AUTHOR INFORMATION

Section 1 of 11

Authored by Patricia Vuguin, MD, MSc, Assistant Professor of Pediatrics, Albert Einstein College of Medicine; Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital at Montefiore

Coauthored by Norvin Perez, MD, Clinical Assistant Professor of Emergency Medicine, Albert Einstein College of Medicine; Consulting Staff, Department of Emergency Medicine, Montefiore Medical Center; Maribel M Monsalve, MD, Consulting Staff, Northeast Florida Pediatrics Associates

Patricia Vuguin, MD, MSc, is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, and Lawson-Wilkins Pediatric Endocrine Society

Edited by Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Children's Hospital of Philadelphia; Assistant Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Patricia Vuguin, MD, MSc
Editor's Email:	Stephan A Grupp, MD, PhD

eMedicine Journal, June 5 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 11

Background: The nomenclature for pheochromocytoma and paraganglioma is inconsistent. The term paraganglioma refers to any extra-adrenal or nonfunctional tumor of the paraganglion system. Functional tumors are referred to as extra-adrenal pheochromocytomas.

Pheochromocytoma, a tumor of neuroendocrine origin, is a rare tumor found in children and adults and 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. 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:

• In the US: 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 known geographic predilection exists.

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. Over 15 (±6) years, 42 patients died, as 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 11

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 B1 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: 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 safely be 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.

• 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. 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 (Dannenberg, 2005).

  • Recently, Jimenez et al (2006) suggested that the age for screening of sporadic pheochromocytoma should be reduced to patients younger than 20 years. 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. 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.

DIFFERENTIALS

Section 4 of 11

Coarctation of the Aorta
Hypertension
Neuroblastoma

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 11

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


• • 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


• • 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.
  
  
  
• Recently, 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.

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.



• CT scan and MRI


• • 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 metaiodobenzylguanidine (MIBG), 131I- or 123I-MIBG


• • 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: This can be used to evaluate for pulmonary edema.

Other Tests:

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

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 11

Medical Care:

• Initial care and diagnostic workup


• • 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.



• 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.



• MIBG therapy is another option. MIBG is taken up by chromaffin cells specifically. The value of radiation therapy in patients with malignant pheochromocytoma is debatable. The results with this disease 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. On the other hand, if the treatment is fairly aggressive, palliation therapy (pain, catecholamine excess) may be long term (years).

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 11

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 Name	Phenoxybenzamine (Dibenzyline) -- Alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension. The agent decreases sympathetic tone on the vasculature, dilates blood vessels, and lowers arterial blood pressure. Long-acting properties produce and maintain a chemical sympathectomy. Lowers supine and upright blood pressures. Does not affect the parasympathetic nervous system.
Adult Dose	10 mg PO bid initially; increase dose by 10-mg increments every other day until an optimal dosage is obtained; usual dosage range is 20-40 mg PO bid/tid
Pediatric Dose	0.2 mg/kg PO initially (not to exceed 5-10 mg bid); gradually increase according to BP to 0.25-1 mg/kg/d PO divided q6-8h
Contraindications	Documented hypersensitivity; MI; evidence of CAD; those in whom a fall in blood pressure would be undesirable
Interactions	Coadministration with alpha-adrenergic agonists decreases effects of phenoxybenzamine; beta-blockers increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use cautiously during lactation; change position slowly; frequent and small meals are recommended to avoid GI upset; avoid tasks that require visual acuity; monitor heart rate and blood pressure; report unusual swelling of the extremities, difficulty in breathing, dizziness, lightheadedness, or fainting; caution in tachycardia, peptic ulcer, and gastritis; cerebrovascular occlusions and myocardial infarctions can occur following phentolamine administration

Drug Name	Phentolamine (Regitine) -- Nonselective alpha-adrenergic blocking agent. Drug action is transient and alpha-adrenergic blockade incomplete. 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. Alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on the alpha-receptors. First-line agent to treat hypertensive crisis.
Adult Dose	Prevention or control of hypertension in pheochromocytomas: 5 mg IV/IM 1-2 h before surgery; repeat prn; administer 5 mg IV during surgery as indicated to control paroxysms of hypertension, tachycardia, respiratory depression, or seizures
Pediatric Dose	Preoperative reduction of elevated BP: 1 mg IV/IM 1-2 h (0.05-0.1 mg/kg/dose, not to exceed 5 mg/dose) before surgery; repeat prn; administer 1 mg IV during surgery as indicated to control paroxysms of hypertension, tachycardia, respiratory depression, and convulsions
Contraindications	Documented hypersensitivity; evidence of CAD; renal impairment
Interactions	Decreases vasoconstrictor and hypertensive effects of epinephrine and ephedrine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May produce weakness, dizziness, and nausea; acute and prolonged hypotensive episodes; tachycardia; and arrhythmias

