the occurrence of headaches, palpitations, and sweating in a person with hypertension should alert the physician to consider the diagnosis of pheochromocytoma.

Table I.

Most Common Symptoms and Signs in Patients (Almost All Adults) With Pheochromocytoma Associated With Paroxysmal or Persistent Hypertension

Symptoms	Paroxysmal	Persistent
	n=37	n=39
	%	%
Headaches (severe)	92	72
Excessive sweating (generalized)	65	69
Palpitations with or without tachycardia	73	51
Anxiety, nervousness, fear of impending death, or panic	60	28
Tremulousness	51	26
Pain in chest, abdomen (usually epigastric), lumbar regions, lower abdomen, or groin	48	28
Nausea with or without vomiting	43	26
Weakness, fatigue, prostration	38	15
Weight loss (severe)	14	15
Dyspnea	11	18
Warmth or heat intolerance	13	15
Noteworthy are painless hematuria, urinary frequency, nocturia, and tenesmus in pheochromocytoma of the urinary bladder.
Signs
Hypertension with or without wide fluctuations (rarely paroxysmal hypotension or hypertension alternating with hypotension, or hypertension absent)
Hypertension induced by physical maneuver such as exercise, postural change, or palpation and massage of flank or mass elsewhere
Orthostatic hypotension with or without postural tachycardia
Paradoxical blood pressure response to certain antihypertensive drugs; marked pressor response with induction of anesthesia
Sweating
Tachycardia or reflex bradycardia, very forceful heartbeat, arrhythmia
Pallor of face and upper part of body (rarely flushing)
Anxious, frightened, troubled appearance
Leanness or underweight
Hypertensive retinopathy
Modified from Clinical and Experimental Pheochromocytoma. 2

Hypermetabolism may cause considerable weight loss, but some patients, especially those with paroxysmal hypertension, may remain obese. Severe constipation or pseudo‐obstruction may occur in patients with sustained hypertension because catecholamines inhibit peristalsis. Ischemic enterocolitis with intestinal necrosis may complicate intense mesenteric artery vasoconstriction caused by hypercatecholaminemia. Secretion of vasoactive intestinal peptide, serotonin, or calcitonin by some pheochromocytomas may cause diarrhea. Severe Watery Diarrhea may be accompanied by Hypokalemia and Hypochlorhydria or Achlorhydria (Verner‐Morrison WDHH or WDHA syndrome). ² Marked systolic and diastolic hypertension usually accompanies paroxysmal attacks, which occur in 45% of patients; rarely, paroxysms will convert to sustained hypertension. With sustained hypertension, which occurs in 50% of patients, blood pressures may fluctuate widely, and paroxysms may result from variations in circulating catecholamines. Very rarely, hypertension alternates with hypotension (with predominantly epinephrine‐secreting tumors).

At least 5% of patients remain normotensive, especially those with familial pheochromocytoma. Patterns of hypertension in familial disease remain consistent (i.e., family members have either sustained or paroxysmal hypertension).

Orthostatic hypotension in untreated hypertensive patients suggests pheochromocytoma. When this occurs, blood pressure usually decreases to normotensive levels; rarely, the blood pressure falls to shock levels and is accompanied by tachycardia. Resistance to antihypertensive therapy, paradoxical blood pressure increases during treatment with β blockers, or marked pressor responses to conditions mentioned above that may precipitate attacks should suggest pheochromocytoma.

Pallor and tachycardia (or reflex bradycardia) frequently occur, and, rarely, flushing is observed during hypertensive paroxysms. Retinopathy is not infrequent when hypertension is severe and sustained, but it rarely occurs when hypertension is paroxysmal. Occasionally, a fine tremor and Raynaud's phenomenon are noted. Slight temperature elevation is common and severe hyperpyrexia may rarely occur.

In children, polydipsia, polyuria, and convulsions may occur. Attacks of pheochromocytoma may be aggravated or may subside during pregnancy and can be confused with eclampsia; shock may occur with labor or after delivery and may mimic a ruptured uterus. Tumors in the bladder may cause painless hematuria, and attacks may occur during micturition or bladder distention.

