Pediatric Pheochromocytoma 

Updated: Sep 20, 2019
Author: Patricia Myriam Vuguin, MD, MSc; Chief Editor: Max J Coppes, MD, PhD, MBA 

Overview

Background

Pheochromocytoma is a rare catecholamine-secreting tumor that arises from chromaffin cells of the sympathetic nervous system (adrenal medulla or and sympathetic chain); however, the tumor may develop anywhere in the body "catecholamine-secreting paragangliomas" ("extraadrenal pheochromocytomas"). 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. Pheochromocytomas and catecholamine-secreting paragangliomas have a similar clinical presentation, but the risk for associated neoplasms, risk for malignancy, and genetic testing is different between the tumors.

Release of catecholamines into the circulation by these tumors causes significant hypertension. The classic clinical presentation includes paroxysmal attacks of headaches, pallor, palpitations, and diaphoresis.

Pheochromocytoma may be inherited as an autosomal dominant trait. Several genes (SDHD, SDHB, SDHC) that belong to the mitochondrial complex II have been identified as involved in the so-called pheochromocytoma-paraganglioma syndrome. (See Etiology.)

Pheochromocytomas occur in both children and adults.[1] In children, pheochromocytoma is more frequently associated with other familial syndromes, such as neurofibromatosis, von Hippel-Lindau disease, tuberous sclerosis, 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 (see the images below, as well as Workup).

Axial, T2-weighted MRI scan showing large left sup Axial, T2-weighted MRI scan showing large left suprarenal mass of high signal intensity on a T2-weighted image. The mass is a pheochromocytoma.
Abdominal CT scan demonstrating left suprarenal ma Abdominal CT scan demonstrating left suprarenal mass of soft tissue attenuation representing a paraganglioma.

Treatment is with surgical removal. Chemotherapy and radiotherapy have been used in metastatic and unresectable pheochromocytoma, but their value is questionable. (See Treatment.)

For a discussion of pheochromocytoma in adults, see the Medscape article Pheochromocytoma.

Pathophysiology

Pheochromocytoma is a tumor of neuroendocrine origin. In the fifth week of fetal 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 following:

  • Bladder wall

  • Prostate

  • Behind the liver

  • Hepatic hilum

  • Renal hilum

  • Rectum

  • Gonads

Catecholamine biosynthesis and metabolism

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.

Catecholamines in pheochromocytomas

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.

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.

Pheochromocytomas in patients with von Hippel-Lindau syndrome and MEN type 2 differ in the types and amounts of catecholamines produced and the resulting signs and symptoms. Eisenhofer et al reported that the rate constant for baseline catecholamine secretion was 20-fold higher from tumors in von Hippel-Lindau syndrome (n = 47) than from MEN2 tumors (n = 32), but catecholamine release in response to glucagon occurred only in MEN2 tumors.[2]

Thus, the differences in catecholamine release may contribute to clinical differences in the secretion of neurotransmitters or hormones and the subsequent clinical presentation.[2]

Animal models

Over the last 2 decades, various mouse and rat models have been created presenting with pheochromocytomas, which include models presenting tumors that are to a certain degree biochemically and/or molecularly similar to human pheochromocytomas and develop metastases. In addition, cell lines such as mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells have been introduced and they both showed metastatic behavior. It appears these MPC and MTT cells are biochemically and molecularly similar to some human pheochromocytomas, are easily visualized, and respond to different therapies.[3]

Pheochromocytoma is inducible in rats by various nongenotoxic substances that may act indirectly by stimulating chromaffin cell proliferation. The nerve growth factor-responsive PC12 cell line, established from a rat pheochromocytoma, has served as a research tool for almost 30 years for many aspects of neurobiology involving normal and neoplastic conditions.

Pheochromocytoma cell lines from neurofibromatosis knockout mice supplement the PC12 line and have generated additional applications.[4] Two mice models of metastatic pheochromocytoma have been established: one used tail vein injection of mouse pheochromocytoma cells[5] ; the other involved the conditional knockout of the pten protein.[6] Thus, the use of mouse models allows further study into the pathogenesis of human malignant pheochromocytoma and into therapeutic strategies for these tumors.

Clinical consequences

Bone lesions have been described following changes in the microcirculation.

Myocarditis characterized by focal degeneration and necrosis of myocardial fibers with infiltration of histiocytes, plasma cells, and other signs of inflammation may be present.

