What is the management approach for patients with elevated metanephrines (metanephrine levels) suggestive of pheochromocytoma or paraganglioma?

Management of Elevated Metanephrines Suggestive of Pheochromocytoma or Paraganglioma

Patients with elevated metanephrines suggestive of pheochromocytoma or paraganglioma should undergo a structured diagnostic and management approach based on the degree of elevation, with immediate imaging indicated for levels ≥4 times the upper limit of normal. 1, 2

Initial Biochemical Assessment

• Plasma free metanephrines is the preferred first-line test for suspected pheochromocytoma/paraganglioma (PPGL) due to its superior diagnostic performance (sensitivity 96-100%, specificity 89-98%) 1
• Urinary fractionated metanephrines are an acceptable alternative with high sensitivity (86-97%) and specificity (86-95%) 1, 3
• 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 1, 2
• Plasma methoxytyramine measurement can help assess the likelihood of malignant disease 1, 2

Management Algorithm Based on Metanephrine Levels

• For levels ≥4 times the upper limit of normal:

  • Results are highly consistent with pheochromocytoma/paraganglioma 1, 2
  • Proceed immediately to imaging to localize the lesion 1
  • MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 1, 2

• For levels 2-4 times the upper limit of normal:

  • Suggests possible pheochromocytoma/paraganglioma 1
  • Repeat testing in 2 months 1
  • Consider genetic testing, especially in younger patients 1, 2

• For marginally elevated levels (1-2 times upper limit):

  • May represent false positives 1
  • Consider repeat testing in 6 months 1
  • Consider clonidine suppression test (100% specificity, 96% sensitivity) 1, 4
  • If plasma testing is equivocal, perform a 24-hour urine collection for catecholamines and metanephrines 1, 2

Imaging After Biochemical Confirmation

• MRI is preferred for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast for CT 1, 2
• For head/neck paragangliomas, MRI with angiography sequences is recommended as the first modality to assess multifocality and tumor extension 5
• If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck 1
• For patients with established disease, FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation 1, 2
• Whole-body MRI should be performed at least every 2–3 years to detect new PPGLs, metastases, or progression in patients with known disease 5

Preoperative Management

• For functional PPGLs, preoperative alpha-blockade with phenoxybenzamine is recommended to prevent perioperative hemodynamic instability 5, 6
• Phenoxybenzamine is indicated to control episodes of hypertension and sweating in pheochromocytoma 6
• If tachycardia is excessive, beta-blockers may be used concomitantly, but only after adequate alpha-blockade 6
• Metyrosine and calcium channel blockers can be used as adjuncts to alpha-blockade 5

Long-term Surveillance

• Patients with PPGL (regardless of surgical history) should undergo annual blood pressure measurements, clinical assessment, and biochemical measurements 5
• Measurement of plasma or urine metanephrines should be performed by 8 weeks post-treatment for functional PPGLs 5
• Imaging should be done at 3–6 months post-treatment 5
• Patients with SDHB mutations require more intensive surveillance due to higher risk of malignancy 1, 2

Special Considerations

• All decisions in patients with PPGLs should be discussed and managed by an expert interdisciplinary tumor team 5
• Avoid fine needle biopsy of suspected pheochromocytoma as it is contraindicated due to risk of hypertensive crisis 1, 2
• For patients with metastatic disease, targeted radionuclide therapy is recommended as first-line systemic therapy for SSTR- or MIBG-positive metastatic tumors 5
• Chemotherapy is recommended as first-line therapy in cases of rapid progression or high visceral tumor burden 5

Common Pitfalls to Avoid

• Failing to ensure proper patient preparation before testing (medications, posture, fasting status) can lead to false results 1
• Relying solely on imaging without biochemical confirmation 1, 7
• Not considering extra-adrenal locations when adrenal imaging is negative 1, 8
• Overlooking the need for specialized imaging protocols optimized for adrenal evaluation 1
• Starting beta-blockers before adequate alpha-blockade, which can precipitate a hypertensive crisis 6, 9