What is the workup for pheochromocytoma?

Diagnostic Workup for Pheochromocytoma

The optimal workup for pheochromocytoma begins with measurement of plasma free metanephrines as the first-line biochemical test, followed by anatomical imaging with CT/MRI and functional imaging when appropriate. 1

Biochemical Testing

Initial Testing

• Plasma free metanephrines is the preferred initial test with highest sensitivity (99%) and specificity (89%) 2
  • Most sensitive single test for excluding or confirming pheochromocytoma
  • Negative result effectively rules out pheochromocytoma (negative likelihood ratio 0.02) 3

Follow-up Testing

• If plasma metanephrines are equivocal (less than fourfold elevation):
  • Perform 24-hour urine collection for catecholamines and metanephrines 1
  • Urinary fractionated metanephrines have 97% sensitivity but lower specificity (69%) 2

Important Considerations

• Avoid medications that can interfere with testing (e.g., sulfasalazine) 4
• Collect samples after patient has been supine and resting for at least 30 minutes
• Fasting state preferred for plasma metanephrines

Imaging Studies

Anatomical Imaging

• CT or MRI of abdomen as first-line imaging 1
  • MRI preferred for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast for CT 1
  • CT thorax to evaluate for metastatic disease 1

Functional Imaging

• Indicated after positive biochemical testing to:

  • Confirm diagnosis
  • Detect multifocal disease
  • Identify metastases

• Options for functional imaging:

  1. FDG-PET/CT - preferred for suspected malignant pheochromocytoma, especially with SDHB mutations 1
  2. MIBG scintigraphy - highly specific (81-90% sensitive) 5
  3. DOTATATE-PET/CT - for detecting metastatic disease 1
  4. FDOPA-PET - superior for detection of pheochromocytomas in hereditary syndromes 1

Genetic Testing

• Consider genetic testing for all patients with pheochromocytoma, especially:

  • Young patients (≤40 years)
  • Those with multifocal, bilateral, or extra-adrenal disease
  • Family history of pheochromocytoma or related syndromes
  • Malignant pheochromocytoma

• Key genes to test: SDHx (especially SDHB), RET, VHL, NF1, TMEM127, MAX 1

Risk Stratification for Malignancy

High-risk features include:

• Extra-adrenal location
• Tumor size >5 cm
• SDHB mutation
• Elevated plasma methoxytyramine (>3x upper limit) 1
• PASS score ≥4 1

Common Pitfalls to Avoid

1. False positive biochemical results due to:

   • Medications (tricyclic antidepressants, MAOIs, sympathomimetics)
   • Acute stress or illness
   • Improper sample collection/handling

2. Biopsy of suspected pheochromocytoma - contraindicated due to risk of hypertensive crisis 1

3. Inadequate preoperative preparation - can lead to intraoperative hypertensive crisis

4. Missing hereditary syndromes - failure to perform genetic testing can miss familial cases

5. Incomplete imaging - failure to detect multifocal or metastatic disease

Follow-up After Diagnosis

• For patients with confirmed pheochromocytoma:
  • Annual surveillance with plasma metanephrines
  • Periodic imaging based on risk of recurrence
  • Lifelong follow-up recommended, especially for those with genetic syndromes or malignant disease 1

By following this systematic approach to the workup of pheochromocytoma, clinicians can ensure timely diagnosis and appropriate management to reduce morbidity and mortality associated with this potentially life-threatening condition.