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.

Etiology

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 involved are SDHB, SDHC, and SDHD.

Of the 4 components of mitochondrial complex II (succinate dehydrogenase [SDH] A, B, C, and D), SDHC and SDHD anchor the catalytic subunits SDHA and SDHB 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 delineated causes of pheochromocytoma in a study of 314 patients with pheochromocytoma or functional paraganglioma.[7] 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). 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.

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.

Epidemiology

In the United States, the reported annual incidence rate of pheochromocytomas is approximately 1 per 100,000 population, with 10-20% of cases occurring in children or adolescents. The frequency of bilateral tumors is higher in children than in adults (20% vs 5-10%), while that of malignant tumors is lower (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 is noted. In 30-40% of children with pheochromocytomas, tumors are found in both adrenal and extra-adrenal areas or in only extra-adrenal areas.

Race-, sex-, and age-related demographics

Pheochromocytomas have been described in Japanese, Chinese, black, European, and white families. No geographic predilection is known.

Although pheochromocytomas are found in both sexes, the male-to-female ratio is 2:1. In a study by Lai et al, female patients have significantly more self-reported pheochromocytoma signs and symptoms compared with males; these include the following[8] :

  • Headache (80% vs 52%)

  • Dizziness (83% vs 39%)

  • Anxiety (85% vs 50%)

  • Tremor (64% vs 33%)

  • Weight change (88% vs 43%)

  • Numbness (57% vs 24%)

  • Changes in energy level (89% vs 64%)

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

A 2011 study that identified 41 subjects with metastatic pheochromocytomas and compared them with 108 subjects with apparently benign pheochromocytomas showed that metastatic pheochromocytomas presented at a significantly younger age (41.4 ±14·7 y vs 50.2 ±13.7 y; P< .001), were larger (8.38 ±3·27 cm vs 6·18 ±2.75 cm; P< .001), had more frequent secretion of norepinephrine, and had a higher occurrence of necrosis.[9]

Prognosis

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

Uncontrolled hypertension may lead to serious, even fatal, morbidity, such as the following:

  • Myocardial infarction

  • Stroke

  • Arrhythmias

  • Irreversible shock

  • Renal failure

  • Dissecting aortic aneurysm

Special consideration must be given to prepare these patients for surgery, because 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%.

A study by Khorram-Manesh et al of the long-term outcome in Swedish patients who underwent surgical treatment of pheochromocytoma from 1950-1997 found that over 15 (±6) years, 42 patients died, compared with 23.6 deaths expected in the general population.[10] 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.

A retrospective study by Timmers et al in the Netherlands documented that metastases, but not cardiovascular mortality, reduced life expectancy in 69 patients who had undergone surgical resection of apparently benign pheochromocytoma.[11] Kaplan-Meier estimates for 5-year and 10-year survival since surgery were 85.8% and 74.2% for patients compared with 95.5% and 89.4% in the reference population.

Two patients died of surgical complications. All 10 patients with metastatic disease died, including 3 diagnosed at first surgery. At follow-up, 40 patients were alive and recurrence-free, and 3 patients were lost to follow up. Two patients experienced a benign recurrence. A significant decrease in blood pressure was observed in 64% of patients with hypertension prior to surgery; however, they remained hypertensive after surgery.[11]

Pheochromocytoma during pregnancy represents a condition with potentially high maternal and fetal mortality. However, in current practice, pheochromocytoma in pregnancy is recognized earlier, and, in conjunction with improved medical management, maternal mortality has decreased to less than 5%.[12]

 

Presentation

History

It has been shown that a relatively large number of these tumors remain undiagnosed during life, suggesting that some of those tumors present with nonspecific signs and symptoms. In addition, the low medical alertness in evaluating the signs and symptoms could represent a silent clinical presentation—the subclinical pheochromocytoma. It is also known that the clinical picture depends on the capacity of the tumors to release catecholamines and/or other peptides. Subclinical pheochromocytomas are often discovered as incidentalomas during radiological procedures or during routine screening for pheochromocytoma in carriers of mutations in 1 of the 10 currently identified tumor-susceptibility genes.[13]

Pheochromocytomas typically produce paroxysmal episodes that may include any of the following:

  • 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

  • Pain in the neck, shoulder, extremities, or flank

  • Tinnitus

  • Dysarthria

  • 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.

