What is the differential diagnosis of pheochromocytoma?

Differential Diagnosis of Pheochromocytoma

When evaluating a patient with suspected pheochromocytoma, the key differential diagnoses include adrenocortical carcinoma (ACC), primary aldosteronism, Cushing's syndrome, panic/anxiety disorders, hyperthyroidism, and other causes of secondary hypertension—with imaging and biochemical testing being essential to distinguish these entities.

Primary Adrenal Mass Differentials

Adrenocortical Carcinoma (ACC)

• ACC is the most critical differential when imaging reveals an adrenal mass, as both ACC and malignant pheochromocytomas appear inhomogeneous with irregular margins and irregular enhancement on CT/MRI 1.
• It is difficult to distinguish ACC from malignant pheochromocytoma using conventional imaging alone 1.
• In patients with a clearly established diagnosis of pheochromocytoma, steroid analysis can be skipped (and conversely, for established ACC, catecholamine workup can be omitted) 1.
• ACC typically presents with hormonal excess patterns different from pheochromocytoma: glucocorticoid excess (1 mg dexamethasone suppression test), sex steroid excess (DHEA-S, 17-OH progesterone, androstenedione), or mineralocorticoid excess 1.
• Fine needle biopsy is contraindicated in suspected pheochromocytoma due to risk of hypertensive crisis 1.

Benign Adrenal Adenoma

• Benign adenomas show characteristic imaging features: Hounsfield units <10 on unenhanced CT, rapid washout on 15-minute delayed contrast-enhanced CT, or signal intensity loss on opposed-phase MRI 1.
• These imaging characteristics strongly suggest benign pathology and help exclude pheochromocytoma 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 1.
• Key distinguishing features: hypokalemia (though often absent early), suppressed renin activity with elevated aldosterone-to-renin ratio 1, 2.
• Unlike pheochromocytoma, primary aldosteronism typically causes sustained hypertension without the classic triad of headache, palpitations, and sweating 1.

Cushing's Syndrome

• Hypertension is present in 70-90% of patients with Cushing's syndrome, with 17% having severe hypertension 1.
• Distinguishing features include cushingoid appearance, central obesity, striae, and proximal muscle weakness—absent in pheochromocytoma 1.
• Screening with 1 mg dexamethasone suppression test differentiates from pheochromocytoma 1.

Non-Endocrine Differentials

Panic/Anxiety Disorders

• Panic disorders commonly mimic pheochromocytoma with episodic symptoms of palpitations, sweating, and anxiety 3, 4.
• The classic triad of headache, palpitations, and sweating occurring episodically has 90% diagnostic specificity for pheochromocytoma when accompanied by hypertension 1, 5.
• Plasma free metanephrines have 99% sensitivity and 89% specificity, making this the definitive test to exclude pheochromocytoma 1, 3, 5.

Hyperthyroidism

• Hyperthyroidism presents with tachycardia, palpitations, sweating, and anxiety similar to pheochromocytoma 4.
• Distinguishing features: heat intolerance, weight loss despite increased appetite, tremor, and elevated thyroid function tests 4.

Essential/Resistant Hypertension

• Pheochromocytoma prevalence is 0.1-0.6% in general hypertensive populations but up to 4% in resistant hypertension 1, 5.
• Increased blood pressure variability is characteristic of pheochromocytoma and represents an independent cardiovascular risk factor 3, 5.
• 50% of pheochromocytoma patients have sustained hypertension and 50% have paroxysmal hypertension 3, 5.

Diagnostic Approach to Differentiation

Biochemical Testing

• Plasma free metanephrines (normetanephrine and metanephrine) are the best screening test with 99% sensitivity 1, 3, 5.
• If plasma testing is inconclusive, 24-hour urine fractionated metanephrines and catecholamines should be performed 3, 4.
• Plasma methoxytyramine levels help assess malignancy risk in confirmed pheochromocytoma 1, 3.

Imaging Differentiation

• MRI is preferred over CT for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast 1, 5.
• FDG-PET is superior to MIBG scintigraphy for distinguishing malignant from benign lesions, particularly in SDHB mutation carriers 1.
• CT should be the first choice for suspected ACC as it is less expensive 1.

Critical Clinical Pitfalls

Delayed Diagnosis

• Despite improved diagnostics, the average time from initial symptoms to diagnosis remains 3 years 3.
• In autopsy studies, pheochromocytoma contributed to 55% of deaths and was not suspected in 75% of cases 1, 3.
• Clinicians must maintain high suspicion in patients with resistant hypertension, especially with the classic triad 1, 5.

Hereditary Syndromes

• Approximately 35% of pheochromocytomas are hereditary, associated with MEN 2, VHL, NF1, and SDH mutations 3, 5, 6.
• All first-degree relatives of pheochromocytoma patients should undergo biochemical testing 2.
• Genetic testing should be considered in most patients, particularly those with family history, young age, bilateral/multiple tumors, or extra-adrenal location 3, 6.

Drug-Induced Crises

• Multiple medications can precipitate hypertensive crises in undiagnosed pheochromocytoma, including phenothiazines, antiemetics, and steroids 7.