What is the recommended lab testing for pheochromocytoma?

Recommended Lab Testing for Pheochromocytoma

Plasma free metanephrines measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the single best first-line test for diagnosing pheochromocytoma, with the highest sensitivity (96-100%) and specificity (89-98%). 1, 2, 3

Initial Biochemical Testing Approach

First-Line Test Selection

• Measure plasma free metanephrines (normetanephrine, metanephrine, and methoxytyramine) as the preferred initial test due to superior diagnostic performance compared to all other biochemical markers 1, 2, 3

• Urinary fractionated metanephrines (24-hour collection) are an acceptable alternative with high sensitivity (86-97%) and specificity (86-95%), particularly useful for pediatric patients not yet continent or when plasma collection is impractical 4, 1, 2

• Analysis should be performed using LC-MS/MS methodology, which provides better accuracy and is not affected by common antihypertensive medications 4, 1, 5

Critical Collection Requirements

• Plasma free metanephrines must be collected after 30 minutes of rest in the supine position to minimize false positives, ideally from an indwelling venous catheter 4, 1, 2

• Methoxytyramine should be sampled after an overnight fast 4

• If sampling is performed sitting rather than supine, 25% of results will be falsely elevated and require repeat testing 4

Interpretation Algorithm Based on Results

Highly Elevated Results (≥4× Upper Limit of Normal)

• Results ≥4 times the upper limit of normal are diagnostic of pheochromocytoma/paraganglioma and warrant immediate imaging to localize the tumor 1, 2

• Proceed directly to MRI of abdomen (preferred over CT due to hypertensive crisis risk with IV contrast) 4, 2, 6

Moderately Elevated Results (2-4× Upper Limit of Normal)

• Repeat biochemical testing in 2 months 1, 2

• Consider genetic testing for hereditary syndromes, especially in younger patients 1, 2

• If clinical suspicion remains high, proceed to clonidine suppression test (100% specificity, 96% sensitivity) 1, 2

Marginally Elevated Results (1-2× Upper Limit of Normal)

• Repeat testing in 6 months 1, 2

• Consider clonidine suppression test to exclude false positivity 1, 2

• Review for interfering medications (tricyclic antidepressants, MAO inhibitors, levodopa) and conditions (obesity, obstructive sleep apnea) 4, 1

Follow-Up Testing for Equivocal Results

When Initial Plasma Testing is Inconclusive

• If plasma metanephrines show less than fourfold elevation with strong clinical suspicion, perform 24-hour urine collection for fractionated metanephrines and catecholamines 1, 2

• The Endocrine Society recommends clonidine suppression testing for equivocal biochemical results with persistent clinical suspicion 4, 1

Additional Markers for Risk Stratification

• Plasma methoxytyramine measurement helps assess malignancy risk, with levels >3× upper limit indicating high risk of metastatic disease 4, 1, 6

• Isolated elevation of methoxytyramine suggests paraganglioma or rare dopamine-producing pheochromocytoma 4

• High normetanephrine suggests adrenal pheochromocytoma, while isolated methoxytyramine elevation suggests extra-adrenal paraganglioma 4

Common Pitfalls and How to Avoid Them

False Positive Prevention

• Ensure proper patient positioning (supine for 30 minutes) before plasma collection - this single factor causes 25% of false positives when ignored 4, 1

• False positive elevations from hypertension, obesity, or sleep apnea are usually <4× upper limit of normal 1

• Tricyclic antidepressants and MAO inhibitors increase metanephrine and normetanephrine; levodopa raises methoxytyramine 4

• Alpha-1 selective blockers like doxazosin do NOT interfere with metanephrine measurements and need not be discontinued 1

False Negative Prevention

• Very small tumors or microscopic disease may not produce elevated metanephrines 7

• Rare dopamine-only producing tumors require methoxytyramine measurement for detection 4, 7

• If biochemical testing is negative but clinical suspicion remains high (classic triad of headache, palpitations, sweating with hypertension), consider MIBG scintigraphy 8, 9

Special Population Considerations

Hereditary Syndromes

• For patients with SDHB mutations, measure all three metanephrines including methoxytyramine, as these tumors have higher malignancy risk (up to 70%) 4, 6

• Begin surveillance at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes, or age 2 years for von Hippel-Lindau syndrome 1, 2

• SDHD and SDHAF2 mutations show maternal imprinting - only paternal inheritance causes disease 6

Pediatric Patients

• Urine fractionated metanephrines may be more practical once children are continent 1, 2

• Plasma testing requires careful attention to collection technique in anxious children 1

What NOT to Do

• Never perform fine needle biopsy of suspected pheochromocytoma - this is absolutely contraindicated due to risk of hypertensive crisis 4, 2

• Do not rely on imaging alone without biochemical confirmation 2

• Do not measure only total metanephrines or vanillylmandelic acid - these have inferior sensitivity (77% and 64% respectively) 3

• Do not use plasma catecholamines alone as the initial test - sensitivity is only 84% compared to 99% for plasma free metanephrines 3