AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Pheochromocytoma, a tumor of neuroendocrine origin, is a rare tumor found in children and adults and is a cause of essential hypertension. Pheochromocytoma is a catecholamine-secreting tumor that arises from chromaffin cells of the sympathetic nervous system (adrenal medulla and sympathetic chain); however, the tumor may develop anywhere in the body. These tumors release catecholamines into the circulation, causing significant hypertension. The classic clinical presentation includes paroxysmal attacks of headaches, pallor, palpitations, and diaphoresis.

Pheochromocytoma may be inherited as an autosomal dominant trait. Recently, several genes (SDHD, SDHB, SDHC) that belong to the mitochondrial complex II have been identified as involved in the so-called pheochromocytoma-paraganglioma syndrome. The term paraganglioma refers to any extra-adrenal or nonfunctional tumor of the paraganglion system, whereas functional tumors are referred to as extra-adrenal pheochromocytomas.

In children, pheochromocytoma is more frequently associated with other familial syndromes, such as neurofibromatosis, von Hippel-Lindau disease, tuberous sclerosis, and Sturge-Weber syndrome, and as a component of multiple endocrine neoplasia (MEN) syndromes (MEN 2A, MEN 2B). Familial cases are often bilateral or multicentric within an individual adrenal gland. Adrenal pheochromocytomas are most often found on the right side and are sporadic, unilateral, and intra-adrenal. Approximately 6-10% of the tumors are malignant.

Usually, extra-adrenal tumors (extra-adrenal pheochromocytomas or paragangliomas) are located in the abdomen along the sympathetic chain and constitute about 10% of sporadic cases. Tumors have also been found in the neck, mediastinum, urinary bladder, and virtually every other site. Tumors vary from approximately 1-10 cm in diameter. Slowly growing metastases to bone, liver, lymph nodes, and lung can arise from malignant tumors.

Early diagnosis is important because the tumor may be fatal if undiagnosed, especially in pregnant women during delivery or in patients undergoing surgery for other disorders. Diagnosis can be made based on elevated levels of urinary catecholamines, but localization may require various modalities.

Pathophysiology

Pheochromocytoma is a tumor of neuroendocrine origin. In the fifth week of development, neuroblastic cells migrate from the thoracic neural crest to form the sympathetic chains and preaortic ganglia. These cells are believed to be the precursors of neuroblastomas and ganglioneuromas. Chromaffin cells migrate a second time to the adrenal medulla; the chromaffin cells settle near the sympathetic ganglia, the vagus nerve, paraganglia, and carotid arteries. Other, less common sites of extra-adrenal chromaffin tissues include the bladder wall, prostate, behind the liver, hepatic and renal hili, rectum, and gonads.

The pathophysiology of the pheochromocytoma is best appreciated with an understanding of catecholamine biochemistry. The following is an abbreviated version of the important steps in the biosynthesis and metabolism of catecholamines.

Tyrosine ® Dihydroxyphenylalanine (DOPA) ® Dopamine (DA) ® Norepinephrine + Epinephrine ® Homovanillic acid (HVA) + Vanillylmandelic acid (VMA)

The biosynthesis and storage of catecholamines in chromaffin cell tumors may differ from the biosynthesis and storage in the normal medulla. However, the granules are morphologically and functionally similar to the granules from the adrenal medulla. The increase in tissue turnover suggests an alteration in the regulation of the catecholamine biosynthesis and possibly suggests an alteration in the feedback inhibition of tyrosine hydroxylase, the key enzyme in the production of catecholamines.

Pheochromocytomas, unlike the normal adrenal medulla, are not innervated, and catecholamine release is not initiated by neural impulses. Changes in direct flow, pressure, chemicals, drugs, and angiotensin II may initiate the release of catecholamines into the circulation.

Most pheochromocytomas in children predominantly produce norepinephrine, unlike the normal adrenal medulla, which, in humans, contains 85% epinephrine. Rarely, tumors produce epinephrine exclusively; in some cases, the clinical picture is dominated by signs of beta-receptor stimulation, such as tachycardia and hypermetabolism. However, in most cases, predicting the pattern of catecholamine secretion based on the clinical picture is impossible.

To determine catecholamine hypersecretion, norepinephrine, epinephrine, and their catabolic products (VMA, HVA) are measured in the urine. This measurement is the cornerstone of pheochromocytoma diagnosis. A total urinary catecholamine excretion that exceeds 300 mcg/d is commonly found, provided that the patient is symptomatic or hypertensive at the time of the collection. Specific assays of epinephrine are frequently beneficial because excretion in excess of 50 mcg/d suggests an adrenal lesion. In patients with benign pheochromocytoma, excretion levels of DA and DA metabolites, such as HVA, are usually normal. Increased levels of urinary DA of HVA excretion suggests malignancy.