Other manifestations of hypercatecholaminemia and/or hypertension include such complications as congestive heart failure with or without cardiomyopathy, myocardial infarction or arrhythmias, cerebrovascular accident, encephalopathy, shock, hemorrhagic necrosis within a pheochromocytoma, and dissecting aneurysm.

LABORATORY AND ELECTROCARDIOGRAPHIC ABNORMALITIES

Laboratory abnormalities are sometimes caused by pheochromocytoma and coexisting endocrine conditions, e.g., multiple endocrine neoplasia and Cushing's syndrome. Hyperglycemia and increased triglyceride concentrations may result from hypercatecholaminemia; hyperglycemia (without diabetes mellitus) is a frequent occurrence and a clue to the presence of pheochromocytoma. Rarely, pheochromocytomas (or an associated cerebellar hemangioblastoma) secrete erythropoietin and cause polycythemia. ²

Severe catecholamine‐induced ischemia involving multiple organs may result in lactic acidosis and elevations of pancreatic, hepatic, and cardiac enzymes. Hypertension may be exacerbated by elevated plasma concentrations of renin, angiotensin II, and aldosterone resulting from catecholamine stimulation of renal β₁‐adrenergic receptors or, rarely, from renal artery spasm or compression by a pheochromocytoma or coexisting neurofibroma. ²

Arrhythmias or electorcardiograph (EKG) changes suggesting myocardial ischemia, damage, or left ventricular strain may develop. Their transient appearance during paroxysms suggests pheochromocytoma in the absence of other causes. Permanent EKG changes can result from hypertension, myocardial ischemia, or catecholamine cardiomyopathy. ²

FAMILIAL PHEOCHROMOCYTOMA

It is important to recognize that 10%–15% of pheochromocytomas are familial; these are associated with multiple endocrine neoplasms (MEN), Von Hippel‐Lindau disease (VHL), carotid body tumors, or neurofibromatosis type 1. Coexistence of pheochromocytoma with medullary thyroid carcinoma (MTC) or C‐cell hyperplasia, and sometimes with parathyroid neoplasms or hyperplasia, constitutes MEN type 2a. Coexistence of pheochromocytoma with MTC, mucosal neuromas, thickened corneal nerves, alimentary tract ganglioneuromatosis, and often a marfanoid habitus constitutes MEN type 2b. Hyperparathyroidism occurs in ≊50% of patients with MEN type 2a but rarely in type 2b. Calcitonin, serotonin, and prostaglandin may be released from MTC and cause severe diarrhea. Patients with pheochromocytoma should be screened for MTC or premalignant C‐cell hyperplasia, which may occur many years before pheochromocytoma. ² One large study of pheochromocytoma coexisting with the MEN 2 syndrome revealed that MTC always preceded the occurrence of pheochromocytomas. ⁴ Hypercalcitonemia suggests MTC or C‐cell hyperplasia; however, hypercalcitonemia occurs in other conditions and occasionally in pheochromocytoma without MTC. Similarly, hypercalcemia may not indicate MEN, since it may result from a parathyroid‐like hormone released from some pheochromocytomas. Therefore, re‐evaluation for MEN should be performed after pheochromocytoma removal. ²

Von Recklinghausen's neurofibromatosis, often with café au lait spots, coexists in 5% of patients with pheochromocytoma, whereas pheochromocytoma occurs in 1 % of persons with neurofibromatosis. Pheochromocytomas coexist in about 14% of patients with hemangioblastoma of the cerebellum (or other portions of the central nervous system) and retinal angioma, i.e., VHL. Therefore, patients with pheochromocytoma should be screened for evidence of MTC, hyperparathyroidism, and VHL; patients with the latter diseases or neurofibromatosis (if hypertension exists) should also be screened for pheochromocytoma. ² , ⁵ If familial disease is established, then first‐degree relatives should be interviewed, examined, and investigated for genetic mutations, e.g., receptor tyrosine kinase proto‐oncogene (RET) on chromosome 10 for MEN type 2a or 2b, on chromosome 3p for VHL, and on chromosome 11q for carotid body paragangliomas. ² , ⁶ Those with these genetic alterations should be screened for presence of a pheochromocytoma with appropriate biochemical tests and imaging studies. It is noteworthy that familial VHL may coexist not only with pheochromocytoma but commonly with renal and pancreatic cysts, renal carcinoma, and cystadenoma of the epididymis; very rarely, VHL may be associated with MTC, carcinoid, pituitary adenoma, neuroblastoma, and angiomas and cysts elsewhere. ⁷ Mutation of chromosome 17q occurs in familial Von Recklinghausen's disease.