Drug Name	Prazosin (Minipress) -- Postsynaptic alpha1-antagonist; decreases blood pressure with minimal risk of reflex tachycardia.
Adult Dose	1 mg PO bid/tid initially; increase prn; not to exceed 20 mg/d PO divided bid/tid
Pediatric Dose	Initial: 5 mcg/kg PO test dose Maintenance: 25-150 mcg/kg/d divided q6h; not to exceed 15 mg/d
Contraindications	Documented hypersensitivity
Interactions	Severity and duration of hypotension following first dose of prazosin may be increased in patients receiving beta-adrenergic blocking drugs (eg, propranolol) or verapamil; indomethacin may decrease antihypertensive activity of prazosin; prazosin may decrease antihypertensive effects of clonidine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Marked orthostatic hypotension, syncope, and loss of consciousness may occur with first dose; rash, pruritus, alopecia, diaphoresis, lupus erythematosus, dizziness, headache, drowsiness, lack of energy, nausea, palpitations, and weakness can occur; decrease dose in severe renal insufficiency

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 Name	Propranolol (Inderal) -- 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. May be used to treat excessive beta-receptor stimulation in patients with inoperable metastatic pheochromocytoma. Has membrane-stabilizing activity and decreases automaticity of contractions. Decreases effects of the sympathetic nervous system on the heart and juxtaglomerular apparatus, release of renin, and blood pressure. Acts in the CNS to reduce sympathetic outflow and vasoconstrictor tone. Not suitable for emergency treatment of hypertension. Do not administer IV in hypertensive emergencies.
Adult Dose	Hypertension: 40 mg/dose PO bid; may increase 10-20 mg/dose q3-5d; not to exceed 640 mg/d Pheochromocytoma preoperatively: 60 mg/d PO for 3 d in divided doses; inoperable tumor, 30 mg/d PO in divided doses
Pediatric Dose	0.5-1 mg/kg/d PO divided q6-12h initially; may increase dose q3-5d prn; not to exceed 8 mg/kg/d
Contraindications	Documented hypersensitivity; sinus bradycardia; second- or third-degree heart block; cardiogenic shock; CHF; asthma; COPD
Interactions	Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease propranolol effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity of propranolol; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase with propranolol
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Can cause dizziness, fatigue, gastric pain, flatulence, constipation, diarrhea, nausea, vomiting, bradycardia, cardiac arrhythmias, AV nodal block, bronchospasm, impotence, decrease in exercise tolerance, hyperglycemia, or hypoglycemia; may decrease signs of acute hypoglycemia and hyperthyroidism; use cautiously in hypoglycemia and diabetes, thyrotoxicosis, hepatic dysfunction

Drug Name	Labetalol (Normodyne, Trandate) -- Blocks beta1-, alpha-, and beta2-adrenergic receptor sites, thus decreasing blood pressure.
Adult Dose	Incremental doses starting at 20-40 mg IV; a response should be obtained within 5 min and a maximum effect at 10 min; IV dose can be doubled q30-60min until target BP is achieved; not to exceed 300 mg total dose
Pediatric Dose	Limited data available for pediatric hypertensive emergencies; initial doses of 0.2-0.5 mg/kg/dose IV as intermittent bolus; not to exceed 20 mg/dose; alternatively, a continuous IV infusion of 0.4-1 mg/kg/h IV; may increase as warranted; not to exceed 3 mg/kg/h
Contraindications	Documented hypersensitivity; cardiogenic shock; pulmonary edema; bradycardia; atrioventricular block; uncompensated congestive heart failure; reactive airway disease; severe bradycardia
Interactions	Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia, resulting from nitroglycerin use, without interfering with hypotensive effects; cimetidine may increase labetalol blood levels; glutethimide may decrease labetalol effects by inducing microsomal enzymes
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in impaired hepatic function; discontinue therapy upon signs of liver dysfunction; a lower response rate and higher incidence of toxicity may be observed in elderly patients