The actions of catecholamines are mediated by the alpha-adrenergic and beta-adrenergic receptors. Alpha1 receptors cause arteriolar constriction. Alpha2 receptors mediate the presynaptic feedback inhibition of norepinephrine release and decrease insulin secretion. Beta1 receptors increase cardiac rate and contractility. Beta2 receptors cause arteriolar and venous dilation and relaxation of tracheobronchial smooth muscle. The symptoms associated with pheochromocytomas are caused by the physiologic and pharmacologic effects of large amounts of circulating norepinephrine and epinephrine.

Tumor size correlates with the ratio of free catecholamine metabolites in the urine. Small pheochromocytomas tend to have low concentrations of catecholamines with high turnover and low urinary VMA-catecholamines ratios. Conversely, large tumors tend to have high concentrations of catecholamines, low turnover rates, and high urinary VMA-catecholamine catecholamine ratios. Small tumors that store catecholamines well or metabolize a substantial amount of catecholamines within the tumor grow larger before becoming manifest.

Frequency

United States

The reported incidence rate of pheochromocytomas is approximately 1 case per 100,000 persons, with 10-20% of cases occurring in children or adolescents. Children have a higher frequency of bilateral tumors than adults (20% vs 5-10%) and a lower incidence of malignancy (3.5% vs 3-14%). More than one third of affected children have multiple tumors, most of which are recurrent. In children, 70% of cases are unilateral, 70% of cases are confined to adrenal locations, and an increased association with familial syndromes exists. In 30-40% of children with pheochromocytomas, tumors are found in both adrenal and extra-adrenal areas or in only extra-adrenal areas. No geographic predilection is known.

Mortality/Morbidity

The prognosis of this disease appears to be related to tumor quantity and the degree of uncontrolled hypertension, as well as the presence of metastatic disease. Serious morbidity and mortality may be associated with uncontrolled hypertension, including myocardial infarction, stroke, arrhythmias, irreversible shock, renal failure, and dissecting aortic aneurysm. Special consideration must be given to prepare these patients for surgery, in whom dramatic blood pressure swings may be observed. Malignant pheochromocytomas, which are rare in children, are locally invasive and may spread to distant areas that do not contain chromaffin cells, including the liver, lung, bone, and lymph nodes. The mean 5-year survival rate in patients with malignant pheochromocytomas is 40%.

Recently, Khorram-Manesh et al, a group in Sweden, analyzed the long-term outcome of surgically treated patients who had pheochromocytoma between 1950 and 1997.¹ Over 15 (±6) years, 42 patients died, compared with 23.6 deaths expected in the general population (P < 0.001). Besides older age at primary surgery, elevated urinary excretion of methoxy-catecholamines was the only observed mortality risk factor. Preoperative and postoperative hypertension did not influence the mortality risk compared with controls.

Sex

Although pheochromocytomas are found in both sexes, the male-to-female ratio is 2:1.

Age

In childhood, pheochromocytomas present most frequently in children aged 6-14 years (average, 11 y).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Pheochromocytomas may cause various clinical signs, including paroxysms of hypertension (80%), diaphoresis (71%), palpitation with or without tachycardia (64%), pallor (40%), nausea with or without vomiting (42%), tremor (31%), weakness or exhaustion (28%), nervousness or anxiety (22%), epigastric pain (22%), chest pain (19%), dyspnea (19%), flushing or warmth (18%), numbness or paresthesia (11%), blurred vision (11%), tightness of throat, dizziness, convulsion, neck or shoulder pain, extremities pain, flank pain, tinnitus, dysarthria, and unsteadiness. These paroxysms occur at varying intervals, from several times a day to once every month or more; however, in children, hypertension is most often sustained. All patients with pheochromocytoma experience hypertension at some point.