DIFFERENTIAL DIAGNOSIS

Table II lists conditions that may suggest pheochromocytoma. Many of these conditions can be excluded clinically. It is important to note that many types of stress can also significantly elevate concentrations of plasma and urinary catecholamines and their metabolites, but few conditions increase them to levels that occur with pheochromocytoma. ²

Table II.

Differential Diagnosis of Pheochromocytoma ²

All hypertensive patients (sustained and paroxysmal) when diagnosis is unknown

Anxiety, panic attacks, psychoneurosis, tension states

Hyperthyroidism

Paroxysmal tachycardia

Hyperdynamic β‐adrenergic circulatory state

Menopause

Vasodilating headache (migraine and cluster headaches)

Coronary insufficiency syndrome

Renal parenchymal or renal arterial disease with hypertension

Focal arterial insufficiency of the brain; cerebral vasculitis

Intracranial lesions (with or without increased intracranial pressure)

Autonomic hyper‐reflexia

Diencephalic seizure; Page's syndrome; dopamine surges

Preeclampsia (or eclampsia with convulsions)

Hypertensive crises associated with monoamine oxidase inhibitors

Hypoglycemia

Neuroblastoma; ganglioneuroblastoma; ganglioneuroma

Acute infectious disease; acute abdomen (cardiovascular catastrophe)

Unexplained shock

Neurofibromatosis (with hypertension)

Rare causes of paroxysmal hypertension (adrenal medullary hyperplasia; acute porphyria; clonidine withdrawal; baroreflex failure; pseudopheochromocytoma: factitious—induced by certain illegal, prescription, and nonprescription drugs); fatal familial insomnia

Conditions in italics may increase the excretion of catecholamines and/or metabolites.

Pheochromocytoma should be considered in cases of unexplained shock, ⁸ especially if accompanied by abdominal pain, pulmonary edema, or intensive mydriasis unresponsive to light. If a patient presents with multiple‐system organ failure, high fever, encephalopathy, severe hypertension or hypotension, and lactic acidosis (i.e., pheochromocytoma multisystem crisis), ⁹ pheochromocytoma should also be considered. Rarely, hemorrhagic necrosis in a pheochromocytoma presents as an acute abdomen or cardiovascular crisis.

Consumption of certain illegal substances (amphetamine, cocaine, phencyclidine, lysergic acid diethylamide, and some prescription and nonprescription drugs containing phenylpropanolamine or ephedrine) may cause manifestations mimicking pheochromocytoma. Factitious production of manifestations (pseudo‐pheochromocytoma) should be considered in emotionally disturbed persons with access to prescription or illicit drugs. ²

Physicians must forever recall that pheochromocytoma wears many disguises. We know of two women who were thought to have cerebral vasculitis because of neurologic deficits and segmental narrowing of cerebral arteries on angiography. Subsequently, pheochromocytomas were found to be responsible for these manifestations. ²

Unrecognized pheochromocytoma in pregnancy carries a high risk of maternal and fetal mortality. Manifestations may first appear in pregnancy, remit after delivery, and return in a subsequent pregnancy. Missing the diagnosis of pheochromocytoma may be responsible for a patient's sudden death. Therefore, it is crucial that the differential diagnosis be carefully considered. Conditions listed in Table II are discussed in detail elsewhere. ²

DIAGNOSIS

About 95% of patients experience headache, sweating, or palpitations, and all patients with sustained or paroxysmal hypertension who have manifestations suggesting pheochromocytoma should be screened for the tumor. Asymptomatic patients with hypertension of unknown cause should be screened if they have laboratory or EKG abnormalities caused by hyper‐catecholaminemia, radiographic or magnetic resonance imaging (MRI) evidence suggesting pheochromocytoma, or diseases sometimes co‐existing with pheochromocytomas. Screening should be performed by measuring plasma free metanephrines or catecholamines and 24‐hour urine fractionated metanephrines. Urinary catecholamines, total metanephrines, and vanillylmandelic acid (VMA) measurements are less reliable. ⁶ Blood should be collected from patients in a basal state, as recommended for plasma catecholamine measurements. ² (Currently, plasma metanephrine measurements are commercially available only at the Mayo Clinic.)