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.

Other associated cardiovascular complications seen mainly in adults include serious ventricular arrhythmias or conduction disturbances, reversible dilated or hypertrophic cardiomyopathy, and Takotsubo cardiomyopathy (also known as stress-induced cardiomyopathy).[14]

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, reflect 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 result from 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, along with other laboratory markers of dehydration, such as elevation of the blood urea (BUN) level and hematocrit, usually resolves 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.

In severe cases, precordial pain may radiate into the arms. Pulmonary edema and cardiac and hepatic enlargement may also develop.

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 Examination

Patients with pheochromocytomas usually have a thin body habitus. The presence of obesity does not rule out pheochromocytomas, however.

Hypertension may be present in both arms and legs. During a paroxysm, the blood pressure may range from 180-260 mm Hg systolic and from 120-210 mm Hg diastolic. Upon cardiovascular examination, tachycardia with forceful heartbeat is often found and is easily palpable. Postural hypotension may be present

Patients may feel warm and have pallor of the face and chest. Body perspiration and cool, moist hands and feet may also be found.

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.

Hypertensive retinopathy and cardiomyopathy are often present. Ophthalmoscopic examination may reveal papilledema, hemorrhages, exudates, and arterial constriction.

 

DDx

Diagnostic Considerations

Misdiagnosis of pheochromocytoma is not uncommon. A 2009 study revealed that over a 10-year period, the overdiagnosis rate was 23% and the underdiagnosis rate was 25%.[15] The most common causes of overdiagnosis were misinterpretation of borderline biochemical test results and overzealous imaging. The most common cause of underdiagnosis was failure to consider and test for pheochromocytoma.

Overdiagnosis subjected patients to unnecessary adrenalectomy and its complications. Underdiagnosis resulted in dangerous adrenal biopsy or adrenalectomy with hypertensive crisis and nearly doubled the length of stay in hospital.

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.

Adrenal incidentalomas 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.

All adrenal tumors with suggestive radiological findings (attenuation values expressed in Hounsfield units), most functional tumors, and all tumors larger than 4 cm that lack characteristic benign imaging features should be surgically excised. All patients should undergo hormonal evaluation for subclinical Cushing syndrome and pheochromocytoma, and those with hypertension should also be evaluated for hyperaldosteronism.

Annual biochemical follow-up of most patients with adrenal incidentalomas, especially if the tumor is larger than 3 cm, for up to 5 years has been proposed as a safety measure. Patients with adrenal masses smaller than 4 cm and a noncontrast attenuation value of more than 10 Hounsfield units should have a repeat computed tomography study in 3-6 months and then yearly for 2 years. Adrenal tumors with indeterminate radiological features that grow to at least 0.8 cm over 3-12 months may be considered for surgical resection.[16]

Other problems to be considered in the differential diagnosis of pheochromocytoma include the following:

  • Ganglioneuromas

  • Severe anxiety states

  • Autonomic epilepsy

  • Hypertensive crisis associated with paraplegia, tabes dorsalis, lead poisoning, acute intermittent porphyria

  • Monoamine oxidase inhibitor toxicity

Differential Diagnoses

 

Workup

Approach Considerations

Perform initial workup of pheochromocytoma using the history, physical examination, laboratory, and diagnostic test findings. Indications for evaluation include the following:

  • High blood pressure or recurrent hot flushes that are indicative of blood pressure peaks. Hypertension with features suggestive of secondary hypertension, after exclusion of other causes, especially renovascular disease and hypertension in association with other symptoms of sympathetic overactivity, such as episodic headache, sweating, and tachycardia or palpitations, if the symptoms are not explained by sympathomimetic drugs or panic disorder
  • Papilledema, focal neurologic deficits, or unrelenting headache, if other causes of intracranial hypertension have been excluded
  • An adrenal mass
  • Family history of multiple endocrine neoplasia type 2 (MEN 2) or von Hippel-Lindau disease

The cornerstone of pheochromocytoma diagnosis is the measurement of fractionated metanephrines and catecholamines in a 24-hour urine collection, or plasma fractionated metanephrines if an accurate urine collection is not feasible. When interpreting the results of biochemical testing, it is important to take into account the patient's age.  If one of these tumors is identified, the patient should also be evaluated for an underlying genetic mutation, since these are common and their presence affects clinical management.

