What is the best initial test for pheochromocytoma workup?

Best Initial Test for Pheochromocytoma Workup

The best initial test for pheochromocytoma workup is measurement of fractionated metanephrines in 24-hour urine or plasma-free metanephrines. 1, 2

Biochemical Testing Options

• Plasma-free metanephrines have the highest sensitivity (96-100%) and specificity (89-98%) for diagnosing pheochromocytoma, making them the preferred first-line test 2, 3
• Urinary fractionated metanephrines are an acceptable alternative with high sensitivity (86-97%) and specificity (86-95%) 2, 4
• Additional measurement of plasma methoxytyramine (when available) provides useful information to assess the likelihood of malignancy 1, 2
• Plasma-free metanephrines should ideally be collected from an indwelling venous catheter after the patient has been lying supine for 30 minutes to limit false positive results 4

Interpretation of Results

• Results ≥4 times the upper limit of normal are highly consistent with pheochromocytoma/paraganglioma and warrant immediate imaging 4
• Results 2-4 times the upper limit of normal require repeat testing and consideration of genetic testing 4
• Marginally elevated levels may require clonidine suppression testing to exclude false positivity 4, 5
• False positive elevations (usually <4 times upper limit of normal) can occur with obesity, obstructive sleep apnea, or use of tricyclic antidepressants 4

Diagnostic Algorithm

1. Initial biochemical testing: Measure plasma-free metanephrines or 24-hour urinary fractionated metanephrines 1, 2
2. If positive: Proceed to imaging studies (CT or MRI of abdomen) 1, 2
3. If equivocal: Consider repeat testing under standardized conditions or clonidine suppression test 4, 5
4. If initial imaging negative but biochemical evidence positive: Extend imaging to include chest and neck, and consider functional imaging (FDG-PET, DOTATATE-PET, MIBG scintigraphy) 2

Comparative Test Performance

• Plasma-free metanephrines have superior diagnostic performance compared to other tests, with sensitivity of 99% and specificity of 89% 3
• Urinary fractionated metanephrines have slightly lower sensitivity (97%) and specificity (69%) compared to plasma testing 3
• Urinary catecholamines (sensitivity 86%, specificity 88%) and plasma catecholamines (sensitivity 84%, specificity 81%) are less reliable 3, 6
• Urinary vanillylmandelic acid has the lowest sensitivity (64%) but high specificity (95%) 3, 6

Important Considerations

• Biopsy of suspected pheochromocytoma is contraindicated due to risk of hypertensive crisis 1, 2
• Biochemical testing should always precede imaging for suspected pheochromocytoma 2, 7
• Even with negative imaging, if biochemical evidence strongly suggests pheochromocytoma, further investigation is warranted 2
• Patients with SDHB mutations require more intensive surveillance due to higher risk of malignancy 2, 4

Common Pitfalls to Avoid

• Relying solely on CT imaging without biochemical confirmation 2
• Failing to consider extra-adrenal locations when adrenal imaging is negative 2
• Not recognizing that some pheochromocytomas may have atypical imaging appearances 2
• Overlooking the need for specialized imaging protocols optimized for adrenal evaluation 2

By following this evidence-based approach with initial biochemical testing using plasma-free or urinary fractionated metanephrines, clinicians can achieve the highest diagnostic accuracy for pheochromocytoma workup, minimizing both false negatives and false positives.