What is the recommended approach for diagnosing and managing pheochromocytoma?

Diagnostic and Management Approach for Pheochromocytoma

The most effective diagnostic approach for pheochromocytoma is measurement of plasma free metanephrines, which has the highest sensitivity (96-100%) and specificity (89-98%), making it the test of first choice for diagnosing this condition. 1

Initial Diagnostic Workup

• Measure plasma free metanephrines as the primary screening test due to its superior sensitivity (99%) and specificity (89%) compared to other biochemical tests 1, 2
• Alternatively, 24-hour urinary fractionated metanephrines can be used with high sensitivity (86-97%) and specificity (86-95%) 1, 2
• For equivocal results (1-4 times upper limit of normal), consider repeating testing and performing clonidine suppression test, which has 100% specificity and 96% sensitivity 1
• False positive results are common with levels <4 times the upper limit of normal and may occur with obesity, obstructive sleep apnea, or use of tricyclic antidepressants 1

When to Suspect Pheochromocytoma

• Early-onset hypertension (<30 years) 1
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 1
• Paroxysmal hypertension with classic symptoms (headache, palpitations, pallor, and sweating) 1
• Significant blood pressure variability 1
• Family history of pheochromocytoma 1

Imaging Studies

• After positive biochemical testing, proceed to anatomical imaging with CT or MRI of the abdomen 3
• MRI is preferred for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast for CT 4
• For patients with established pheochromocytoma, FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation 4
• Fine needle biopsy of suspected pheochromocytoma is contraindicated due to risk of hypertensive crisis 4

Management Algorithm Based on Metanephrine Levels

• For levels ≥4 times the upper limit of normal, results are consistent with pheochromocytoma/paraganglioma and immediate imaging is recommended 1
• For levels 2-4 times the upper limit of normal, repeat testing in 2 months and consider genetic testing 1
• For marginally elevated levels, repeat testing in 6 months and consider clonidine suppression test 1

Genetic Considerations

• Consider genetic testing in patients with family history, young age at diagnosis, bilateral or multifocal disease, or extra-adrenal location 3
• Associated genetic syndromes include MEN2, VHL, NF1, and hereditary paraganglioma syndromes 3
• SDHB mutations are associated with higher risk of aggressive behavior and metastatic disease 4

Treatment Approach

• Complete surgical extirpation (R0 resection) is the mainstay of potentially curative treatment 3
• Preoperative alpha-blockade with phenoxybenzamine is indicated to control episodes of hypertension and sweating 5
• If tachycardia is excessive, a beta-blocking agent may be used concomitantly with alpha-blockade 5
• For malignant pheochromocytoma, cytoreductive surgery might be considered 3

Follow-up Protocol

• Biochemical testing approximately 14 days following surgery to check for remaining disease 3
• Long-term follow-up includes clinical evaluation, biochemical testing, and imaging with CT of thorax and abdomen as clinically indicated 3
• Patients with SDHB mutations require more intensive surveillance due to higher risk of malignancy 4

Pitfalls and Caveats

• Preanalytical factors can influence metanephrine measurement and cause false positive results, including medications like tricyclic antidepressants and sulfasalazine 6
• 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
• A PASS (Pheochromocytoma of the Adrenal gland Scaled Score) score of ≥4, a large primary tumor, and/or a mutation in the SDHB gene should alert the clinician to carry out extended and prolonged (life-long) monitoring 4