A complete blood count (CBC) and metabolic panel are indicated. On urinalysis, proteinuria may be found because of hypertension. Plasma catecholamines may be measured during a paroxysm. Tests for both suppression and stimulation of catecholamine release have been proposed.

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. Scintigraphy may be a valuable adjunct in the detection of extra-adrenal lesions.

Chest radiography can be used to evaluate for pulmonary edema.

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

Urinary Catecholamine 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

  • Homovanillic acid (HVA)

  • Vanillylmandelic acid (VMA)

Creatinine levels should be determined for each 24-hour collection to assess the adequacy of the collection. If possible, the collection should be made while the patient is at rest and without recent exposure to radiographic contrast medium.

Foods and medications and foods that are known to interfere with the assay should be avoided. Foods that can increase urinary catecholamines include the following:

  • Coffee

  • Tea

  • Bananas

  • Chocolate

  • Cocoa

  • Citrus fruits

  • Vanilla

The following drugs can increase catecholamine measurements:

  • Caffeine

  • Acetaminophen (Tylenol)

  • Levodopa

  • Lithium

  • Aminophylline

  • Chloral hydrate

  • Clonidine

  • Disulfiram

  • Erythromycin

  • Insulin

  • Methenamine

  • Methyldopa

  • Nicotinic acid (large doses)

  • Quinidine

  • Tetracyclines

  • Nitroglycerin

Drugs that can decrease catecholamine measurements include the following:

  • Clonidine

  • Disulfiram

  • Guanethidine

  • Imipramine

  • Monoamine oxidase inhibitors (MAOIs)

  • Phenothiazines

  • Salicylates

  • Reserpine

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.

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.

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 mg/day suggests an adrenal lesion. In patients with benign pheochromocytoma, excretion levels of dopamine (DA) and DA metabolites, such as homovanillic acid (HVA), are usually normal. An increased level of urinary DA or HVA suggests malignancy.

In adults, the following conditions are also associated with an elevated dopamine (DA) level:

  • Overcollection of urine

  • Drug effects (eg, levodopa, methyldopa, clozapine, antidepressants, metoclopramide)

  • Clinical effects (including those due to pheochromocytoma, carcinoid tumor, and pregnancy)

In children, high urine DA levels are found in the following conditions, addition to pheochromocytoma:

  • Neuroblastoma

  • Costello syndrome

  • Leukemia

  • Menkes disease

  • Rhabdomyosarcoma of the bladder

Tumor size correlates with the ratio of free catecholamine metabolites in the urine. Patients with 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.

Metanephrine Measurement

Metanephrine is a metabolite of epinephrine. Free plasma metanephrine levels have been found to be a highly sensitive (100%) and specific (96.7%) measure, yielding a negative predictive value of 100%. 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.

Using upper cut-offs established in the reference population, measurements of plasma-free metabolites provided superior diagnostic performance compared with deconjugated metabolites according to measures of both sensitivity (97% vs 92%, P = .002) and specificity (93% vs 89%, P = .012).[17]

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. Cut-offs for positivity with this study 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% and specificity is 95.0%

  • Metanephrine fraction sensitivity is 56.9% and specificity is 95.0%

  • Elevation of either normetanephrine or metanephrine fraction sensitivity is 97.1% and specificity is 91.1%

Areas under the receiver operating characteristic (ROC) curves are as follows:

  • Total metanephrines - 0.991 (95% confidence index [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)

In a study of 22 patients with histologically proven pheochromocytoma, plasma free metanephrine level measurement has shown 100% sensitivity and 97.6% specificity. In comparison, sensitivity and specificity of other tests were as follows[18] :

  • Plasma catecholamine levels - 78.6% and 70.7%

  • Urinary catecholamines - 78.6% and 87.8%

  • Urinary metanephrines - 85.7% and 95.1%

  • Urinary hydroxymethoxymandelic acid - 93% and 75.8%

All patients with pheochromocytoma had plasma free metanephrine levels at least 27% above the upper limit of the reference range. Only 3 other patients had concentrations of more than 50% above the upper limit of the reference range.[18]

In a similar study of 159 outpatients tested in a tertiary referral center for pheochromocytoma over a 4-year period, the sensitivity of urinary free metanephrine level measurement was 100% (25 of 25 patients), and the specificity was 94% (116 of 123 patients).[19] The sensitivity and specificity of other studies was as follows:

  • Urinary catecholamines - 84% (21 of 25 patients) and 99% (127 of 129 patients)

  • Urinary VMA - 72% (18 of 25 patients) and 96% (130 of 134 patients)

  • Plasma catecholamines - 76% (16 of 21 patients) and 88% (66 of 75 patients)

Thus, metanephrines measured in either plasma or urine seemed to be the test of choice for detection of pheochromocytomas.