Biochemical and Pharmacologic Tests.

Plasma free (unconjugated) metanephrines and catecholamines, and urinary catecholamines and metanephrines are almost invariably elevated with sustained or paroxysmal hypertension due to pheochromocytoma. Plasma and urinary catecholamines and urinary metanephrines may, however, occasionally be normal during normotensive periods. Therefore, it is imperative in some patients to obtain blood during spontaneous or provoked hypertension or to collect urine following a hypertensive episode. Recent experience ⁶ in a large, multicenter study revealed that normal concentrations of plasma free metanephrines (metanephrine and normetanephrine), even in the absence of hypertension, virtually eliminate the presence of sporadic and familial pheochromocytomas, with a test sensitivity of 100% and 97%, respectively. This high degree of sensitivity for detecting pheochromocytomas with plasma free metanephrines has also been reported by Raber et al. ¹⁰ Concentrations of plasma normetanephrine and metanephrine greater than 2.5 pmol (458 pg)/mL and 0.9 pmol (177 pg)/mL, respectively, always indicated the presence of a pheochromocytoma. Plasma catecholamines were 93% sensitive for detecting sporadic pheochromocytoma; however, sensitivity for familial tumors was only 66%. Fractionated urinary metanephrines, measured by high‐pressure liquid chromatography, was almost as sensitive as plasma free metanephrines, whereas urinary catecholamines, total metanephrines (measured by spectrophotometry), and VMA were progressively less sensitive, especially for detection of familial disease (93%, 89%, and 83%, respectively, for sporadic and 75%, 60%, and 43% for familial tumors) (Dr. Graeme Eisenhofer, personal communication, 2002). When available, plasma free metanephrines and normetanephrines or fractionated urine metanephrines should be determined to detect pheochromocytoma because of their remarkable sensitivity. However, since none of these biochemical tests is totally specific (especially for sporadic pheochromocytomas), repeating a combination of these tests may help to exclude or establish the presence of a tumor.

A small number of patients with essential hypertension or neurogenic hypertension and manifestations simulating pheochromocytoma have borderline or moderate elevations of plasma catecholamines (i.e., 600–2000 pg/mL at basal conditions). The clonidine suppression test is quite safe and exceptionally reliable in differentiating neurogenic hypertension from pheochromocytic hypertension; ¹¹ , ¹² clonidine suppresses sympathetic nerve activity and plasma norepinephrine by more than 50% or to normal concentrations in neurogenic hypertension, but not in patients with pheochromocytoma. Epinephrine changes, however, are not reliable diagnostically; sometimes, significant increases in epinephrine consistent with pheochromocytoma occur during clonidine suppression. Beta blockers must be avoided for at least 48 hours before testing, since they may prevent suppression of catecholamines and also aggravate clonidine‐induced hypotension and bradycardia. ² False‐positive clonidine tests have been reported in patients taking diuretics or tricyclic antidepressants. ¹³ , ¹⁴

Catecholamine assay of blood drawn from an indwelling catheter in patients recumbent for 1 hour often differentiates neurogenic from pheochromocytic hypertension; we reserve clonidine suppression testing for those whose catecholamines remain elevated despite 1‐hour recumbency. Few drugs other than those containing catecholamines, i.e., isoproterenol, methyldopa, levodopa, Levophed™, tricyclic antidepressants, and phenoxybenzamine, may cause actual or spurious plasma catecholamine elevations determined radioenzymatically; however, these drugs and certain other drugs (e.g., labetalol, benzodiazepines, or acetaminophen) may interfere with high‐pressure liquid chromatographic assays of plasma and urinary catecholamines or their metabolites. Monoamine oxidase inhibitors can elevate urinary and plasma metanephrines and decrease VMA levels. Sudden cessation of clonidine treatment may elevate plasma and urinary catecholamines and their metabolites, whereas metyrosine can decrease catecholamine production and sometimes reduce urine catecholamines and their metabolites to normal concentrations. Radio‐opaque media containing methylglucamine can obscure elevations of total metanephrines. (Physicians should familiarize themselves with drugs that may increase plasma catecholamines.) Finally, it must be appreciated that a variety of stressful conditions (e.g., strenuous exercise, myocardial infarction, congestive heart failure, hypoglycemia, hypotension, increased intracranial pressure, hypoxia, acidosis, surgery, trauma, some illicit, nonprescription and prescription drugs) may stimulate the sympathetic nervous system and increase catecholamine secretion. ²