Drug Name	Esmolol (Brevibloc) -- 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. Short half-life of 8 min allows for titration to desired effect and quick discontinuation if needed.
Adult Dose	Loading dose: 500 mcg/kg IV over 1 min, followed by 50 mcg/kg/min for 4 min; if an adequate BP is not achieved within 5 min, repeat loading dose and increase infusion to 100 mcg/kg/min; repeat loading dose and titrate infusion rate upwards at 50 mcg/kg/min every 5 min prn; stop further loading doses once therapeutic blood pressure is reached
Pediatric Dose	Infants and children: Limited information exists; suggested dose is 100-500 mcg/kg IV administered over 1 min initially, followed by 200 mcg/kg/min IV; titrate upward by 50-100 mcg/kg/min q5-10min until heart rate or BP decrease by >10%, typical dose 550 mcg/kg/min (range = 300-1000 mcg/kg/min)
Contraindications	Documented hypersensitivity; uncompensated congestive heart failure; bradycardia; cardiogenic shock; AV conduction abnormalities
Interactions	Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels of esmolol, possibly resulting in decreased pharmacologic effect; cardiotoxicity of esmolol may increase when administered concurrently with sparfloxacin, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; toxicity of esmolol increases when administered concurrently with digoxin, flecainide, acetaminophen, clonidine, epinephrine, nifedipine, prazosin, haloperidol, phenothiazines, and catecholamine-depleting agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Beta-adrenergic blockers may mask signs and symptoms of acute hypoglycemia and clinical signs of hyperthyroidism; symptoms of hyperthyroidism, including thyroid storm, may worsen when medication is abruptly withdrawn; withdraw drug slowly and monitor patient closely

Drug Category: Nitrates -- These agents provide peripheral and coronary vasodilation.

Drug Name	Sodium nitroprusside (Nipride, Nitropress) -- Acts directly on vascular smooth muscle to cause vasodilatation, reduce BP, and increased inotropic effect.
Adult Dose	0.3-0.5 mcg/kg/min IV continuous IV infusion initially, titrate upward by 0.5 mcg/kg/min increments to effect; usual dose is 3-4 mcg/kg/min; infusion rates >10 mcg/kg/min may lead to cyanide toxicity
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; subaortic stenosis; idiopathic hypertrophic, atrial fibrillation or flutter; decreased cerebral perfusion; situations of compensatory hypertension
Interactions	Additive effects when administered with other antihypertensive agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in increased intracranial pressure, hepatic failure, severe renal impairment, and hypothyroidism; in renal or hepatic insufficiency, nitroprusside levels may increase and can cause cyanide toxicity; sodium nitroprusside can lower blood pressure and, thus, should be used only in patients with mean arterial pressures >70 mm Hg

Drug Category: Antiarrhythmic agents -- These agents alter the electrophysiologic mechanisms responsible for arrhythmia.

Drug Name	Amiodarone (Cordarone) -- May inhibit AV conduction and sinus node function. 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.
Adult Dose	Rapid loading: 5 mg/kg IV; not to exceed 450 mg; mixed in D5W infused over 10-30 min; not to exceed 50 mg/kg
Pediatric Dose	Loading dose: 10-15 mg/kg/d or 600-800 mg/1.73 m2/d PO for 4-14 d or until adequate control of arrhythmia is attained, reduce to 5 mg/kg/d or 200-400 mg/1.73 m2/d for several weeks Limited data available for IV loading dose Maintenance dose: 2.5 mg/kg/d PO or lowest effective dose following loading
Contraindications	Documented hypersensitivity; complete AV block; intraventricular conduction defects; protease inhibitors (eg, indinavir, ritonavir, amprenavir, nelfinavir) inhibit amiodarone metabolism, resulting in increased serum levels, and may prolong QT interval; coadministration may increase myopathy and rhabdomyolysis risk associated with HMG-CoA reductase inhibitors (eg, simvastatin); other drugs that prolong the QT interval (eg, fluoroquinolones, erythromycin, dofetilide, tricyclic antidepressants, thioridazine) may increase life-threatening arrhythmia risk
Interactions	Increases effect and blood levels of theophylline, quinidine, procainamide, phenytoin, methotrexate, flecainide, digoxin, cyclosporine, beta-blockers, and anticoagulants; cardiotoxicity of amiodarone is increased by ritonavir, sparfloxacin, and disopyramide; coadministration with calcium channel blockers may cause an additive effect and decrease myocardial contractility further; cimetidine may increase amiodarone levels
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in breastfeeding women, thyroid or liver disease, may cause proarrhythmic effect, optic neuritis, CNS toxicity, hypothyroidism, hepatotoxicity, interstitial pneumonitis or pulmonary fibrosis; CNS and GI toxicity may occur and typically dissipate with dose reduction