• Hypertension appears to be uniformly present and is sustained in 80-90% of affected children at the time of diagnosis. Occasionally, children with sustained hypertension also have paroxysmal episodes. The paroxysms are occasionally precipitated by excitement or a particular physical activity, such as bending over or lifting a heavy object.
• Convulsions secondary to hypertensive encephalopathy may occur.
• The blood pressure may range from 180-260 mm Hg systolic and from 120-210 mm Hg diastolic.
• • Wide fluctuations in blood pressure are characteristic, and marked increases may be followed by hypotension and syncope.
  • When the blood pressure is elevated, postural hypotension may also be present.
• Headache is the most frequent symptom in children (75%), followed by sweating in two thirds of patients and nausea and vomiting in half of patients. These headaches are usually described as pounding.
• Pallor is usually present because of the intense alpha-receptor–mediated peripheral vasoconstriction, which causes cool moist hands and feet and facial pallor.
• Palpitations mediated by beta1 receptors result in increased cardiac output and heart rate.
• Hyperthermia or flushing secondary to decreased heat loss and increased metabolism leads to reflex sweating.
• Poor weight gain or severe cachexia may develop because of hypermetabolism. The child may have a good appetite but, because of hypermetabolism, does not gain weight.
• Polyuria and polydipsia may be found as a result of increased glycolysis and alpha-receptor–mediated inhibition of insulin release. This insulin inhibition causes an increase in blood sugar levels and glucose intolerance. As a result, patients may present with diabetes mellitus or glucose intolerance, most commonly during paroxysms.
• Hypercalcemia is an uncommon but well-recognized complication that may reflect associated hyperparathyroidism, particularly in familial cases.
• A syndrome consisting of watery diarrhea, hypokalemia, and achlorhydria secondary to the ectopic production of vasoactive intestinal peptide has been described. This syndrome and other laboratory markers of dehydration, such as elevation of the BUN and hematocrit levels, usually resolve when the tumor is removed.
• The clinical course of pheochromocytoma may be adversely affected by drugs or diagnostic studies that affect catecholamine metabolism, such as opiates, cold medicine, decongestants, and some contrast dyes.
• Hypertensive retinopathy and cardiomyopathy are often present. Ophthalmoscopic examination may reveal papilledema, hemorrhages, exudates, and arterial constriction.
• Bone lesions have been described following changes in the microcirculation.
• In severe cases, precordial pain may radiate into the arms. Pulmonary edema and cardiac and hepatic enlargement may also develop.
• Myocarditis characterized by focal degeneration and necrosis of myocardial fibers with infiltration of histiocytes, plasma cells, and other signs of inflammation may be present.
• Affected children are often emotionally labile and have an anxious expression. Occasionally, these children are labeled hyperactive with an attention deficit disorder.
• Nocturnal enuresis that does not respond to fluid restriction and voiding before bedtime may develop.

Physical

• Hypertension present in both arms and legs may develop.
• Patients with pheochromocytomas usually have a thin body habitus, but the presence of obesity does not rule out pheochromocytomas.
• Upon cardiovascular examination, tachycardia with forceful heartbeat is often found and is easily palpable.
• Patients may feel warm and have pallor of the face and chest.
• Body perspiration and cool moist hands and feet are also found upon physical examination.
• A mass may be palpable in the neck or in deep palpation of the abdomen. Deep palpation of the abdomen may produce a typical paroxysm.
• Postural hypotension caused by chronic constriction of the arterial and venous beds leads to a reduction in plasma volume. The inability to further constrict the bed upon arising results in postural hypotension.

Causes

Pheochromocytoma occurs wherever chromaffin tissue is found.

• Mutations in genes that code for 3 of the 4 components of mitochondrial complex II can cause paragangliomas and pheochromocytomas. The 3 genes include SDHB, SDHC, and SDHD.
• • SDHC and SDHD anchor the catalytic subunits (SDHA, SDHB) of mitochondrial complex II in the inner mitochondrial membrane. SDHD is maternally imprinted, whereas SDHB and SDHC are not. Although SDHD and, to a lesser degree, SDHB mutations have been found in many cases of hereditary paragangliomas, SDHC mutations are rare.
  • Amar et al (2005) studied 314 patients with pheochromocytoma or functional paraganglioma.² Fifty six patients had family history, syndromic disease, or both, and 258 patients had sporadic presentation. Among the 56 patients with a family history, syndromic presentation, or both, 13 had neurofibromatosis type 1, and 43 had germline mutations on the VHL, RET, SDHD, or SDHB genes (16, 15, 9, and 3 patients, respectively). Only 11% of the patients with sporadic disease had a germline mutation (18 patients had a SDHB mutation, 9 patients had a VHL mutation, 2 patients had a SDHD mutation, and 1 patient had a RET mutation). Carriers were young and frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, usually extra-adrenal, and malignant.
  • Genetic testing should be performed in all patients with pheochromocytoma who have a family history of pheochromocytoma or paraganglioma syndrome, all patients with bilateral or multicentric adrenal pheochromocytomas, all patients with sympathetic paragangliomas, especially multiple tumors, and all patients younger than 35 years.³
  • Recently, Jimenez et al (2006) suggested that the age for screening of sporadic pheochromocytoma should be reduced to patients younger than 20 years.⁴ Their recommendation was based on a study done by Neumann et al (2002), which found that hereditary disease (70% of cases are VHL mutations) is usually seen in young patients.⁵ Furthermore, in patients older than 50 years, the probability of having any genetic mutation is less than 1.3%. Thus, genetic testing should be done in young adults, focusing on ruling out VHL mutations first, followed by mutations in MEN2, SDHB, and SDHD.
• Pheochromocytomas are usually sporadic, but they may be familial and appear as a component of other syndromes, such as MEN 2A (medullary thyroid carcinoma, parathyroid hyperplasia, pheochromocytoma). Germline mutations of the ret proto-oncogene on chromosome 10 (10q11.2) have been found in families with MEN 2A and MEN 2B (medullary thyroid carcinoma, neuromas, pheochromocytoma).
• In von Hippel-Lindau syndrome, specific mutations determine the varied clinical manifestations, which, in addition to pheochromocytomas, include retinal angiomas; cerebellar hemangioblastomas; and renal, pancreatic, and epididymal tumors. A germline mutation in a tumor suppressor gene on chromosome 3 has been identified.
• Pheochromocytoma is also associated with tuberous sclerosis, Sturge-Weber syndrome, and ataxia-telangiectasia.
• Malignant pheochromocytomas occur in 10-15% of cases. Histological discrimination from benign cases is unreliable. Possible tissue markers for malignancy have been characterized, including different angiogenetic factors, including cyclooxygenase-2, secretogranin II-derived peptide, and heat-shock protein 90 (hsp90), which are mutations in the SDHB gene that encode succinate dehydrogenase subunit B. Expression of human telomerase reverse transcriptase (hTERT) with concomitant high telomerase activity or high Ki-67 immunoreactivity apparently identifies invasive behavior of the tumor with notable specificity.
• Altered states of hsp90 and hTERT may not only be useful for the classification of pheochromocytomas as malignant but could also hold therapeutic potential because cancer cells might be especially dependent on hsp90 to ensure correct folding and function of the large quantities of mutated and overexpressed oncoproteins.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Ganglioneuromas
Severe anxiety states
Autonomic epilepsy
Toxicity, Monoamine Oxidase Inhibitor
Hypertensive crisis associated with paraplegia, tabes dorsalis, Lead Poisoning, Porphyria, Acute Intermittent