Only very rarely is a glucagon provocative test, combined with plasma catecholamine quantitation, required to establish the presence of a paroxysmally secreting pheochromocytoma. This test should be performed with precautions to counteract hypertensive crises, arrhythmias, or hypotension. Induction of α‐adrenergic blockade prior to testing prevents a hypertensive response without influencing a diagnostic rise in plasma catecholamines. ²

Preoperative Localization.

Although significant elevation of plasma or urinary epinephrine or its metabolite (metanephrine) suggests pheochromocytoma in the adrenal, in the organ of Zuckerkandl, and rarely in other extra‐adrenal sites, imaging must establish the tumor location. Preoperative localization is essential for the surgeon.

Current imaging techniques are almost always capable of localizing pheochromocytomas. Consequently, a variety of surgical approaches can often be utilized for tumor excision without abdominal exploration. Computerized tomography (CT) identifies 95% of adrenal pheochromocytomas that are 1 cm or greater; it can localize about 90% of extra‐adrenal abdominal lesions greater than 2 cm. ⁶ Oral and i.v. contrast is necessary for optimal interpretation. CT is reliable in demonstrating chest lesions, although intrapericardial pheochromocytomas may be missed. ¹⁵

MRI is an extremely valuable modality for detecting pheochromocytomas and it is more sensitive and more specific than CT. Signal intensity on MRI may be fairly characteristic for pheochromocytoma; ¹⁶ only rarely will other benign or malignant lesions resemble a pheochromocytoma. ¹⁷ MRI is noninvasive and CT artifacts caused by surgical clips are not encountered; it appears superior to CT in detecting extra‐adrenal abdominal and pelvic lesions, and some cardiac ¹⁸ and familial adrenal pheochromocytomas. ² It is ideal for imaging children and pregnant patients suspected of having a pheochromocytoma, since no radiation is involved.

The radiopharmaceutical agent ¹³¹I‐meta‐iodobenzylguanidine (MIBG) concentrates in 81%–85% of pheochromocytomas; it is highly specific for diagnosis and localization, ¹⁹ , ²⁰ and it may be helpful in identifying adrenal medullary hyperplasia and in detecting metastases, very small tumors, or those in unusual extra‐adrenal (e.g., intrapericardial) locations. ² , ²¹ MIBG uptake may also occur in neuroblastomas, medullary thyroid carcinomas, carcinoids, and small cell lung carcinomas; uptake may be inhibited by certain drugs (e.g., labetalol, reserpine, calcium channel blockers, tricyclic antidepressants, sympathomimetics, cocaine, adrenergic neuron blockers, tranquilizers) and they should be discontinued 1 week before scintigraphy. ² , ²²

¹²³I‐MIBG offers superior image quality and appears especially useful for detecting recurrent and metastatic tumors and those in unusual locations, ² , ⁶ but is not generally available in the United States. Bone scanning with technetium (Tc) 99m may demonstrate metastatic lesions missed by MIGB. Liver metastases are best detected with MRI or CT (metastases frequently involve lymph nodes, liver, lung, and bone, but not brain).

¹¹¹Indium octreotide is another radiopharmaceutical agent taken up by some pheochromocytomas, but it detects only 25% of benign tumors; however, it may occasionally localize metastatic lesions that are missed by ¹²³I‐MIBG. ²³

Imaging studies are usually indicated only after biochemical determinations have established the presence of a pheochromocytoma; occasionally, however, in some subjects suspected of having familial pheochromocytoma it is justifiable to perform imaging studies even without biochemical evidence of the tumor, since some familial tumors may be identified before they secrete significant amounts of catecholamines.