Blood Studies

A CBC count is indicated when infection or abdominal pain is present.

Electrolytes, blood urea nitrogen (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. High levels of calcium may be present because of excess of parathyroid hormone (PTH).

For measurement of plasma catecholamines, 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 and stimulation tests

Suppression tests (eg, phentolamine, clonidine) and stimulation tests (eg, glucagon, histamine, metoclopramide) have both been proposed for improving diagnostic accuracy of plasma catecholamine measurement. Stimulation tests are dangerous; administer with extreme caution.

Consider a glucagon stimulation test if basal plasma catecholamine 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 of clonidine. The clonidine suppression test (0.3 mg) involves the collection of plasma free normetanephrine before and after oral administration of clonidine.

Imaging Studies

When the diagnosis of pheochromocytoma has been established, the tumor must be located to facilitate its surgical removal. Although larger tumors can usually be located easily with ultrasonography, the smallest tumors may require CT scanning or MRI, particularly when located outside the adrenal area. (See the images below.)

Axial, T2-weighted MRI scan showing large left sup Axial, T2-weighted MRI scan showing large left suprarenal mass of high signal intensity on a T2-weighted image. The mass is a pheochromocytoma.
Abdominal CT scan demonstrating left suprarenal ma Abdominal CT scan demonstrating left suprarenal mass of soft tissue attenuation representing a paraganglioma.

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 iodine-131 (131 I) or123 I-metaiodobenzylguanidine (MIBG) allows whole-body exploration. Owing to its high specificity (97%), this morphologic 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.

In patients with adrenal incidentalomas (ie, asymptomatic adrenal masses discovered incidentally during high-resolution imaging procedures, such as CT scanning or MRI), MIBG scintigraphy has been used in combination with measurement of serum chromogranin-A (CgA) to rule in or rule out pheochromocytoma.[20]

CgA is a member of the granin family contained in secretory vesicles of chromaffin adrenal cells. Serum CgA levels increase in patients with pheochromocytoma and other diseases of the chromaffin system. Giovanella et al reported that patients with adrenal incidentalomas larger than 20 mm without clinical or biochemical signs and a positive123 I-MIBG finding had a confirmed pheochromocytoma in all cases.[20] Serum levels of CgA were significantly higher in patients with pheochromocytoma. Giovanella et al suggest that a negative CgA assay result may obviate MIBG imaging.

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.

Positron emission tomography (PET) with radiopharmaceuticals provides functional imaging. It is designed to show substrate precursor uptake, cellular metabolism, or receptor binding in neoplasms with CT as a single modality; hybrid PET/CT directly correlates function and anatomy.

PET scanning uses 3,4-dihydroxy-6-(18)F-fluoro-phenylalanine ([18]F-FDOPA), an amino acid transporter substrate, as an independent marker for detection of benign and malignant pheochromocytomas. It identifies localized pheochromocytoma with a sensitivity of 84.6%, a specificity of 100%, and an accuracy of 92%.[21, 22, 23]

Zelinka et al recommended that bone scintigraphy be used in the staging of patients with malignant pheochromocytoma and paraganglioma, particularly in patients with SDHB mutations. In patients without SDHB mutations, the modality with the best sensitivity for bone metastases was (18)F-FDOPA PET scanning.[24]

Arteriography and Selective Venous Sampling

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 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.

The intra-arterial administration of 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 administered intravenously.