Drug Name	Lidocaine (Xylocaine) -- Class IB antiarrhythmic that increases electrical stimulation threshold of the ventricle, suppressing automaticity of conduction through the tissue.
Adult Dose	0.7-1.4 mg/kg IV push, repeat in 5 min; not to exceed 300 mg/h; follow with an infusion of 2-4 mg/kg/min
Pediatric Dose	Loading dose: 1 mg/kg IV; repeat in 10-15 min for 2 doses Continuous infusion: 20-50 mcg/kg/min IV
Contraindications	Documented hypersensitivity to amide-type local anesthetics; avoid in Adams-Stokes syndrome and Wolf-Parkinson-White syndrome; avoid in severe sinoatrial, AV, or intraventricular block if artificial pacemaker not in place
Interactions	Coadministration with cimetidine or beta-blockers increases toxicity of lidocaine; coadministration with procainamide and tocainide may result in additive cardiodepressant action; may increase effects of succinylcholine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Use a solution without preservatives; caution in heart failure, hepatic disease, hypoxia, hypovolemia or shock, respiratory-depression, and bradycardia; may increase risk of CNS and cardiac adverse effects in elderly patients; high plasma concentrations can cause seizures, heart block, and AV conduction abnormalities

FOLLOW-UP

Section 8 of 11

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 11

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.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is the cornerstone for diagnosis of pheochromocytoma?

A: CT scan
B: Angiogram
C: Physical examination and history
D: Measurement of serum epinephrine and norepinephrine
E: Measurement of epinephrine and norepinephrine catabolic products (vanillylmandelic acid [VMA], homovanillic acid [HVA]) in the urine

The correct answer is E: The cornerstone test to establish the diagnosis of pheochromocytoma is the measurement of HVA and VMA. Arteriography is almost never indicated. CT scan is indicated after diagnosis has been made based on serum and urine.

CME Question 2: Which of the following is the agent of choice for blood pressure control during a hypertensive crisis?

A: Nitroglycerin
B: Beta-blockers
C: Lidocaine
D: Phentolamine
E: Labetalol

The correct answer is D: Phentolamine is an alpha-blocker that is used as the first-line agent during hypertensive crises. Nitrates can be used if phentolamine does not work alone. If further blood pressure control is necessary, initiate beta-blockade.

Pearl Question 1 (T/F): Approximately 10-20% of all pheochromocytomas are found in the pediatric population.

The correct answer is True: Of all pheochromocytomas, 10-20% are found in the pediatric population. More than one third of these children have multiple tumors, and most tumors are recurrent.

Pearl Question 2 (T/F): Of all pheochromocytomas found in the pediatric population, most occur in children aged 6-14 years.

The correct answer is True: Of all pheochromocytomas, 10-20% are found in the pediatric population. Most of the tumors are found in children aged 6-14 years (average, 11 y).

Pearl Question 3 (T/F): In patients with pheochromocytomas, flushing, pallor, diaphoresis, high-grade fever, and hypotension are the most common symptoms and physical findings at the time of presentation.

The correct answer is False: Although low-grade temperatures might be present, a high-grade fever and hypotension suggest infectious etiologies.

Pearl Question 4 (T/F): Wide fluctuations in blood pressure are characteristic in patients with pheochromocytomas.

The correct answer is True: Blood pressure may range from 180-260 mm Hg systolic and 120-210 mm Hg diastolic. These hypertensive episodes may be followed by episodes of hypotension and syncope.

BIBLIOGRAPHY

Section 11 of 11

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• Behrman RE, Kliegman R, eds: Pheochromocytoma. In: Nelson Textbook of Pediatrics. Philadelphia, Pa: WB Saunders Co; 1998: 1741-1743.
• Brouwers FM, Petricoin EF 3rd, Ksinantiva L, et al: Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma. Endocr Relat Cancer 2005 Jun; 12: 263-72[Medline].
• Dannenberg H, van Nederveen FH, Abbou M, et al: Clinical characteristics of pheochromocytoma patients with germline mutations in SDHD. J Clin Oncol 2005 Mar 20; 23(9): 1894-901[Medline].
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• Greenspan FS, Forsham PH, eds: Pheochromocytoma. In: Basic and Clinical Endocrinology. 2nd ed. New York, NY: McGraw Hill; 1986: 336-344.
• Harding JL, Yeh MW, Robinson BG, et al: Potential pitfalls in the diagnosis of phaeochromocytoma. Med J Aust 2005 Jun 20; 182(12): 637-40[Medline][Full Text].
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• 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 1997 Sep-Oct; 14(5): 413-22[Medline].
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• Young JB, Landsberg L: Pheochromocytoma. In: Wilson JD, Foster DW, Kronenberg HM, Williams RH, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa: WB Saunders Co; 1998: 705-716.

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