Although CT and MRI are both highly accurate for localizing pheochromocytomas, we prefer initiating studies with MRI of the abdomen and pelvis, since a bright signal imparted by T2‐weighted images strongly suggests pheochromocytoma; furthermore, small extra‐adrenal tumors are more easily identified by MRI than CT. If a tumor is identified, the high specificity of MIBG uptake by pheochromocytomas can help confirm the diagnosis. If MRI and CT fail to identify a tumor in the abdomen or pelvis, we recommend MRI of the chest and neck and a whole‐body MIBG scan.

Incidentally recognized adrenal masses (incidentalomas) are encountered in 3%–4% of patients examined by CT; an MRI and MIBG can be especially useful in determining whether an incidentaloma is a pheochromocytoma. However, measurement of plasma and urinary catecholamines and their metabolites is essential to establish the diagnosis. A large survey ²⁴ revealed that 4.2% of incidentalomas were pheochromocytomas, but only 43% of these patients were hypertensive, despite urinary catecholamine elevations in 86%.

If efforts to locate a pheochromocytoma fail, sampling blood for catecholamine and free metanephrine and normetanephrine assay from various sites in the vena cava, with fluoroscopic guidance, may localize pheochromocytomas in abdominal, pelvic, intrathoracic, or cervical areas. Adrenal vein catheterization may stimulate catecholamine secretion from normal glands and is less reliable for tumor localization. Also, paroxysmal or variable tumor secretion of catecholamines during vena caval blood sampling may prevent accurate tumor localization. ²

When pheochromocytoma is suspected, the algorithm in Table III can be followed.

TREATMENT

Pheochromocytoma requires a physician, surgeon, and anesthetist who are experienced in its management. If not contraindicated, surgical removal, the only curative procedure, should be performed expeditiously.

MTC, C‐cell hyperplasia, hyperparathyroidism, and VHL should be considered in all patients with pheochromocytoma and in their relatives. Diagnosis and treatment of these conditions should be delayed until after pheochromocytoma removal.

Malignant hypertension, acute cardiovascular or abdominal complications (e.g., hemorrhagic necrosis in a pheochromocytoma), or acceleration in frequency and severity of hypertensive crises may necessitate immediate medical or surgical therapy, or both.

If the patient has very severe hypertension, a rapid i.v. bolus of phentolamine (5 mg) is usually effective in reducing pressure; if there is no response, the dose can be repeated every 2 minutes until blood pressure is adequately reduced. The effect of phentolamine is brief; therefore, repeated hypertensive crises are best controlled by infusing sodium nitroprusside, nitroglycerine, or phentolamine ² , ²⁵ at a rate that normalizes blood pressure. Nitroprusside can cause thiocyanate toxicity if the infusion is prolonged or if renal insufficiency exists.

If immediate surgery is necessary, hypovolemia is corrected by infusion of appropriate fluid and/or blood within 18 hours preoperatively to minimize postoperative hypotension.

Abdominal palpation and stressful procedures should be performed cautiously with drugs available to combat hypertensive crises, hypotension, or arrhythmias. Morphine and phenothiazines should be avoided, since they may precipitate hypertensive crises or hypotension and shock.

Adrenergic Blockade.

Preoperative α₁ and α₂ blockade with phenoxybenzamine (10–30 mg twice daily) or α₁ blockade with prazosin (starting with 1 mg and increasing to 1 or 2 mg two or three times daily) for 1 week or more and continued until surgery usually prevents severe preoperative clinical manifestations, reverses hypovolemia, and promotes smooth anesthetic induction and relatively stable blood pressure during surgery. Other α₁‐adrenergic antagonists (e.g., terazosin or doxazosin) and calcium channel blockers (e.g., nifedipine, nicardipine, diltiazem, verapamil) have effectively controlled pheochromocytic hypertension. Metyrosine (which blocks synthesis of catecholamines) alone or in combination with adrenergic or calcium antagonists may also be helpful in the preoperative control of blood pressure. ² , ²⁶ Complete blockade (with orthostatic hypotension) is contraindicated, since it prevents blood pressure elevations during intra‐ abdominal palpation (which can aid the surgeon in identifying some tumors difficult to locate) or prevents recognition of additional tumors (ordinarily indicated by persistence of hypertension after tumor removal).