Genetic Testing

Genetic testing should be performed in all pediatric patient diagnosed with pheochromocytoma or paraganglioma; mutations are more common in children with these tumors compared with adults { Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.[25]

In addition, genetic testing should be performed an asymptomatic person at risk for disease on the basis of family history of pheochromocytoma or paraganglioma, multiple endocrine neoplasia type 2 (MEN2), or von Hippel-Lindau (VHL) disease should have genetic testing if an affected family member has a known mutation. If a disease-causing mutation is identified, biochemical testing for pheochromocytoma/paraganglioma should be performed. Biochemical testing is not indicated if no mutation is identified and the patient is asymptomatic.[26]

An asymptomatic person with a genetic disorder known to be associated with pheochromocytoma or paraganglioma such as VHL disease (or VHL mutations); MEN2 (or RET mutations); or those with mutations in SDHA, SDHAF2, SDHB, SDHC, and SDHD (collectively known as SDHx), TMEM127, or MAX should have periodic screening for the development of these and any other associated tumors. Blood pressure measurement and biochemical testing and should be performed annually beginning at age five years.

Patients with neurofibromatosis type 1 (NF1) should undergo biochemical testing every three years; patients with MEN2, screening for pheochromocytoma should begin by age 11 years for children with high-risk mutations (ATA-H and ATA-HST categories) and by age 16 years in children with moderate-risk mutations (ATA-MOD category), as recommended in guidelines from the American Thyroid Association (ATA). The preferred case-detection method in pediatric patients with one of these mutations is plasma fractionated metanephrines.[27]

Patients with SDHC and SDHAF2 mutations should have skull base and neck imaging (ultrasound or magnetic resonance imaging [MRI]) every two to three years because of the risk for paragangliomas arising in those locations (which are typically dopaminergic), and periodic abdominal imaging because of the rare association with abdominal paraganglioma.

Patients with SDHD and SDHB mutations should have skull base and neck imaging (ultrasound or MRI) every two to three years; abdominal imaging (computed tomography [CT] or MRI) every two to three years; and total body imaging with Ga-68 DOTATATE positron emission tomography–CT (PET-CT) or 123I-metaiodobenzylguanidine (MIBG) scintigraphy every five years. it is reasonable to begin at age 14 years, or 10 years before the earliest age at diagnosis in the family, whichever is younger.

In addition, genetic testing should be performed in patients with pheochromocytoma who have the following[28] :

  • A family history of pheochromocytoma or paraganglioma syndrome
  • Multifocal tumors
  • Bilateral or multicentric adrenal pheochromocytomas
  • Sympathetic paragangliomas, especially multiple tumors

Those characteristics are highly associated with the presence of a germline mutation. Because several genes are involved in the genetics of pheochromocytoma and paraganglioma, prioritizing the gene (or genes) to be tested first using simple clinical information can reduce the efforts and costs of this analysis.[29]

Jimenez et al suggested that the age for screening of sporadic pheochromocytoma should be reduced to patients younger than 20 years.[30] Their recommendation was based on a study done by Neumann et al, which found that hereditary disease (70% of cases are VHL mutations) is usually seen in young patients.[31]  Other suggest that patients with apparently sporadic disease (ie, no associated syndrome or family history) also should undergo genetic testing, because germline mutations are present in up to 25 percent of patients with sporadic disease.[32]

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.

A study aimed to genetically characterize sporadic pheochromocytoma and paraganglioma cases and propose an evidence-based algorithm for genetic testing, prioritizing DNA source. The study recommended prioritizing testing for germline mutations in patients with head and neck pheochromocytoma and paraganglioma, thoracic pheochromocytoma and paraganglioma, and for somatic mutations in those with pheochromocytomas. Of note, the authors also recommended that pediatric and metastatic cases should be included in their algorithm for genetic testing.[33]

The clinicians offering and performing the genetic testing should provide or make available adequate counselling and preventive treatment. Considering collaborating with referral centers as well as research groups would help coordinate the management of these families.

Gene Expression Profiling

Researchers are studying the use of gene expression profiling to distinguish between metastatic and benign pheochromocytomas, as this differentiation cannot be reliably done by histopathologically.[34, 35, 36] Malignant potential appears to be largely characterized by a less-differentiated pattern of gene expression.[36]

Suh et al identified 10 differentially expressed genes that had high diagnostic accuracy; 5 of these genes in combination had an area under the receiver operating characteristic (ROC) curve of 0.96 for distinguishing benign versus malignant tumors.[35] .

It has been shown that a comprehensive next-generation sequencing (NGS)–based strategy for the diagnosis of pheochromocytoma and paraganglioma patients by testing simultaneously for mutations in MAX, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL using the proof-of-principle study has a sensitivity of 98.7%.[37]

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.

Malignant pheochromocytomas occur in 10-15% of cases. Histologic 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.