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The standard method for confirming the diagnosis of pheochromocytomas is to measure the following urinary catecholamines and their metabolites in a 24-hour specimen:
• • Epinephrine
  • Norepinephrine
  • Dopamine
  • Metanephrine
  • HVA
  • VMA
• Creatinine levels should be determined for each 24-hour collection to assess its adequacy. If possible, the collection should be made while the patient is at rest, taking no medication, and without recent exposure to radiographic contrast medium.
• Medications and foods that are known to interfere with the assay should be avoided.
• Urine should be acidified (pH <3) and kept cold during and after the collection. The diagnostic yield is increased if the patient is symptomatic during the collection period.
• The major cause of false-positive catecholamine excretion results is administration of exogenous catecholamines, such as levodopa, methyldopa, and labetalol, which can elevate urine concentration for as long as 2 weeks.
• Excessive stimulation of the sympathoadrenal system, such as those occurring in hypoglycemia, strenuous exertion, increased intracranial pressure, and clonidine withdrawal, may also increase catecholamine excretion enough to provide a false-positive result.
• In adults, the conditions associated with an elevated DA level include overcollection of urine, drug effects (eg, levodopa, methyldopa, clozapine, antidepressants, metoclopramide), and clinical effects (including those due to pheochromocytoma, carcinoid tumor, and pregnancy). In children, high urine DA levels are found in cases of neuroblastoma, Costello syndrome, leukemia, pheochromocytoma, Menkes disease, and rhabdomyosarcoma of the bladder.
• Other studies include the following:
• • CBC count: This test is indicated when infection or abdominal pain is present.
  • Electrolytes, BUN, creatinine, and glucose determinations: Evaluate for lactic acidosis; renal failure secondary to hypertension, renal damage, or both; and hyperglycemia or hypoglycemia caused by the impaired insulin response.
  • Calcium measurement: High levels may be present because of excess of parathyroid hormone (PTH).
  • Urinalysis: Proteins may be found in the urine because of hypertension.
• Measurement of plasma catecholamines is as follows:
• • Patients must be in a basal and calm state.
  • The measurement reflects only that single moment when the blood sample was obtained.
  • Basal levels of more than 2 ng/dL support the diagnosis, whereas values of less than 0.5 ng/dL make the diagnosis unlikely.
  • Suppression tests (eg, phentolamine, clonidine) and stimulation tests (eg, glucagon, histamine, metoclopramide) have both been proposed for improving diagnostic accuracy. Stimulation tests are dangerous. Administer with extreme caution.
  • • Consider a glucagon stimulation test if basal values are from 0.5-1 ng/dL. Patients demonstrate a significant rise in plasma catecholamine levels within minutes of glucagon administration; however, this can lead to severe hypertension.
    • When the values are 1-2 ng/dL, a clonidine suppression test, which is highly sensitive and specific, is indicated. Mildly elevated levels of catecholamines in healthy individuals are suppressed by a dose a clonidine. The clonidine suppression test (0.3 mg) involves the collection of plasma free normetanephrine before and after oral administration of clonidine.
  • Measurement of plasma normetanephrine and metanephrine are useful in screening for pheochromocytomas in patients with a familial predisposition to von Hippel-Lindau disease or MEN type 2.
  • Free plasma metanephrines has been found to be a highly sensitive (100%) and specific (96.7%) measure, yielding a negative predictive value of 100%.
  • Measurement of 24-hour urinary fractionated metanephrines using a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of pheochromocytoma. Twenty-four–hour urinary fractionated metanephrines using tandem mass spectrometry with cut-offs for positivity are defined as follows:
  • • Total metanephrines (sum of the metanephrine fractions) - 5163 nmol/d
    • Normetanephrine fraction - 4001 nmol/d
    • Metanephrine fraction - 1531 nmol/d
  • The diagnostic efficacy of 24-hour urinary fractionated metanephrines using tandem mass spectrometry with cut-offs for positivity is as follows:
  • • Normetanephrine fraction sensitivity is 87.3% (95% confidence interval [CI], 79.4-92.4%), and specificity is 95.0% (95% CI, 92.5-96.8%).
    • Metanephrine fraction sensitivity is 56.9% (95% CI, 47.2-66.1%), and specificity is 95.0% (95% CI, 92.5-96.8%).
    • Elevation of either normetanephrine or metanephrine fraction sensitivity is 97.1% (95% CI, 91.7-99.0%), and specificity is 91.1% (95% CI, 87.9-93.5%).
  • Areas under the receiver operating characteristic (ROC) curves are as follows:
  • • Total metanephrines - 0.991 (95% CI, 0.958-0.996)
    • Normetanephrine fraction - 0.972 (95% CI, 0.955-0.990)
    • Metanephrine fraction - 0.8 (95% CI, 0.741-0.858)
    • Metanephrine and normetanephrine fractions - 0.991 (95% CI, 0.985-0.996) 
  • The detection of a low molecular weight region of serum proteome has helped to distinguish between metastatic and benign forms of pheochromocytomas. If confirmed in larger validation studies, the measurement of these biomarkers could be used to improve the ability to identify patients with metastatic disease.
  • Adrenal incidentalomas (AI) are defined as asymptomatic adrenal masses occasionally discovered during high-resolution imaging procedures, such as CT scanning or MRI. Pheochromocytoma must be excluded before any invasive diagnostic or therapeutic procedure. Chromogranin-A (CgA) is a member of the granin family contained in secretory vesicles of chromaffin adrenal cells. Serum CgA increases in patients affected by pheochromocytoma and other diseases of the chromaffin system. Patients with AIs larger than 20 mm without clinical or biochemical signs and a positive 123I-metaiodobenzylguanidine (MIBG) finding had a confirmed pheochromocytoma in all cases.

