What is the appropriate diagnosis and treatment approach for a patient with suspected pheochromocytoma?

Pheochromocytoma: Diagnosis and Management

Biochemical Diagnosis

Measure plasma free metanephrines as the first-line diagnostic test for suspected pheochromocytoma, as this provides the highest sensitivity (96-100%) and specificity (89-98%) of all available biochemical tests. 1, 2, 3, 4

When to Screen for Pheochromocytoma

Screen patients with any of the following clinical presentations:

• Classic triad: Headache, palpitations, and sweating ("cold sweat") occurring together—this combination has 90-94% diagnostic specificity 1, 2
• Resistant hypertension: BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic (prevalence up to 4% in this population) 1, 2
• Paroxysmal or early-onset hypertension: Especially if onset <30 years of age 1, 2
• Adrenal incidentaloma: Any adrenal mass displaying >10 HU on non-contrast CT 2
• Family history: MEN2, VHL, NF1, or hereditary paraganglioma syndromes 1, 2, 5

Optimal Collection Method for Plasma Free Metanephrines

Collect plasma free metanephrines from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positive results. 1, 3 While clinicians may bypass this ideal approach for initial screening, marginally elevated results should prompt repetition under these optimal conditions. 1

Interpretation Algorithm Based on Metanephrine Levels

If levels are ≥4 times the upper limit of normal: Results are consistent with pheochromocytoma/paraganglioma—proceed immediately to imaging to localize the lesion. 1, 2, 3

If levels are 2-4 times the upper limit of normal: Repeat testing in 2 months (ideally using indwelling catheter with proper positioning) and consider genetic testing for hereditary syndromes. 1, 3

If levels are marginally elevated (1-2 times upper limit): Repeat testing in 6 months using optimal collection conditions, or consider clonidine suppression test (100% specificity, 96% sensitivity). 1, 3, 6

Alternative and Confirmatory Testing

• 24-hour urinary fractionated metanephrines: Acceptable alternative with sensitivity 86-97% and specificity 86-95%, particularly useful for pediatric patients or when plasma testing is equivocal (<4-fold elevation). 1, 3, 4
• Clonidine suppression test: Reserved for equivocal results with strong clinical suspicion (100% specificity, 96% sensitivity). 1, 3, 6
• Plasma methoxytyramine: Measure when available, as elevated levels indicate higher malignancy risk. 1, 3

Critical Testing Pitfalls to Avoid

Confirm that interfering medications and foods were avoided prior to testing—several agents can cause false elevations, though common antihypertensive medications (including alpha-1 selective blockers like doxazosin) do not affect plasma free metanephrine measurements when using LC-MS/MS analysis. 1 False positive elevations are usually <4 times the upper limit of normal and may occur with obesity, obstructive sleep apnea, or tricyclic antidepressants. 1

Imaging Localization

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

First-Line Anatomical Imaging

MRI is preferred over CT for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast. 1, 2, 3 Obtain cross-sectional imaging of chest, abdomen, and pelvis to detect metastases. 1

Functional Imaging Indications

Consider functional imaging (FDG-PET preferred over MIBG, particularly for SDHB mutations) when any high-risk features are present: 1, 3

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

If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck, and consider functional imaging. 1, 3

Absolute Contraindications

Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated due to risk of precipitating fatal hypertensive crisis. 1, 3 All patients with adrenal incidentaloma must systematically rule out pheochromocytoma before any biopsy or intervention. 1

Genetic Testing

Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance. 1, 5, 7 Consider genetic testing in patients with:

• Family history of pheochromocytoma/paraganglioma
• Young age at diagnosis
• Bilateral or multifocal disease
• Extra-adrenal location (paraganglioma)
• SDHB mutations (associated with higher malignancy risk requiring more intensive lifelong surveillance) 1, 2, 3

Begin surveillance at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes, or age 2 years for von Hippel-Lindau syndrome. 1, 3

Preoperative Management

Alpha-adrenergic blockade must be started 7-14 days preoperatively with gradually increasing dosages until blood pressure targets are achieved. 1, 2, 8 Phenoxybenzamine is the FDA-approved agent, typically started at 10 mg twice daily and increased every other day to 20-40 mg 2-3 times daily until optimal blood pressure control. 2, 8

Never initiate beta-blockade alone before alpha-blockade, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation. 1 If tachycardia is excessive after alpha-blockade, a beta-blocking agent may be used concomitantly. 8

Surgical Treatment

Laparoscopic surgical resection is the definitive treatment and is successful in 90% of cases. 2, 9, 7 Pheochromocytomas <5 cm in diameter can be removed laparoscopically; larger tumors should be removed by open surgery. 9

Post-Surgical Surveillance

All patients require long-term surveillance due to risk of malignant recurrence (10% of tumors are malignant), particularly those with SDHB mutations, extra-adrenal tumors, or tumors >5 cm. 1, 2, 9

• Repeat biochemical testing 14 days post-surgery to confirm complete resection
• Follow-up every 3-4 months for 2-3 years, then every 6 months
• Patients with PASS score ≥4, large primary tumor, and/or SDHB mutation require extended and lifelong monitoring 1