 

Treatment

Approach Considerations

Treatment of pheochromocytoma is with surgical removal. 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). 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 outcome in malignant pheochromocytoma appears to be related to the tumor quantity and the aggressiveness of the therapy. Chemotherapy and radiotherapy have been used, but their value is questionable. 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.

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.

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.

Inpatient care is necessary if the patient with pheochromocytoma 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.

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

Surgical Removal

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.

Preoperative blockade of alpha-1 receptors has been used to reduce the risk of hypertensive episodes. Drugs such as urapidil have been shown to produce a significant reduction in hypertensive peaks.[38]

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, which has been shown to be a useful technique in patients with tumors smaller than 7 cm and a body mass index of less than 45 kg/m,[39] 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.

Guidelines for the surgical removal of adrenal masses in pediatric patients has been published in the Journal of Laparoendoscopic & Advanced Surgical Techniques.[40]

A large, multicenter review of children who had undergone laparoscopic adrenalectomy at 12 institutions over a 10-year period identified 140 patients (50% males). Of those patients, 54.3% had left lesions, 42.1% had right lesions, and 3.6% had bilateral lesions. Mean operative time was 130.2 ±63.5 minutes. The most common pathology was neuroblastoma (27.9%), followed by pheochromocytomas (21.4%), ganglioneuromas (15.7%), and adenomas (14.3%). Only 9.9% of the cases required an open surgery. A blood transfusion was required in only 2 cases. At 18 months (median follow-up), only one local recurrence was reported, which was in a patient with a pheochromocytoma.[41]

Bilateral tumors develop in children with multiple endocrine neoplasia type 2 and pheochromocytoma. Bilateral adrenalectomy has been recommended at presentation in these patients.

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 morbidity 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.

Treatment of Unresectable Disease

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).

A long-term study of 18 patients with a diagnosis of malignant pheochromocytoma or paraganglioma who were treated with combination chemotherapy reported a complete response rate of 11% and a partial response rate of 44%. The regimen used was cyclophosphamide at 750 mg/m2, vincristine at 1.4 mg/m2, and dacarbazine at 600 mg/m2 on day 1 and dacarbazine at 600 mg/m2 on day 2, every 21-28 days.[42] The treatment was well tolerated, with only grade I and II toxicities.

In this 22-year follow-up, no difference in overall survival was observed between patients whose tumors objectively shrank and those with stable or progressive disease. All patients with tumors scored as responding reported improvement in their symptoms related to excessive catecholamine release and had objective improvements in blood pressure. Median survival was 3.8 years for patients whose tumors responded to therapy and 1.8 years for patients whose tumors did not respond.

Over the past decade, substantial progress has been made in clinical, biochemical, and radiographic diagnosis of pheochromocytomas. Approximately 50% of patients with malignant pheochromocytomas and sympathetic paragangliomas have been found to carry hereditary germline mutations in the succinate dehydrogenase subunit B gene (SDHB), and antiangiogenic agents such as sunitinib have been found to potentially play a role in the treatment of malignant disease, especially in patients with SDHB mutations.

In some patients, treatment with sunitinib (Sutent; previously known as SU11248) has been associated with partial radiographic response, disease stabilization, decreased fluorodeoxyglucose uptake on positron emission tomography, and improved blood pressure control.[43, 44, 45, 46] Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases, such as platelet-derived growth factor receptors, and vascular endothelial growth factor receptors, which play a role in both tumor angiogenesis and tumor cell proliferation.

The best established strategy is iodine 131I-metaiodobenzylguanidine (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.

Iobenguane I 131 was approved by the FDA in July 2018 for iobenguane scan–positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma in patients aged 12 years or older who require systemic anticancer therapy. Efficacy was shown in a single-arm, open-label, phase 2 clinical trial (n=68) conducted under a special protocol assessment with the FDA. The study met the primary endpoint, with 17 (25%) of the 68 evaluable patients experiencing a 50% or greater reduction of all antihypertensive medication for at least 6 months. Overall tumor response was achieved in 15 (22%).[47]

Octreotide as a single agent seems to be largely ineffective. The value of radiation therapy in patients with malignant pheochromocytoma is debatable.

Long-Term Monitoring

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).

Patients with germline mutation and no evidence of active illness should have continued follow-up for pheochromocytoma.

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.

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.