Imaging Studies

• When the diagnosis has been established, the tumor must be located to facilitate its surgical removal. Although larger tumors can usually be located easily with sonography, the smallest tumors may require CT scanning or MRI, particularly when located outside the adrenal area.
• • The average diameter of a pheochromocytoma is approximately 5 cm at the time of diagnosis, and the sensitivity of CT scanning or MRI approaches 100%, although the specificity is lower. The major drawback of CT scanning is its relatively poor tissue discrimination, particularly in the perinephric zone.
  • A head CT scan is indicated if abnormal neurologic examination findings are noted.
• Scintigraphy with radiolabeled 131I-MIBG or 123I-MIBG is indicated.
• • MIBG scintigraphy allows whole-body exploration. Owing to its high specificity (97%), this morphological study seems to be a valuable adjunct in the detection of extra-adrenal lesions. The main limitation of MIBG scintigraphy is its slightly lower sensitivity (adrenal, 84%; extra-adrenal, 64%) than MRI (adrenal, 97%; extra-adrenal, 88%) or CT scanning (adrenal, 94%; extra-adrenal, 64%). However, despite the lower sensitivity, MIBG scanning offers the greatest specificity, and tumors seen on these images are almost certainly pheochromocytomas. If the MIBG scanning results are positive in a child, consider a diagnosis of neuroblastoma until proven differently.
  • When a pheochromocytoma is suspected biochemically and is not visualized on standard studies, consider the possibility of an intrathoracic or intracranial tumor. MRI is probably the best study for detecting extra-abdominal tumors, although MIBG scanning may help reveal the general location of the tumor. CT scans or MRI can be focused in that region to localize the tumor.
  • MIBG may be used to seek extra-adrenal tumors or to provide additional diagnostic information about adrenal masses found with conventional techniques.
• Arteriography and selective venous sampling are almost never indicated. However, they may be helpful in patients predisposed to multiple tumors or when clinical and biochemical evidence is consistent with pheochromocytoma but are unsupported by other imaging modalities. If a dominant tumor is identified and another smaller lesion is seen (particularly in the contralateral adrenal gland) that does not appear typical for pheochromocytoma on MRI or MIBG scanning, selective venous sampling may resolve the issue.
• Chest radiography can be used to evaluate for pulmonary edema.
• The course of pheochromocytoma may be adversely affected by drugs or diagnostic studies that affect catecholamine metabolism. Severe and fatal crises have been induced by opiates, histamine, corticotropin, saralasin, glucagon, metoclopramide, and pancuronium. The intra-arterial administration or radiographic contrast media releases catecholamines; if pheochromocytoma is suspected, perform arteriography only in patients who have received adrenergic blocking agents. However, radiopaque contrast media can be safely intravenously administered. Cold medicines and decongestants that contain sympathomimetic amines can worsen symptoms. Drugs that block the neuronal uptake of catecholamines, such as guanethidine and tricyclic antidepressants, may enhance the physiological effects of circulating catecholamines.

