What is the workup and management for a patient with suspected pheochromocytoma?

Workup for Pheochromocytoma

Screen all patients with adrenal incidentalomas displaying >10 HU on non-contrast CT or who have signs/symptoms of catecholamine excess using plasma free metanephrines or 24-hour urinary fractionated metanephrines as the initial biochemical test. 1, 2

When to Suspect Pheochromocytoma

Screen for pheochromocytoma in the following clinical scenarios:

• Early-onset hypertension (<30 years of age) 2
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) - prevalence up to 4% in this population 2
• Paroxysmal hypertension with classic triad: headache, palpitations, and sweating ("cold sweat") - when occurring together, this has 90% diagnostic specificity 2
• Significant blood pressure variability or pallor 2
• Family history of pheochromocytoma or associated genetic syndromes (MEN2, VHL, NF1, hereditary paraganglioma syndromes) 2, 3
• Adrenal incidentaloma with >10 HU on non-contrast CT 1, 2

Do not screen patients with unequivocal adrenocortical adenomas confirmed on unenhanced CT (HU <10) and no signs or symptoms of adrenergic excess 1

Biochemical Testing Algorithm

First-Line Testing

Measure plasma free metanephrines OR 24-hour urinary fractionated metanephrines - both have excellent diagnostic performance 1, 2, 3:

• Plasma free metanephrines: 96-100% sensitivity, 89-98% specificity 2
• Urinary fractionated metanephrines: 86-97% sensitivity, 86-95% specificity 2

Critical collection technique for plasma metanephrines: Ideally collect from an indwelling venous catheter after the patient has been lying supine for 30 minutes to limit false positive results 2

Interpretation Based on Metanephrine Levels

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

If levels are 2-4 times the upper limit of normal: 2

• Repeat testing in 2 months
• Consider clonidine suppression test (100% specificity, 96% sensitivity) 2, 4
• Consider genetic testing for hereditary syndromes, especially in younger patients

If levels are marginally elevated (1-2 times upper limit): 2

• Repeat testing in 6 months
• Consider clonidine suppression test to exclude false positivity
• Review medications and conditions that may cause false positives

Common Causes of False Positives

False positive elevations are usually <4 times the upper limit of normal and may occur with: 2

• Obesity
• Obstructive sleep apnea
• Tricyclic antidepressants

Important: Common antihypertensive medications (including alpha-1 selective blockers like doxazosin) do not affect plasma free metanephrine measurements when using LC-MS/MS analysis 2

Second-Line Biochemical Testing

If plasma testing is equivocal (less than fourfold elevation), perform 24-hour urine collection for catecholamines and metanephrines 3

Consider plasma methoxytyramine measurement to assess likelihood of malignant disease, particularly in patients with suspected metastatic disease 3

Imaging Studies

After Positive Biochemical Testing

First-line anatomical imaging: CT or MRI of the abdomen and pelvis 3, 5

• MRI is preferred due to risk of hypertensive crisis with IV contrast for CT 2, 3
• Include chest CT to evaluate for metastatic disease 3

If initial imaging is negative but biochemical evidence is positive: Extend imaging to include chest and neck, and consider functional imaging 2

Functional Imaging

Meta-iodobenzylguanidine (MIBG) scintigraphy: Helpful to detect multifocal disease 3, 5

For patients with established pheochromocytoma: FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation 2

Critical contraindication: Fine needle biopsy of suspected pheochromocytoma is contraindicated due to risk of hypertensive crisis 2, 3

Genetic Testing Considerations

Consider genetic testing in: 3

• Family history of pheochromocytoma/paraganglioma
• Young age at diagnosis
• Bilateral or multifocal disease
• Extra-adrenal location (paraganglioma)

Approximately 25-33% of patients with pheochromocytoma have germline mutations (NF1, VHL, SDHD, SDHB, RET) 3, 5

SDHB mutations are associated with higher risk of aggressive behavior and metastatic disease, requiring more intensive surveillance 2

Pediatric Surveillance Protocols

• For hereditary paraganglioma/pheochromocytoma syndromes: Begin surveillance at age 6-8 years 2
• For von Hippel-Lindau syndrome: Begin surveillance at age 2 years 2

Risk Factors for Malignancy

Malignancy is defined only by presence of metastatic lesions at sites where chromaffin cells are normally absent. Risk factors include: 3

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

Preoperative Management

Alpha-adrenergic blockade is essential before surgery 6, 5:

• Phenoxybenzamine: Start with 10 mg twice daily, increase every other day to 20-40 mg 2-3 times daily until optimal blood pressure control 6
• Typically started 7-14 days before surgery 2
• If tachycardia is excessive, use a beta-blocking agent concomitantly (only after adequate alpha-blockade) 6
• Volume expansion is also essential 5

Multidisciplinary Review

Maintain a low threshold for multidisciplinary review by endocrinologists, surgeons, and radiologists when: 1

• Imaging is not consistent with a benign lesion
• Evidence of hormone hypersecretion exists
• Tumor has grown significantly during follow-up
• Adrenal surgery is being considered