 

Medication

Medication Summary

Although surgical removal is the definitive treatment of pheochromocytoma, pharmacologic therapy plays a critical role in control of blood pressure, both perioperatively and long-term in patients with inoperable disease. Alpha-adrenergic antagonists and beta-adrenergic antagonists, often in combination, as well as nitrates are used for this purpose. Antiarrhythmic agents are used to control the ventricular tachyarrhythmias that these patients may experience.

Alpha-Adrenergic Blocking Agents

Class Summary

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.

Phenoxybenzamine (Dibenzyline)

This alpha1- and alpha2-adrenergic blocking agent blocks circulating epinephrine and norepinephrine action, reducing hypertension. It decreases sympathetic tone on the vasculature, dilates blood vessels, and lowers arterial blood pressure. Long-acting properties produce and maintain a chemical sympathectomy. Phenoxybenzamine lowers supine and upright blood pressures. It does not affect the parasympathetic nervous system.

Phentolamine

Phentolamine is an alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on the alpha-receptors. Drug action is transient and alpha-adrenergic blockade is incomplete. This agent is often used immediately prior to or during adrenalectomy to prevent or control paroxysmal hypertension that results from anesthesia, stress, or operative manipulation of the tumor. It is a first-line agent to treat hypertensive crisis.

Prazosin (Minipress)

Prazosin is a postsynaptic alpha1-antagonist. It decreases blood pressure with minimal risk of reflex tachycardia.

Beta-Adrenergic Blocking Agents

Class Summary

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

Propranolol (Inderal LA, InnoPran XL)

Propranolol is a nonselective beta-adrenergic receptor blocker. After primary treatment with an alpha-receptor blocker, propranolol may be used as adjunctive therapy if control of tachycardia becomes necessary before or during surgery.

This agent may be used to treat excessive beta-receptor stimulation in patients with inoperable metastatic pheochromocytoma. It has membrane-stabilizing activity and decreases automaticity of contractions. It decreases the effects of the sympathetic nervous system on the heart and juxtaglomerular apparatus, release of renin, and blood pressure. It acts in the CNS to reduce sympathetic outflow and vasoconstrictor tone. Propranolol is not suitable for emergency treatment of hypertension; do not administer IV in hypertensive emergencies.

Labetalol (Trandate)

Labetalol blocks beta1-, alpha-, and beta2-adrenergic receptor sites, thus decreasing blood pressure.

Esmolol (Brevibloc)

Esmolol is an excellent drug for use in patients at risk for experiencing complications from beta-blockade, particularly those with reactive airway disease, mild-to-moderate LV dysfunction, and/or peripheral vascular disease. Its short half-life of 8 min allows for titration to desired effect and quick discontinuation if needed.

Vasodilators

Class Summary

These agents provide peripheral and coronary vasodilation.

Sodium nitroprusside (Nitropress)

Sodium nitroprusside acts directly on vascular smooth muscle to cause vasodilatation and reduce blood pressure. It also has a positive inotropic effect.

Antiarrhythmic Agents

Class Summary

These agents alter the electrophysiologic mechanisms responsible for arrhythmia.

Amiodarone (Cordarone, Pacerone, Nexterone)

Amiodarone may inhibit atrioventricular (AV) conduction and sinus node function. This agent prolongs action potential and refractory period in myocardium and inhibits adrenergic stimulation. Before administration, control the ventricular rate and CHF (if present) with digoxin or calcium channel blockers.

Lidocaine (Xylocaine)

Lidocaine is a class IB antiarrhythmic that increases electrical stimulation threshold of the ventricle, suppressing automaticity of conduction through the tissue.

Radiopharmaceuticals

Class Summary

Iobenguane I 131 is the first drug approved by the FDA for rare tumors of the adrenal gland (pheochromocytoma or paraganglioma) that cannot be removed by surgery.

Iobenguane I 131 (Azedra)

Iobenguane is similar in structure to the neurotransmitter norepinephrine (NE) and is subject to the same uptake and accumulation pathways as NE. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues (eg, heart, lungs, adrenal medulla, salivary glands, liver, spleen) as well as tumors of neural crest origin. Following IV administration and cell uptake, radiation resulting from radioactive decay of I 131 causes cell death and tumor necrosis.

Iobenguane I 131 is indicated in adults and children aged 12 years or older for iobenguane scan–positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.