Clinical Manifestations

Pheochromocytomas detected by surveillance of patients who are known carriers of mutations in tumor suppressor genes, such as those with von Hippel–Landau syndrome, may be asymptomatic. Otherwise, patients are detected due to hypertension, which results from excessive secretion of epinephrine and norepinephrine. All patients have hypertension at some time. Paroxysmal hypertension should particularly suggest pheochromocytoma as a diagnostic possibility. In contrast to adults, the hypertension in children is more often sustained rather than paroxysmal. When there are paroxysms of hypertension, the attacks are usually infrequent at first but become more frequent and eventually give way to a continuous hypertensive state. Between attacks of hypertension, the patient may be free of symptoms. During attacks, the patient complains of headache, palpitations, abdominal pain, and dizziness; pallor, vomiting, and sweating also occur. Convulsions and other manifestations of hypertensive encephalopathy may occur. In severe cases, precordial pains radiate into the arms; pulmonary edema and cardiac and hepatic enlargement may develop. Symptoms may be exacerbated by exercise, or with use of over-the-counter medications containing stimulants such as pseudoephedrine. The child has a good appetite but because of the hypermetabolic state does not gain weight, and severe cachexia may develop. Polyuria and polydipsia can be sufficiently severe to suggest diabetes insipidus. Growth failure may be striking. The blood pressure may range from 180 to 260 mm Hg systolic and from 120 to 210 mm Hg diastolic, and the heart may be enlarged. Ophthalmoscopic examination may reveal papilledema, hemorrhages, exudate, and arterial constriction.

Laboratory Findings

The urine may contain protein, a few casts, and occasionally glucose. Gross hematuria suggests that the tumor is in the bladder wall. Polycythemia is occasionally observed. The diagnosis is established by demonstration of elevated blood or urinary levels of catecholamines and their metabolites.

Pheochromocytomas produce norepinephrine and epinephrine. Normally, norepinephrine in plasma is derived from both the adrenal gland and adrenergic nerve endings, whereas epinephrine is derived primarily from the adrenal gland. In contrast to adults with pheochromocytoma in whom both norepinephrine and epinephrine are elevated, children with pheochromocytoma predominantly excrete norepinephrine. Total urinary catecholamine excretion usually exceeds 300 µg/24 hr. Urinary excretion of metanephrines (particularly normetanephrine) are also increased (see Fig. 568-2). Daily urinary excretion of these compounds by unaffected children increases with age. Although urinary excretion of vanillylmandelic acid (VMA, 3-methoxy-4-hydroxymandelic acid), the major metabolite of epinephrine and norepinephrine, is increased, vanilla-containing foods and fruits can produce falsely elevated levels of this compound, which therefore is no longer routinely measured.

Elevated levels of free catecholamines and metanephrines can also be detected in plasma. In children, the best sensitivity and specificity are obtained by measuring plasma normetanephrine, with plasma norepinephrine being next best. Plasma metanephrine and epinephrine are not reliably elevated in children. The best discrimination is obtained by using gender-specific pediatric reference ranges, rather than adult ranges. Additionally, the patient should be instructed to abstain from caffeinated drinks, and to avoid acetaminophen, which can interfere with plasma normetanephrine assays. If possible, the blood sample should be obtained from an indwelling IV catheter, to avoid acute stress associated with venipuncture.

Most tumors in the area of the adrenal gland are readily localized by CT or MRI, but extra-adrenal tumors may be difficult to detect. ¹³¹I-metaiodobenzylguanidine (MBIG) is taken up by chromaffin tissue anywhere in the body and is useful for localizing small tumors. Venous catheterization with sampling of blood at different levels for catecholamine determinations is now only rarely necessary for localizing the tumor.

Differential Diagnosis

Various causes of hypertension in children must be considered, such as renal or renovascular disease; coarctation of the aorta; hyperthyroidism; Cushing syndrome; deficiencies of 11β-hydroxylase, 17α-hydroxylase, or 11β-hydroxysteroid dehydrogenase (type 2 isozyme); primary aldosteronism; adrenocortical tumors; and essential hypertension (Chapter 439). A nonfunctioning kidney may result from compression of a ureter or of a renal artery by a pheochromocytoma. Paroxysmal hypertension may be associated with porphyria or familial dysautonomia. Cerebral disorders, diabetes insipidus, diabetes mellitus, and hyperthyroidism must also be considered in the differential diagnosis. Hypertension in patients with neurofibromatosis may be caused by renal vascular involvement or by concurrent pheochromocytoma.

Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma frequently produce catecholamines, but urinary levels of most catecholamines are higher in patients with pheochromocytoma, although levels of dopamine and homovanillic acid are usually higher in neuroblastoma. Secreting neurogenic tumors often produce hypertension, excessive sweating, flushing, pallor, rash, polyuria, and polydipsia. Chronic diarrhea may be associated with these tumors, particularly with ganglioneuroma, and at times may be sufficiently persistent to suggest celiac disease.

Treatment

These tumors must be removed surgically, but careful preoperative, intraoperative, and postoperative management is essential. Preoperative α- and β-adrenergic blockade and fluid loading are required. Because these tumors are often multiple in children, a thorough transabdominal exploration of all the usual sites offers the best opportunity to find them all. Appropriate choice of anesthesia and expansion of blood volume with appropriate fluids during surgery are critical to avoid a precipitous drop in blood pressure during operation or within 48 hr postoperatively. Manipulation and excision of these tumors result in marked increases in catecholamine secretion that increase blood pressure and heart rate. Surveillance must continue postoperatively.

Although these tumors often appear malignant histologically, the only accurate indicators of malignancy are the presence of metastatic disease, local invasiveness that precludes complete resection, or both. Approximately 10% of all adrenal pheochromocytomas are malignant. Such tumors are rare in childhood; pediatric malignant pheochromocytomas occur more frequently in extra-adrenal sites and are often associated with mutations in the SDHB gene encoding a subunit of succinate dehydrogenase. Prolonged follow-up is indicated because functioning tumors at other sites may be manifested many years after the initial operation. Examination of relatives of affected patients may reveal other individuals harboring unsuspected tumors that may be asymptomatic.