What is the management plan for a patient with suspected pheochromocytoma or paraganglioma undergoing a metanephrines (metanephrines) fractionated free blood test?

Management of Suspected Pheochromocytoma/Paraganglioma with Plasma Free Metanephrines Testing

For patients undergoing plasma free metanephrines testing for suspected pheochromocytoma/paraganglioma, the management algorithm is determined by the degree of elevation: levels ≥4 times the upper limit of normal warrant immediate imaging to localize the tumor, levels 2-4 times upper limit require repeat testing in 2 months, and marginally elevated levels should be retested in 6 months or undergo clonidine suppression testing. 1

Pre-Test Preparation and Collection

Optimal Collection Technique

• 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
• Clinicians may bypass this ideal approach in routine screening, but marginally elevated results must prompt repetition under standardized conditions. 3, 1
• For high-risk populations (hereditary syndromes, strong clinical suspicion), use the indwelling catheter protocol from the outset. 1

Medication and Food Interference

• Confirm that interfering agents were avoided prior to testing, including tricyclic antidepressants, sympathomimetics, and decongestants. 3, 1, 2
• Common antihypertensive medications do not affect plasma free metanephrine measurements when using LC-MS/MS analysis. 1
• Alpha-1 selective blockers like doxazosin do not interfere with metanephrine testing and need not be discontinued. 1

Interpretation Algorithm Based on Metanephrine Levels

Levels ≥4 Times Upper Limit of Normal

• Results are consistent with pheochromocytoma/paraganglioma—proceed immediately to imaging to localize the lesion. 3, 1, 4, 2
• This degree of elevation is diagnostic regardless of collection method. 1
• False positive elevations are usually <4 times the upper limit of normal. 1

Levels 2-4 Times Upper Limit of Normal

• Repeat testing in 2 months, ideally using an indwelling catheter with proper positioning. 3, 1
• Consider genetic testing for hereditary syndromes, especially in younger patients. 1
• Assess for hyperadrenergic symptoms (sustained or intermittent palpitations, tachycardia, diaphoresis, tremors, new-onset hypertension). 1

Marginally Elevated Levels (1-2 Times Upper Limit)

• Repeat testing in 6 months using an indwelling catheter after 30 minutes supine rest. 3, 1
• Consider clonidine suppression test to exclude false positivity, which has 100% specificity and 96% sensitivity. 1, 5
• Age-related increases in normetanephrine can contribute to false positives, particularly in older patients. 6

Imaging After Biochemical Confirmation

First-Line Anatomical Imaging

• MRI of abdomen and pelvis is preferred over CT due to risk of hypertensive crisis with IV contrast. 1, 4, 2
• If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck. 1
• Include chest imaging to evaluate for metastatic disease. 4

Functional Imaging Indications

• Consider functional imaging when high-risk features are present: tumor size ≥5 cm, extra-adrenal paraganglioma, SDHB germline mutation, or plasma methoxytyramine >3-fold above upper limit. 1
• FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation. 1

Critical Pitfalls to Avoid

Contraindicated Procedures

• Never perform fine needle biopsy of suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis. 1
• Never proceed to imaging without biochemical confirmation first. 1

Medication Management

• Never initiate beta-blockade alone before alpha-blockade in suspected pheochromocytoma, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation. 1, 2
• If pheochromocytoma is confirmed and surgery is planned, alpha-adrenergic blockade must be started 7-14 days preoperatively with gradually increasing dosages until blood pressure targets are achieved. 1, 4, 2

Genetic Testing Considerations

Indications for Genetic Testing

• Approximately 25-33% of patients with pheochromocytoma have germline mutations. 4, 2
• Consider genetic testing in patients with family history, young age at diagnosis (<30 years), bilateral or multifocal disease, or extra-adrenal location (paraganglioma). 1, 4, 2
• SDHB mutations are associated with higher risk of aggressive behavior and metastatic disease, requiring more intensive surveillance. 1, 4

Special Populations

Pediatric Patients

• For von Hippel-Lindau syndrome, begin surveillance with plasma free metanephrines at age 2 years. 3, 1
• For hereditary paraganglioma/pheochromocytoma syndromes, begin surveillance at age 6-8 years. 1
• Twenty-four-hour urine fractionated metanephrines are an acceptable alternative once patients are continent of urine. 3, 1

Pregnant Patients

• Pheochromocytoma in pregnancy is rare (1/15,000-1/54,000) but early diagnosis is critical to prevent mortality. 7
• MRI without gadolinium is the preferred imaging method during pregnancy; avoid CT. 7

Alternative Testing Options

24-Hour Urine Fractionated Metanephrines

• Acceptable alternative to plasma testing with sensitivity 86-97% and specificity 86-95%. 1, 8
• May be more practical for pediatric patients once continent of urine. 1
• If plasma testing is equivocal (<4-fold elevation), perform 24-hour urine collection for catecholamines and metanephrines. 1

Plasma Methoxytyramine

• Elevated levels indicate higher malignancy risk and should be measured when available. 1
• Up to 30% of head/neck paragangliomas produce dopamine, indicated by increases in plasma methoxytyramine. 1

Post-Surgical Follow-Up

• Repeat biochemical testing 14 days post-surgery to confirm complete resection. 1
• 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