Preoperative β₁ blockade (e.g., long‐acting metoprolol 50–150 mg once daily or other cardioselective β blockers), if not contraindicated, is used to prevent or treat supraventricular arrhythmias and tachycardia, or if angina occurs. For rapid control of ventricular tachycardia due to atrial fibrillation or flutter, i.v. esmolol (a short‐acting, cardioselective β₁ blocker) may be effective. Ventricular arrhythmias are treated with lidocaine (50–100 mg i.v. bolus). Beta blockers should never be given without first creating a blockade, since β blockade alone can cause marked hypertension. This is particularly apt to occur with nonselective β blockers (e.g., propranolol or nadolol), since they inhibit any vasodilating effect of epinephrine by blocking β₂ receptors and thus enhance vasoconstriction. A relatively cardioselective β₁ blocker (e.g., metoprolol, bisoprolol, or atenolol) is more appropriate, since it has less vascular effect.

Combined α‐ and β1‐adrenergic blockade and metyrosine may be effective in combating severe constipation and the rare complication of intestinal pseudo‐obstruction that results from impaired intestinal motility due to excess catecholamines. ²⁷ Labetalol (an α and β blocker) may effectively control hypertension and other manifestations of pheochromocytomas; however, we do not use it, since it sometimes causes hypertension. ²

Preoperative, Operative, and Postoperative Management.

Preoperatively, diazepam, secobarbital, or meperidine should be given to allay anxiety, which may trigger release of tumor catecholamines. Fentanyl and droperidol are avoided, since they may also trigger release of catecholamines. Atropine is avoided, since it may enhance tachycardia caused by hypercatecholaminemia. A muscle relaxant should be administered before endotracheal intubation to minimize a hypertensive response, and arterial pressure, EKG, and arterial blood gases should be monitored. Isoflurane is the most popular anesthetic, although enflurane is also suitable for pheochromocytoma removal. ²

During intubation and surgery, prompt treatment of hypertensive crises with i.v. nitroprusside, phentolamine, or nitroglycerine and control of arrhythmias with i.v. esmolol and/or lidocaine is crucial. Generous intraoperative volume replacement of significant blood loss is essential to prevent postoperative hypotension. ²

Prior to 1996, there was general agreement that an anterior transperitoneal incision was mandatory to remove intra‐abdominal pheochromocytomas, since tumors may be multiple and extra‐adrenal. However, with the remarkable improvement of imaging techniques and with increasing experience with laparoscopic removal of adrenal and some extra‐adrenal pheochromocytomas, open surgical exploration is now indicated only when tumors are multiple, large, or particularly difficult to remove laparoscopically. The adrenal vein is usually easier to locate in pheochromocytomas that are relatively small, and prompt vein ligation can prevent hypertensive episodes during laparoscopic removal. ²⁸ , ²⁹

Some recommend that only adrenal pheochromocytomas less than 5 cm in diameter should be removed laparoscopically. ²⁹ At the Mayo Clinic, Dr. John van Heerden (personal communication, 2002) believes laparoscopic removal of a pheochromocytoma should be limited to a diameter of 4 cm, since they are usually easy to remove without tumor fracture, which could leave tumor cells in the peritoneal cavity. Laparoscopic tumor removal causes less postoperative pain, a shorter hospitalization, and a better cosmetic result.

Neumann et al. ³⁰ reported successful preservation of adrenocortical function after laparoscopic bilateral adrenal‐sparing surgery for hereditary pheochromocytoma. This avoids lifelong steroid replacement, which is required when bilateral adrenalectomy is indicated in MEN syndromes. Patients with hypercalcitonemia and/or hypercalcemia should be re‐evaluated after pheochromocytoma removal, since return of these elevations to normal eliminates MEN as the cause of these biochemical abnormalities.

