Recognizing the Signs of Pheochromocytoma

Pheochromocytoma is a rare chromaffin cell neoplasm that secretes catecholamines and is usually found in the adrenal medulla. One fourth of these tumors are the result of genetic inheritance. Hypertension is the most common symptom. The classic triad of paroxysmal symptoms?consisting of palpitations, diaphoresis, and headaches?should prompt a consideration of this diagnosis and appropriate laboratory testing. The best biochemical marker is plasma free metanephrines, which is 99% sensitive and 89% specific for diagnosis. Magnetic resonance imaging and radioactive iodine metaiodobenzylguanidine scans are used to localize the tumor before surgery.

, Chief Resident; Scott E. Woods, MD, MPH, Director of Epidemiology; Sam Awada, MD, Resident; Bethesda Family Medicine Residency Program, Cincinnati, Ohio

Aleda Nash, MD

Pheochromocytoma is a rare cause of secondary hypertension. This catecholamine-secreting tumor is usually found in the adrenal medulla. It is curable when properly diagnosed and treated and can be fatal if not recognized. Although not always present, hypertension is the most common symptom. Primary care physicians should consider the possibility of pheochromocytoma when evaluating patients with hypertension, arrhythmias, or panic disorders.

Etiology

Pheochromocytomas are uncommon in normotensive individuals. A large prospective study showed that the average annual incidence rate was approximately 2 cases per 1 million persons, with the rate in women higher than in men (2.26 vs 1.84, respectively).¹ The mean age at diagnosis is 43 years.¹ One study showed that pheochromocytomas were present in 8 of 4180 hypertensive patients.² Tumors are most often located within the adrenal medulla, but 10% to 27% are extraadrenal.^3,4 The tumors are composed of chromaffin cells that synthesize and secrete catecholamines, most frequently norepinephrine and epinephrine.

The "rule of 10s" is often cited to remember the variations in these tumors: 10% bilateral, 10% malignant, 10% extraadrenal, 10% pediatric, and 10% normotensive. Although some research indicates that extraadrenal tumors are at increased risk of being malignant,³ a recent study showed similar risk in patients with adrenal and extraadrenal pheochromocytomas.⁵ With the recent identification of susceptible genes for pheochromocytoma, it is now estimated that 25% of pheochromocytomas are the result of genetic mutations (Table 1).⁶ The familial forms are often bilateral and extraadrenal, and less frequently malignant.

Signs and Symptoms

Patient presentations of pheochromocytomas are variable, ranging from asymptomatic to severe hypertension with headaches, palpitations, and diaphoresis (Table 2).⁷ The most common clinical feature of pheochromocytomas is hypertension. It is usually sudden in onset and associated with a series of other manifestations in episodic crises, often referred to as "paroxysms." However, clinical features often depend on the proportions of each catecholamine the tumor is secreting.

A tumor that is primarily secreting norepinephrine usually produces sustained hypertension, whereas a tumor that is secreting large amounts of epinephrine may produce episodic hypertension.⁸ In contrast, tumors that secrete only epinephrine can produce hypotension.⁸

In patients with pheochromocytomas, sudden elevation in blood pressure is often associated with tachycardia, palpitations, headache, sweating, tremor, apprehension, and/or anxiety. The classic triad of episodic headache, diaphoresis, and palpitations has a sensitivity of 89% and a specificity of 67% for pheochromocytoma.⁷ This constellation of symptoms is the result of the release of excessive quantities of catecholamines from the tumor, which increases the metabolic rate. Abdominal pain, chest pain, nausea, or vomiting occur frequently during paroxysms. The paroxysms may be triggered by surgery, trauma, labor, stress, or any other activity that displaces abdominal contents.

Because of a lack of highly specific symptoms, the differential diagnosis is lengthy (Table 3). Autopsy research and, more recently, the increased use of imaging techniques that have discovered many pheochromocytomas incidentally,⁹ highlight the asymptomatic nature of many pheochromocytomas.

Common cardiac complications include congestive heart failure, myocardial infarction, and arrhythmias, all of which are due to a catecholamine-induced cardiomyopathy. The sudden release of catecholamine from the tumor causes vasomotor constriction of the coronary circulation, leading to ischemia.

Pheochromocytomas may also secrete other hormones, such as somatostatins or adrenocorticotropic hormone, and produce clinical features that resemble Cushing's syndrome. Such patients may have impaired glucose tolerance secondary to the suppression of insulin and stimulation of the hepatic glucose output tract. Most pheochromocytomas secrete mixed catecholamines without dopamine, but a few secrete mixed catecholamines as well as dopamine, and very few secrete dopamine exclusively.

In the only case series of dopamine-secreting tumors conducted, 12 of 50 pheochromocytomas secreted both dopamine and other catecholamines, and 3 secreted only dopamine.¹⁰ Of the 15 patients whose tumors partially or solely secreted dopamine, 10 were normotensive. The absence of hypertension may be related to the ratio of dopamine to other catecholamines. In this study, the dopamine-to-catecholamine ratio was 0.380 (+ 0.274) for hypertensives and 5.470 (+ 4.840) for normotensives, with neither sensitivity nor specificity for diagnosis.

Most symptoms of pheochromocytoma increase in severity, duration, and frequency with time. If left undiagnosed, the condition can be fatal. Thus, you should consider the diagnosis of pheochromocytoma in a patient who displays any of the likely symptoms, especially when those symptoms are resistant to treatment.