Other Tests

• ECG findings may be abnormal, exhibiting changes such as left ventricular hypertrophy, tachycardia, and arrhythmias.

Histologic Findings

Characteristically, pheochromocytomas have 2 populations of cells that can be observed with microscopy and distinguished with immunohistochemistry; the cells in the Zellballen stain positive for chromogranin, neurospecific enolase markers for cells of neuronal derivation, or both, whereas the sustentacular cells stain positive for S-100 protein (a marker for cells of schwannian derivation). With electron microscopy, the cells in the Zellballen show neuronal features with abundant ectoplasmatic processes that contain dense-core neurosecretory granules.

Benign and malignant pheochromocytomas cannot reliably be distinguished with microscopy examination. Features that have been suggested to correlate with malignancy behavior include degree of necrosis, nuclear pleomorphism, mitotic rate, capsular invasion, and vascular invasion; none of these has proven to reliably indicate malignancy. Only the presence of metastatic disease is an absolute indicator of malignancy.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Perform initial workup using the history, physical examination, laboratory, and diagnostic test findings. Indications for evaluation include the following:
• • Patients with high blood pressure or recurrent hot flushes that are indicative of blood pressure peaks
  • Patients with an adrenal mass
  • Screening of relatives of patients with MEN 2 or von Hippel-Lindau disease
• Schedule surgical removal only after successful pharmacotherapy to block the effects of catecholamine excess. Blockade of the alpha-adrenergic receptors in the preoperative phase is widely recommended, with additional beta-receptor blockade to treat cardiac dysrhythmias.
• Perform procedures in a hospital with the capability for intensive intraoperative and postoperative monitoring and therapy.
• During a hypertensive crisis, immediately institute alpha-blockade with phentolamine. Nitroprusside also should be used for uncontrolled hypertension.
• For further blood pressure control, initiate beta-blockade (esmolol-labetalol). A beta-blockade that is initiated without prior alpha-blockade can further exacerbate hypertension. As vasoconstriction is relieved, use vigorous fluid resuscitation to maintain a normal blood pressure.
• Ventricular tachyarrhythmias can be treated with lidocaine and amiodarone.
• The results of malignant pheochromocytoma appear to be related to the tumor quantity and the aggressiveness of the therapy. The long-term survival rate in patients with untreated malignant or unresectable tumors is unclear. Because of the rarity of the condition, no randomized clinical trials concerning the treatment of malignant pheochromocytoma have been performed.
• Chemotherapy and radiotherapy have been of questionable value in patients with unresectable disease. Unresectable disease may be rendered resectable by intensive chemotherapy. Chemotherapy currently has a response rate of approximately 50%. Unless chemotherapy allows surgical removal of the entire tumor, it is not usually curative. However, chemotherapy offers good palliation (for years) in a significant number of patients. On the other hand, if the treatment is fairly aggressive, palliation therapy (pain, catecholamine excess) may be long term (years).
• The strategy established best is 131I-MIBG therapy, which is well tolerated. MIBG is specifically taken up by chromaffin cells. MIBG can induce remission for a limited period in a significant proportion of patients. Similar to MIBG, cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, can induce remission for a limited period. Octreotide as a single agent seems to be largely ineffective. The value of radiation therapy in patients with malignant pheochromocytoma is debatable.

Surgical Care

Surgery to remove pheochromocytomas is a high-risk procedure because of several reasons. Substantial comorbidity must be expected, including catecholamine-induced myocardiopathy. Intraoperative manipulation of the tumor may induce excessive catecholamine excretion, resulting in a life-threatening hypertensive crisis. Hypotensive crisis may occur because of a postoperative drop of catecholamines.

Transabdominal surgery has been the traditional approach; it allows early ligation of the adrenal vein to minimize systemic catecholamine release during manipulation. This approach also facilitates exploration of the sympathetic chain for multifocality.

Other options include a subcostal or posterior extraperitoneal approach that offers rapid recovery and avoids the risk of transperitoneal surgery (adhesions, bowel obstruction). Alternatively, a laparoscopic adrenalectomy can be considered; tumors as large as 11 cm have been successfully removed. The contraindications to laparoscopy include evidence of soft-tissue or vascular extra-adrenal extension. Bilateral tumors develop in children with multiple endocrine neoplasia type 2 and pheochromocytoma, and bilateral adrenalectomy has been recommended at presentation.

