A 65-year-old male with labile hypertension, episodes of angina relieved with nitroglycerin, and elevated creatinine presents for right adrenalectomy for a recently diagnosed adrenal mass on MRI. Patient has occasional palpitations and diaphoresis. Stress test revealed no signs of acute ischemia. Cardiac catheterization revealed two-vessel coronary artery disease [1].

Catecholamines secreting neuroendocrine tumors arising from the chromaffin cells of the sympathoadrenal system are known as pheochromocytomas. A rare and potentially lethal neuroendocrine tumor, pheochromocytomas are typically found in the adrenal gland. However, extraadrenal pheochromocytomas are tumors that originate in the ganglia of the sympathetic nervous system. More specifically, 85% of pheochromocytomas are adrenal and 15% are extraadrenal. Extraadrenal sites include cranial nerves, sympathetic ganglia in the pelvis, mediastinum or neck. The most common extraadrenal site in the abdomen is at the origin of the inferior mesenteric artery called the area of Zuckerkandl [2].

Pheochromocytoma occurs in about 0.01–0.1% of patients with hypertension [3]. The actual incidence of pheochromocytoma is difficult to report accurately due to historic inconsistencies in the precise definition of pheochromocytoma. Estimates are 500–1600 cases per year yielding a prevalence of 1:6500 to 1:2500 in the United States [4]. While pheochromocytomas may occur at any age, they are most common in the fourth to fifth decades of life. Among men and women, pheochromocytoma is equally common [5].

Adrenal glands have two functionally separate units contained within one capsule. The adrenal cortex and the adrenal medulla are two different units within the adrenal gland each having distinct embryologic and functional characteristics [6]. The adrenal cortex has three functional zones and secretes mineralocorticoids, glucocorticoids, and sex steroids. The adrenal medulla synthesizes and secretes catecolamines. These catecholamines include epinephrine, norepinephrine, and dopamine and modulate the body’s sympathetic response to stress. Excessive secretion of epinephrine and norepinephrine from the adrenal medulla are responsible for the signs and symptoms associated with pheochromocytomas.

The English meaning of the word pheochromocytoma as interpreted from the Greek language is “dusky-colored tumor” referring to the color these cells acquire when stained with chromium salts [7]. During embryonic development, the chromaffin cells that evolve into pheochromocytomas settle near the sympathetic ganglia, vagus nerve, paraganglia, and carotid arteries. Some of these chromaffin tissues may land in other sites such as the renal and hepatic hili, gonads, bladder wall, prostate, and rectum [8]. The effect of large amounts of catecholamines in circulation, specifically epinephrine and norepinephrine, is responsible for the pathophysiologic processes that occur in patients with pheochromocytoma.

Alpha-adrenergic and beta-adrenergic receptors mediate the actions of catecholamines. Vascular constriction is a result of alpha-1 receptor stimulation. Alpha-2 receptors mediate the presynaptic feedback inhibition of norepinephrine release. Cardiac rate and contractility is increased by beta-1 receptor activity. Beta-2 receptor receptors modulate arteriolar and venous dilation and relaxation of bronchial smooth muscle [8]. Excessive secretion of the catecholamines epinephrine, norepinephrine, and rarely dopamine into circulation leads to severe and refractory hypertension.

Some precipitants of hypertensive crisis in patients with pheochromocytoma include [9]:

Although pheochromocytoma is the cause of sustained hypertension in less than 0.1% of hypertensive patients, approximately 50% of patients with pheochromocytoma have sustained hypertension. Paroxysms of palpitations, hypertension, diaphoresis, headaches, and feelings of impending doom may be present at the time of diagnosis [4].

By system:

Headache, diaphoresis, feelings of apprehension and anxiety, tremors, hypertensive encephalopathy, seizures

Hypertension, palpitations, tachycardia, diaphoresis, pallor, dyspnea, orthopnea, postural hypotension (volume contraction), congestive heart failure, pulmonary edema, cardiomyopathy, tachyarrythmias

Nausea, diarrhea, abdominal pain, malnutrition, weight loss, metabolic disturbances including impaired glucose control and insulin resistance

The “classic triad” of symptoms in a patient with pheochromocytoma includes episodic headache, sweating, and tachycardia. These symptoms strongly suggest a diagnosis of pheochromocytoma. Approximately 50% of patients will have paroxysmal hypertension making hypertension, paroxysmal or sustained, the most common sign of pheochromocytoma. Headaches occur in up to 90% of symptomatic patients; while up to 70% of symptomatic patients experience sweating [10, 11].

Diagnosis is based on clinical manifestations. Once a clinical diagnosis is made, biochemical diagnostic tests to detect excessive catecholamine excretion are indicated. These tests include plasma metanephrine testing, and 24 h urine collection for catecholamines and metanephrines [12, 13].

Test selection is based on risk. Patients at high risk include those with predisposing genetic syndromes or family and/or a personal history of pheochromocytoma. When associated with multiple endocrine neoplasia type 2 (MEN2), symptoms are present in approximately 50% of patients; however, only one-third of patients have hypertension [14]. In patient populations considered high risk, plasma metanephrine testing is preferred. Urine 24 h collection for catecholamines and metanephrines is indicated in patients at lower risk.

Other biochemical tests include urinary vanillylmandellic acid (VMA) levels and clonidine suppression test. Urinary VMA level is an older and less expensive test, but it is nonspecific. Clonidine suppression test lowers plasma catecholamines in patients without tumor and has no effect on patients with pheochromocytoma [7].

Imaging studies such as abdominal CT scanning or MRI should be performed after the above testing confirms the diagnosis of pheochromocytoma.

Treatment of choice for pheochromocytoma is surgical resection. In order to avoid high rates of mortality, optimization, and presurgical medical stabilization requires a multidisciplinary approach. A collaborative effort with experienced healthcare providers including surgeon(s), anesthesiologist(s), and an endocrinologist offers the lowest possible surgical risk to the patient.