Diagnosis

Several laboratory tests can help uncover the presence of a pheochromocytoma. The best biochemical marker is plasma metanephrines (Table 4). This test is 99% sensitive and 89% specific for diagnosis.¹¹ Although other biochemical tests have higher specificities, combining different tests does not improve the diagnostic yield beyond that of a single plasma free metanephrines determination.¹¹ A computed tomography (CT) or magnetic resonance imaging (MRI) scan of the adrenal glands can usually confirm the diagnosis and localize the lesion.

Radioactive iodine (¹³¹I) metaiodobenzylguanidine scans may be needed to characterize lesions when test results are indeterminate or localize extraadrenal pheochromocytomas known to be metastatic, recurrent, or multiple. Both MRI and ¹³¹I metaiodobenzylguanidine scans have a sensitivity of 100%, whereas CT has a sensitivity of 89%.¹² The specificity of ¹³¹I metaiodobenzylguanidine scans is 100% and of MRI and CT is only about 50%.¹³

An incidental adrenal mass measuring 3 cm or less poses minimal danger and requires only limited follow-up.¹⁴ A tumor larger than 5 cm should be removed. Adrenal tumors with the following features are at high risk for malignancy: 1) CT attenuation coefficient more than 10 Hounsfield units; 2) size more than 5 cm in diameter or increased at reevaluation; and 3) intratumor necrosis or evidence of capsular invasion.¹⁵

The increased incidence of pheochromocytomas reported reflects the use of imaging modalities. In a study of 284 patients with pheochromocytomas, 41% were diagnosed between 1978 and 1992, compared with 59% between 1993 and 1997.⁹ This represents a 50% increase in about one third the time.

Treatment

In a patient with pheochromocytoma, blood pressure is managed with alpha¹-adrenergic antagonist therapy, typically phenoxybenzamine HCl (Dibenzyline). If hypertension is not fully controlled with alpha blockade, beta blockade with propranolol HCl (Inderal) is added. Beta blockade should never precede alpha blockade, to avoid inducing an exaggerated pressor response. Patients with severe hypertensive crises may require intravenous nitroprusside sodium (Nitropress).

Before surgery, opiates, narcotic antagonists, histamines, or sympathomimetic agents should be avoided because they may provoke a hypertensive crisis by stimulating the release of catecholamines from the tumor. Postoperatively, about 30% of patients have persistent but nonparoxysmal hypertension.⁴ Since 90% of pheochromocytomas are benign, surgical removal is usually completely curative.

Malignancy is not a histologic diagnosis; it is based on local invasion or the presence of distant metastatic spread. Common sites for metastasis are the retroperitoneum, bone, liver, and lymph nodes. In malignant tumors, the prognosis is variable. One study showed a 5-year survival rate of 57% for patients with malignant intraadrenal tumors and 74% for patients with malignant extraadrenal tumors.¹⁶ In another study, the 10-year survival rate of those with malignant pheochromocytomas was 45%.¹⁷ Although metastatic lesions tend to grow slowly, response to chemotherapy is relatively poor. Long-term follow-up is mandatory. Tumors have recurred up to 15 years after resection.⁵

Illustrative Case

A 26-year-old previously healthy white woman reported palpitations, chest pain, paresthesias, and progressive dyspnea for several weeks. She had also developed new-onset episodic emesis accompanied by severe headaches.

Physical examination showed her temperature, 36.8?C; blood pressure, 122/80 mm Hg; pulse, 102 beats/min; and oxygen saturation, 98% on room air. Examination of the head, eyes, ears, nose, and throat was unremarkable, and the lungs were clear to auscultation. Cardiovascular examination revealed tachycardia but normal rhythm with no murmurs, rubs, or gallops. The rest of the examination was normal.

Electrocardiography (ECG), chest x-ray, and blood glucose measurements were all normal, except for tachycardia depicted on the ECG. A spiral CT scan of the chest was negative for pulmonary embolism but did reveal an 11 cm by 10 cm by 9 cm mass in the right upper quadrant of the abdomen. An MRI scan was ordered to better visualize the mass (Figure 1).

The patient was admitted for evaluation. Results of serum hormonal testing were all normal. A 24-hour urine collection revealed profound elevations of urinary catecholamines, urinary metanephrines, and especially dopamine. The dopamine-to-catecholamine ratio was 6.05.

The adrenal mass was surgically removed (Figure 2). Histologic examination revealed a lobulated/islet pattern typical of pheochromocytoma (Figure 3).

Conclusion

The availability of sensitive and specific immunoassays and imaging techniques allows physicians to make a confident diagnosis of pheochromocytoma. The triad of headache, sweating attacks, and tachycardia in a hypertensive patient should prompt a search for pheochromocytoma. If the tumor is benign, the prognosis is usually excellent. If malignant, the 10-year survival is less than 50%.

Self-Assessment Test

1. All the following statements about pheochromocytomas are true, except:

• About one fourth are the result of genetic mutations
• Patients may have visual disturbances

2. Which of these conditions is NOT a common complication of pheochromocytoma?

• Cor pulmonale
• Tachycardia

3. All the following features of a pheochromocytoma increase risk of malignancy, except:

• CT attenuation coefficient of 11 Hounsfield units
• Capsular invasion

4. Which of these biochemical tests is most accurate for diagnosis?

• Plasma metanephrines
• Plasma catecholamines

5. Which of the following statements about the treatment of pheochromocytomas is NOT true?

• Beta-blocker therapy can be added to alpha¹-blocker therapy
• About 30% of patients have paroxysmal hypertension postsurgey.

(Answers at end of reference list)

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Answers:

1. A; 2. B; 3. A; 4. B; 5. D