• Careful and intensive monitoring of the patient's status throughout the perioperative period is imperative.
• Hypotension that develops after tumor removal reflects reversal of the volume-contracted state and should respond to judicious replacement of fluids.
• Some patients may develop pulmonary edema, possibly as a result of impaired myocardial function and the inability to tolerate intravenous fluids.
• When the tumor is removed, the blood pressure usually falls to approximately 90/60 mm Hg. Lack of a fall in pressure at the time of tumor removal indicates the presence of additional tumor tissue.
• When bilateral adrenal tumors are found and both adrenals are removed, adrenocortical lifelong steroid replacement is required. Significant morbility is associated with bilateral adrenalectomy. Because of these risks, some clinicians have recommended adrenal-sparing surgery in patients who have bilateral tumors or who are at particular risk for a metachronous contralateral tumor.

Consultations

Obtain consultations as needed for comorbid conditions and their definitive treatment (eg, pediatric surgeon, cardiologist, ophthalmologist, endocrinologist).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

To provide optimal treatment of patients with pheochromocytomas, an understanding of the pathophysiology produced by excessive catecholamines and an acquaintance with the action of adrenergic antagonists and other drugs used in the treatment of these patients is necessary.

Drug Category: Alpha-adrenergic blocking agents

These agents are used preoperatively in combination with beta-blockers. At low doses, alpha-adrenergic receptor blockers may be used as monotherapy in the treatment of hypertension. At higher doses, the agents may cause sodium and fluid to accumulate. As a result, concurrent diuretic therapy may be required to maintain the hypotensive effects of the alpha-receptor blockers.

Drug Category: Beta-adrenergic blocking agents

These agents are used as adjunctive therapy for cardiac effects. The agents inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation.

Drug Category: Nitrates

These agents provide peripheral and coronary vasodilation.

Drug Category: Antiarrhythmic agents

These agents alter the electrophysiologic mechanisms responsible for arrhythmia.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Further inpatient care is necessary if the patient has episodes of sustained hypertension or life-threatening paroxysms.
• Close monitoring is required, making an intensive care unit the most suitable place for admission. In this setting, the patient is prepared for surgical removal of the tumor.

Further Outpatient Care

• Follow-up: All patients should undergo catecholamines measurements approximately 1 week postoperation to confirm a cure. Long-term follow-up is required because of the possibility of metachronous recurrence. Levels of catecholamines should be measured yearly until the likelihood of recurrence is very low (>5 y).
• Long-term medical management: In some patients, long-term medical management is necessary because of disseminated malignancy or some other intercurrent illness that makes surgery inappropriate. Most tumors grow slowly, and the manifestations of catecholamine excess can be controlled by adrenergic blocking agents in conjunction with metyrosine, which reduces catecholamine biosynthesis by the tumor.
• Malignant pheochromocytoma: Pheochromocytoma usually recurs in the retroperitoneum or appears as metastatic deposits in bone, lung, or liver. Recurrence can be found years after the initial surgery. Radiation therapy is usually not effective but may be of value for control of metastatic disease in bone. Limited success has been reported with combination therapy consisting of cyclophosphamide, vincristine, and dacarbazine. As an alternative, high doses of 131I-MIBG can be used repeatedly.

Prognosis

• The prognosis in patients with pheochromocytomas appears to be related to tumor size, degree of uncontrolled hypertension, and the presence of metastatic disease.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize signs and symptoms of excessive catecholamine exposure
• Failure to consider and evaluate for pheochromocytoma in children who have hypertension or children who have symptoms strongly suggestive of pheochromocytoma in the absence of hypertension
• Failure to evaluate children at risk for pheochromocytoma because of an inherited condition
• Failure to arrange timely and appropriate follow-up care

