What is the differential diagnosis of pheochromocytoma?

Differential Diagnosis of Pheochromocytoma

The differential diagnosis of pheochromocytoma includes adrenocortical carcinoma (most critical when an adrenal mass is present), primary aldosteronism (present in ~20% of resistant hypertension), Cushing's syndrome, panic/anxiety disorders, hyperthyroidism, and essential hypertension with paroxysmal features. 1

Primary Adrenal Mass Differentials

When imaging reveals an adrenal mass, the most critical differential is adrenocortical carcinoma (ACC), as both ACC and malignant pheochromocytomas appear inhomogeneous with irregular margins and irregular enhancement on CT/MRI. 1

• Distinguishing ACC from malignant pheochromocytoma using conventional imaging alone is extremely difficult. 1
• ACC typically presents with different hormonal excess patterns including glucocorticoid excess, sex steroid excess, or mineralocorticoid excess—unlike the catecholamine excess of pheochromocytoma. 1
• In patients with clearly established pheochromocytoma, steroid analysis can be skipped; conversely, for established ACC, catecholamine workup can be omitted. 1
• Fine needle biopsy is absolutely contraindicated in suspected pheochromocytoma due to risk of hypertensive crisis. 1

Endocrine Causes of Hypertension

Primary Aldosteronism

• Primary aldosteronism has a prevalence of approximately 20% in patients with resistant hypertension, making it a critical differential that must be excluded. 1
• Unlike pheochromocytoma, primary aldosteronism typically causes sustained hypertension without the classic triad of headache, palpitations, and sweating. 1
• The PAC/PRA ratio (plasma aldosterone concentration to plasma renin activity) should be obtained in patients with resistant hypertension or hypokalemia. 2

Cushing's Syndrome

• Hypertension is present in 70-90% of patients with Cushing's syndrome, with 17% having severe hypertension. 1
• Screening with 1 mg dexamethasone suppression test differentiates Cushing's syndrome from pheochromocytoma. 1

Non-Endocrine Mimics

Panic/Anxiety Disorders

• Anxiety or panic is a common symptom in patients with pheochromocytoma, making panic disorders a frequent mimic. 3
• The classic triad of headache, palpitations, and sweating occurring episodically has 90% diagnostic specificity for pheochromocytoma when present. 4

Hyperthyroidism

• Hyperthyroidism may mimic pheochromocytoma with tachycardia, sweating, and hypermetabolism. 5
• Thyroid function tests readily distinguish between these conditions. 5

Essential Hypertension with Paroxysmal Features

• Approximately 95% of pheochromocytoma patients present with hypertension, with 50% having sustained and 50% having paroxysmal hypertension. 3, 4
• Increased blood pressure variability is characteristic of pheochromocytoma and is an independent risk factor for cardiovascular morbidity and mortality. 3

Diagnostic Approach to Differentiation

Plasma free metanephrines are the best screening test with 99% sensitivity for pheochromocytoma, making this the first-line test to confirm or exclude the diagnosis. 1, 3

• If plasma test results are inconclusive, a 24-hour urine fractionated metanephrine and catecholamine collection should be performed. 3
• Plasma methoxytyramine levels help assess malignancy risk in confirmed pheochromocytoma. 1, 3
• MRI is preferred over CT for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast. 1, 4

Critical Clinical Pitfalls

• Despite improved diagnostics, the average time from initial symptoms to diagnosis remains 3 years, highlighting the importance of maintaining clinical suspicion. 1, 3
• In autopsy studies, pheochromocytoma contributed to 55% of deaths and was not suspected in 75% of cases. 1, 3
• Approximately 35% of pheochromocytomas are hereditary, associated with MEN 2, VHL, NF1, and SDH mutations, so genetic testing should be considered in most patients. 1, 4, 6
• Many drugs (phenothiazines, antiemetics, steroids) can precipitate hypertensive crises in undiagnosed pheochromocytoma. 7