What is the diagnostic approach for a 20-50 year old patient presenting with episodes of hypertension, sweating, headaches, and palpitations, suspected of having pheochromocytoma?

Diagnosis of Pheochromocytoma

Initial Biochemical Testing

Measure plasma free metanephrines as the first-line diagnostic test for suspected pheochromocytoma, as this provides the highest sensitivity (96-100%) and reliably excludes the tumor when normal. 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 minimize false positive results 1, 2
• If the ideal collection method is not feasible, testing can proceed, but marginally elevated results must be repeated under proper conditions 1
• 24-hour urinary fractionated metanephrines are an acceptable alternative with high sensitivity (86-97%) and specificity (86-95%), particularly useful for pediatric patients or when plasma collection is impractical 1, 2

Clinical Context for Testing

The classic triad of headache, palpitations, and sweating in a hypertensive patient has 93.8% specificity and 90.9% sensitivity for pheochromocytoma, with 99.9% exclusion value when absent 1. Screen patients presenting with:

• Paroxysmal hypertension with classic symptoms (headache, sweating, palpitations) 1
• Early-onset hypertension (<30 years) or resistant hypertension 1
• Significant blood pressure variability 1, 3
• Family history of pheochromocytoma or associated genetic syndromes 1
• Adrenal incidentaloma (must exclude pheochromocytoma before any biopsy) 1

Interpretation Algorithm Based on Metanephrine Levels

For levels ≥4 times the upper limit of normal: Proceed immediately to imaging for tumor localization, as this degree of elevation is diagnostic for pheochromocytoma/paraganglioma 1, 2

For levels 2-4 times the upper limit of normal: Repeat testing in 2 months and consider genetic testing for hereditary syndromes, especially in younger patients 1, 2

For marginally elevated levels (1-2 times upper limit): Repeat testing in 6 months using proper collection technique (indwelling catheter, 30 minutes supine) or perform clonidine suppression test 1, 2

Confirmatory Testing for Equivocal Results

• If plasma testing shows less than fourfold elevation with strong clinical suspicion, perform 24-hour urine collection for fractionated metanephrines and catecholamines 1, 2
• The clonidine suppression test has 100% specificity and 96% sensitivity for distinguishing true pheochromocytoma from false positives in equivocal cases 1, 2
• Plasma methoxytyramine measurement helps assess malignancy risk when available 1, 3, 2

Common Causes of False Positives

False positive elevations are usually <4 times the upper limit of normal and may occur with 1:

• Obesity, obstructive sleep apnea 1
• Tricyclic antidepressants 1
• Improper collection technique (not supine, stress during collection) 1
• Common antihypertensive medications do NOT affect plasma free metanephrine measurements when using LC-MS/MS analysis 1

Imaging After Biochemical Confirmation

Never proceed to imaging without biochemical confirmation first, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures. 1

• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 1, 2
• If initial abdominal imaging is negative but biochemistry is positive, extend imaging to chest and neck 1, 2
• For established pheochromocytoma, FDG-PET is superior to MIBG for detecting malignant tumors, particularly with SDHB mutations 1, 2

Functional Imaging Indications

Consider functional imaging when high-risk features are present 1:

• Tumor size ≥5 cm 1, 3
• Extra-adrenal paraganglioma 1, 3
• SDHB germline mutation 1, 3
• Plasma methoxytyramine >3-fold above upper limit 1, 3

Critical Safety Considerations

Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated due to risk of fatal hypertensive crisis. 1, 2

• All patients with suspected pheochromocytoma must undergo biochemical confirmation before any intervention 1
• Avoid contrast-enhanced CT or invasive procedures until pheochromocytoma is definitively excluded 1
• Never initiate beta-blockade alone before alpha-blockade, as this precipitates severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 1

Genetic Testing Considerations

Approximately 35% of pheochromocytomas are hereditary 3. Genetic testing should be considered for 1, 3:

• Patients ≤50 years old with confirmed pheochromocytoma 1
• Extra-adrenal tumors or bilateral adrenal tumors 1
• Family history of pheochromocytoma or associated syndromes 3
• SDHB mutations confer higher risk of malignancy and require intensive lifelong surveillance 1

Pediatric Surveillance

For hereditary syndromes, begin surveillance 1:

• Age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes 1
• Age 2 years for von Hippel-Lindau syndrome 1

Post-Surgical Follow-Up

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 1, 3
• Follow-up every 3-4 months for 2-3 years, then every 6 months 1
• All patients require long-term surveillance due to risk of malignant recurrence, particularly those with SDHB mutations, extra-adrenal tumors, or tumors >5 cm 1