Pheochromocytoma, a tumor of neuroendocrine origin, is a rare tumor found in children and adults and is a cause of essential hypertension. Pheochromocytoma is a catecholamine-secreting tumor that arises from chromaffin cells of the sympathetic nervous system (adrenal medulla and sympathetic chain); however, the tumor may develop anywhere in the body. These tumors release catecholamines into the circulation, causing significant hypertension. The classic clinical presentation includes paroxysmal attacks of headaches, pallor, palpitations, and diaphoresis.
Pheochromocytoma may be inherited as an autosomal dominant trait. Recently, several genes (SDHD, SDHB, SDHC) that belong to the mitochondrial complex II have been identified as involved in the so-called pheochromocytoma-paraganglioma syndrome. The term paraganglioma refers to any extra-adrenal or nonfunctional tumor of the paraganglion system, whereas functional tumors are referred to as extra-adrenal pheochromocytomas.
In children, pheochromocytoma is more frequently associated with other familial syndromes, such as neurofibromatosis, von Hippel-Lindau disease, tuberous sclerosis, and Sturge-Weber syndrome, and as a component of multiple endocrine neoplasia (MEN) syndromes (MEN 2A, MEN 2B). Familial cases are often bilateral or multicentric within an individual adrenal gland. Adrenal pheochromocytomas are most often found on the right side and are sporadic, unilateral, and intra-adrenal. Approximately 6-10% of the tumors are malignant.
Usually, extra-adrenal tumors (extra-adrenal pheochromocytomas or paragangliomas) are located in the abdomen along the sympathetic chain and constitute about 10% of sporadic cases. Tumors have also been found in the neck, mediastinum, urinary bladder, and virtually every other site. Tumors vary from approximately 1-10 cm in diameter. Slowly growing metastases to bone, liver, lymph nodes, and lung can arise from malignant tumors.
Early diagnosis is important because the tumor may be fatal if undiagnosed, especially in pregnant women during delivery or in patients undergoing surgery for other disorders. Diagnosis can be made based on elevated levels of urinary catecholamines, but localization may require various modalities.
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 chromafin cell tumors may differ from the biosynthesis and storage in the normal medulla. However, the granules are morphologically and functionally similar to the granules from the adrenal medulla. The increase in tissue turnover suggests an alteration in the regulation of the catecholamine biosynthesis and possibly suggests an alteration in the feedback inhibition of tyrosine hydroxylase, the key enzyme in the production of catecholamines.
Pheochromocytomas, unlike the normal adrenal medulla, are not innervated, and catecholamine release is not initiated by neural impulses. Changes in direct flow, pressure, chemicals, drugs, and angiotensin II may initiate the release of catecholamines into the circulation.
Most pheochromocytomas in children predominantly produce norepinephrine, unlike the normal adrenal medulla, which, in humans, contains 85% epinephrine. Rarely, tumors produce epinephrine exclusively; in some cases, the clinical picture is dominated by signs of beta-receptor stimulation, such as tachycardia and hypermetabolism. However, in most cases, predicting the pattern of catecholamine secretion based on the clinical picture is impossible.
To determine catecholamine hypersecretion, norepinephrine, epinephrine, and their catabolic products (VMA, HVA) are measured in the urine. This measurement is the cornerstone of pheochromocytoma diagnosis. A total urinary catecholamine excretion that exceeds 300 mcg/d is commonly found, provided that the patient is symptomatic or hypertensive at the time of the collection. Specific assays of epinephrine are frequently beneficial because excretion in excess of 50 mcg/d suggests an adrenal lesion. In patients with benign pheochromocytoma, excretion levels of DA and DA metabolites, such as HVA, are usually normal. Increased levels of urinary DA of HVA excretion suggests malignancy.
The actions of catecholamines are mediated by the alpha-adrenergic and beta-adrenergic receptors. Alpha1 receptors cause arteriolar constriction. Alpha2 receptors mediate the presynaptic feedback inhibition of norepinephrine release and decrease insulin secretion. Beta1 receptors increase cardiac rate and contractility. Beta2 receptors cause arteriolar and venous dilation and relaxation of tracheobronchial smooth muscle. The symptoms associated with pheochromocytomas are caused by the physiologic and pharmacologic effects of large amounts of circulating norepinephrine and epinephrine.
Tumor size correlates with the ratio of free catecholamine metabolites in the urine. Small pheochromocytomas tend to have low concentrations of catecholamines with high turnover and low urinary VMA-catecholamines ratios. Conversely, large tumors tend to have high concentrations of catecholamines, low turnover rates, and high urinary VMA-catecholamine catecholamine ratios. Small tumors that store catecholamines well or metabolize a substantial amount of catecholamines within the tumor grow larger before becoming manifest.
Frequency United States
The reported incidence rate of pheochromocytomas is approximately 1 case per 100,000 persons, with 10-20% of cases occurring in children or adolescents. Children have a higher frequency of bilateral tumors than adults (20% vs 5-10%) and a lower incidence of malignancy (3.5% vs 3-14%). More than one third of affected children have multiple tumors, most of which are recurrent. In children, 70% of cases are unilateral, 70% of cases are confined to adrenal locations, and an increased association with familial syndromes exists. In 30-40% of children with pheochromocytomas, tumors are found in both adrenal and extra-adrenal areas or in only extra-adrenal areas. No geographic predilection is known.
The prognosis of this disease appears to be related to tumor quantity and the degree of uncontrolled hypertension, as well as the presence of metastatic disease. Serious morbidity and mortality may be associated with uncontrolled hypertension, including myocardial infarction, stroke, arrhythmias, irreversible shock, renal failure, and dissecting aortic aneurysm. Special consideration must be given to prepare these patients for surgery, in whom dramatic blood pressure swings may be observed. Malignant pheochromocytomas, which are rare in children, are locally invasive and may spread to distant areas that do not contain chromaffin cells, including the liver, lung, bone, and lymph nodes. The mean 5-year survival rate in patients with malignant pheochromocytomas is 40%.
Recently, Khorram-Manesh et al, a group in Sweden, analyzed the long-term outcome of surgically treated patients who had pheochromocytoma between 1950 and 1997.1 Over 15 (±6) years, 42 patients died, compared with 23.6 deaths expected in the general population (P < 0.001). Besides older age at primary surgery, elevated urinary excretion of methoxy-catecholamines was the only observed mortality risk factor. Preoperative and postoperative hypertension did not influence the mortality risk compared with controls.Sex
Although pheochromocytomas are found in both sexes, the male-to-female ratio isAge
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.