Special Concerns

• Pregnancy in women with pheochromocytoma is associated with a maternal and fetal mortality rate of 40-56%. Antenatal diagnosis reduces maternal and fetal mortality rate to 0% and 15%, respectively.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Khorram-Manesh A, Ahlman H, Nilsson O, et al. Long-term outcome of a large series of patients surgically treated for pheochromocytoma. J Intern Med. Jul 2005;258(1):55-66. [Medline].
2. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. Dec 1 2005;23(34):8812-8. [Medline].
3. Dannenberg H, van Nederveen FH, Abbou M, et al. Clinical characteristics of pheochromocytoma patients with germline mutations in SDHD. J Clin Oncol. Mar 20 2005;23(9):1894-901. [Medline].
4. Jimenez C, Cote G, Arnold A, Gagel RF. Should Patients with Apparently Sporadic Pheochromocytomas or Paragangliomas be Screened for Hereditary Syndromes?. J Clin Endocrinol Metab. May 30 2006;[Medline]. [Full Text].
5. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. May 9 2002;346(19):1459-66. [Medline].
6. Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. Oct 2007;92(10):3822-8. [Medline].
7. Behrman RE, Kliegman R, eds. Pheochromocytoma. In: Nelson Textbook of Pediatrics. Philadelphia, Pa:. WB Saunders Co;1998:1741-1743.
8. Brouwers FM, Petricoin EF 3rd, Ksinantiva L, et al. Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma. Endocr Relat Cancer. Jun 2005;12:263-72. [Medline].
9. Davidson DF. Elevated urinary dopamine in adults and children. Ann Clin Biochem. May 2005;42(Pt 3):200-7. [Medline].
10. Ein SH, Shandling B, Wesson D, Filler R. Recurrent pheochromocytomas in children. J Pediatr Surg. Oct 1990;25(10):1063-5. [Medline].
11. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. Sep 1 2003;63(17):5615-21. [Medline].
12. Giovanella L, Ceriani L, Balerna M, et al. Diagnostic value of serum chromogranin-A combined with MIBG scintigraphy in patients with adrenal incidentalomas. Q J Nucl Med Mol Imaging. Jun 1 2007;[Medline].
13. Greenspan FS, Forsham PH, eds. Pheochromocytoma. In: Basic and Clinical Endocrinology. 2^nd ed. New York, NY: McGraw Hill; 1986:336-44.
14. Harding JL, Yeh MW, Robinson BG, et al. Potential pitfalls in the diagnosis of phaeochromocytoma. Med J Aust. Jun 20 2005;182(12):637-40. [Medline]. [Full Text].
15. Kohane DS, Ingelfinger JR, Nimkin K, Wu CL. Case records of the Massachusetts General Hospital. Case 16-2005. A nine-year-old girl with headaches and hypertension. N Engl J Med. May 26 2005;352(21):2223-31. [Medline].
16. Luo Z, Li J, Qin Y, et al. Differential expression of human telomerase catalytic subunit mRNA by in situ hybridization in pheochromocytomas. Endocr Pathol. 2006;17(4):387-98. [Medline].
17. Mannelli M, Simi L, Gagliano MS, et al. Genetics and biology of pheochromocytoma. Exp Clin Endocrinol Diabetes. Mar 2007;115(3):160-5. [Medline].
18. Mittendorf EA, Evans DB, Lee JE, Perrier ND. Pheochromocytoma: advances in genetics, diagnosis, localization, and treatment. Hematol Oncol Clin North Am. 2007;21:509-25. [Medline].
19. Muller U, Troidi C, Niemann S. SDHC mutations in hereditary paraganglioma/pheochromocytoma Review. Familiar Cancer. 2004;4:9-12. [Medline].
20. Neumayer C, Moritz A, Asari R, et al. Novel SDHD germ-line mutations in pheochromocytoma patients. Eur J Clin Invest. Jul 2007;37(7):544-51. [Medline].
21. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. Feb 2007;3(2):92-102. [Medline].
22. Perel Y, Schlumberger M, Marguerite G, et al. Pheochromocytoma and paraganglioma in children: a report of 24 cases of the French Society of Pediatric Oncology. Pediatr Hematol Oncol. Sep-Oct 1997;14(5):413-22. [Medline].
23. Perry CG, Sawka AM, Singh R, Thabane L, Bajnarek J, Young WF. The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma. Clin Endocrinol (Oxf). May 2007;66:71-8. [Medline].
24. Ross JH. Pheochromocytoma. Special considerations in children. Urol Clin North Am. Aug 2000;27(3):393-402. [Medline].
25. Scholz T, Eisenhofer G, Pacak K, Dralle H, Lehnert H. Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab. April 2007;92:1217-25. [Medline].
26. Scholz T, Schulz C, Klose S, Lehnert H. Diagnostic management of benign and malignant pheochromocytoma. Exp Clin Endocrinol Diabetes. Mar 2007;115(3):155-9. [Medline].
27. Stackpole RH, Melicow MM, Uson AC. Pheochromocytoma in children. Report of 9 case and review of the first 100 published cases with follow-up studies. J Pediatr. Aug 1963;63:314-30. [Medline].
28. Turner MC, Lieberman E, DeQuattro V. The perioperative management of pheochromocytoma in children. Clin Pediatr (Phila). Oct 1992;31(10):583-9. [Medline].
29. Vaclavik J, Stejskal D, Lacnak B, et al. Free plasma metanephrines as a screening test for pheochromocytoma in low-risk patients. J Hypertens. Jul 2007;25(7):1427-31. [Medline].
30. Young JB, Landsberg L. Pheochromocytoma. In: Wilson JD, Foster DW, Kronenberg HM, Williams RH, eds. Williams Textbook of Endocrinology. 9^th ed. Philadelphia, Pa: WB Saunders Co; 1998:705-16.
31. Zapanti E, Ilias I. Pheochromocytoma: physiopathologic implications and diagnostic evaluation. Ann N Y Acad Sci. Nov 2006;1088:346-60. [Medline].

Article Last Updated: Dec 10, 2007