Pheochromocytomas of the chest, neck, and urinary bladder require special surgical procedures; otherwise, management is similar to that of abdominal tumors. Pheochromocytomas discovered during pregnancy should be removed, but if pregnancy is carried to term, a cesarian section is advisable to avoid the stress of labor and vaginal delivery.

Close postoperative observation is mandatory. Hypovolemia and hemorrhage at operative sites can cause hypotension requiring volume replacement. Hypertension may result from fluid overload, pain, urinary retention, hypoxia, hypercarbia, or residual pheochromocytoma. Inadvertent renal artery ligation may cause hyper‐reninemia, but hypertension would probably not occur for several days or weeks postoperatively. ²

Severe, transient hypoglycemia with central nervous system manifestations and coma may occur within 2 hours following operation. Hypoglycemia results from increased insulin secretion, which α blockers may augment by reducing inhibition of catecholamines on insulin secretion. Beta blockers can impair recovery from hypoglycemia by reducing gluconeogenesis and glycogenolysis, and can mask hypoglycemic signs by preventing tachycardia and tremor; sweating may also be impaired. ³¹ Blood glucose should be repeatedly analyzed for several hours postoperatively and hypoglycemia treated promptly. Initiating an infusion of 5% dextrose in water immediately following tumor removal and continuing it for several hours will prevent hypoglycemia.

About 25% of patients remain hypertensive following tumor removal. This is possibly due to coexisting essential hypertension. Five‐year survival for patients with benign pheochromocytoma is 95%, but varies from 36%–50% with malignant tumors. In medical centers with extensive experience in treating pheochromocytomas, operative mortality has been low (0%–3.3%). ² Expertise is essential!

Long‐Term Medical Management.

If a malignant pheochromocytoma cannot be totally removed, as much as possible should be resected to minimize functioning tumor tissue. Radiation therapy of metastases in bone may be effective. Irradiation with radioactive MIBG may temporarily reduce the size and catecholamine secretion in about 25% of tumors, but inevitably all patients relapse within 2 years; this therapy is rarely used in the United States. ²

When patients with metastatic disease become symptomatic and tumors appear especially aggressive, combination i.v. chemotherapy with cyclophosphamide, vincristine, and dacarbazine is indicated, since it will reduce tumor mass, catecholamine excretion, and symptomatology in 50% of patients. ³² Antihypertensive medication should be increased before treatment, and one should be prepared to treat hypertensive crises, since chemotherapy will damage tumor cells, resulting in the release of catecholamines. ²

Alpha and β blockers may control symptomatology and blood pressure for many years in patients with metastatic tumors. Beta blockers may also prevent catecholamine cardiomyopathy. Metyrosine can markedly inhibit catecholamine synthesis and reduce symptomatology, and it may be helpful in the treatment of catecholamine cardiomyopathy. As malignant metastases continue to grow, larger doses of metyrosine are usually required to minimize hypercatecholaminemia and delay its detrimental effects; however, large doses may cause undesirable side effects, e.g., crystalluria and renal damage, psychic disturbance, and occasionally a Parkinson‐like syndrome.

An occasional patient with metastatic pheochromocytoma will develop a hypersecretory disorder with severe diarrhea that may respond to i.v. somatostatin.

Finally, it is noteworthy that some beneficial results in treating metastatic pheochromocytomas in the liver with radiofrequency ablation have been observed in several patients treated at the Mayo Clinic (Dr. William F. Young, personal communication, 2002). A probe, which is passed percutaneously into an hepatic metastatic lesion, delivers sufficient heat to destroy the metastasis and replace it with an empty cyst.

CONCLUSION

Pheochromocytoma is a rare and treacherous tumor, since, if not recognized and treated appropriately, it is invariably fatal. Physicians must be especially alert to recognize and diagnostically evaluate all patients with sustained or paroxysmal hypertension associated with headaches, sweating, or palpitations. Biochemical and imaging studies can almost always confirm or refute the diagnosis of this catecholamine‐secreting tumor. Surgical removal is usually curative. Pheochromocytomas that are malignant may often be treated for prolonged periods with antihypertensive drugs and chemotherapy.

Acknowledgment: This report was supported by the National Hypertension Association. We wish to thank Alla Krayko and Ruth Johnston for their expert secretarial assistance.