eMedicine Specialties > Pediatrics: General Medicine > Oncology

Pheochromocytoma

Author: Patricia Myriam Vuguin, MD, MSc, Associate Professor of Pediatrics, Department of Pediatric Endocrinology, Albert Einstein College of Medicine; Consulting Staff, Children's Hospital at Montefiore
Contributor Information and Disclosures

Updated: Aug 27, 2009

Introduction

Background

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

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

In children, pheochromocytoma is more frequently associated with other familial syndromes, such as neurofibromatosis, von Hippel-Lindau disease, tuberous sclerosis, 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.

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 studied catecholamine secretion from tumors in patients with von Hippel-Lindau syndrome (n = 47) and MEN2 (n = 32). The rate constant for baseline catecholamine secretion was 20-fold higher in VHL than in MEN2 tumors, but catecholamine release was responsive only to glucagon in MEN2 tumors. Thus, the difference in the catecholamine release may contribute to clinical differences in the secretion of neurotransmitters or hormones and the subsequent presentation of a disease.¹

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. Recently developed pheochromocytoma cell lines from neurofibromatosis knockout mice supplement the PC12 line and have generated additional applications.²  Two mice models of metastatic pheochromocytoma have been established; one used tail vein injection of mouse pheochromocytoma cells³ or the conditional knockout of pten protein.⁴ Thus, the use of mouse models allows further study into the pathogenesis of human malignant pheochromocytoma and into therapeutic strategies for these tumors.

Frequency

United States

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

A recent study revealed that, over a 10-year period, the overdiagnosis rate was 23% and the underdiagnosis rate was 25%.⁵ 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, whereas underdiagnosis resulted in dangerous adrenal biopsy or adrenalectomy with hypertensive crisis and nearly doubled the length of stay in hospital.

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%.

Khorram-Manesh et al, a group in Sweden, analyzed the long-term outcome of surgically treated patients who had pheochromocytoma from 1950-1997.⁶ Over 15 (±6) years, 42 patients died, compared with 23.6 deaths expected in the general population (P < 0.001). Besides older age at primary surgery, elevated urinary excretion of methoxy-catecholamines was the only observed mortality risk factor. Preoperative and postoperative hypertension did not influence the mortality risk compared with controls.

In a study by Timmers et al in the Netherlands, data on clinical presentation, treatment, postsurgical blood pressure, and recurrence, metastasis, and death were collected in 69 patients and compared with a matched reference population.⁷ Kaplan-Meier estimates for 5-year and 10-year survival since surgery were 85.8% (95% confidence interval [CI], 77.2-94.4%) and 74.2% (95% CI, 62.0-86.4%) for patients compared with 95.5% and 89.4% in the reference population (P <0.05). 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.

Race

Pheochromocytomas have been described in Japanese, Chinese, black, European, and white families.

Sex

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 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%), and changes in energy level (89% vs 64%).⁸

Age

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

Clinical

History

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

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

Physical

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

Causes

Pheochromocytoma occurs wherever chromaffin tissue is found.

• Mutations in genes that code for 3 of the 4 components of mitochondrial complex II can cause paragangliomas and pheochromocytomas. The 3 genes include SDHB, SDHC, and SDHD.
  • SDHC and SDHD anchor the catalytic subunits (SDHA, SDHB) of mitochondrial complex II in the inner mitochondrial membrane. SDHD is maternally imprinted, whereas SDHB and SDHC are not. Although SDHD and, to a lesser degree, SDHB mutations have been found in many cases of hereditary paragangliomas, SDHC mutations are rare.
  • Amar et al studied 314 patients with pheochromocytoma or functional paraganglioma.⁹ 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.¹⁰
  • Jimenez et al suggested that the age for screening of sporadic pheochromocytoma should be reduced to patients younger than 20 years.¹¹ 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.¹² 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.

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