What is the approach to diagnosing and managing pheochromocytoma?

Diagnosis of Pheochromocytoma

Measure plasma-free metanephrines as the first-line diagnostic test for pheochromocytoma, as this provides the highest sensitivity (99%) and negative predictive value, reliably excluding the tumor when normal. 1, 2

Initial Biochemical Testing

All patients with suspected pheochromocytoma must undergo biochemical confirmation before any intervention, as unrecognized tumors can cause life-threatening hypertensive crises. 1

First-Line Test

• Plasma-free metanephrines are the single best screening test, with 99% sensitivity and 89% specificity 2
• Urinary fractionated metanephrines are an acceptable alternative (97% sensitivity, 69% specificity) and may be preferred for pediatric patients not yet continent of urine 3, 2
• For optimal plasma collection, use an indwelling venous catheter after the patient has been supine for 30 minutes to minimize false positives 3

Interpretation Algorithm

• If plasma metanephrines are ≥4 times the upper limit of normal: proceed directly to imaging 3
• If 2-4 times upper limit: repeat testing in 2 months and consider genetic testing 3
• If marginally elevated with strong clinical suspicion: perform clonidine suppression test (100% specificity, 96% sensitivity) 3, 4
• If equivocal plasma results: obtain 24-hour urine for fractionated metanephrines and catecholamines 3

Additional Biomarkers

• Measure plasma methoxytyramine when available, as elevated levels indicate higher malignancy risk 1
• This is particularly important for assessing metastatic potential 1

Clinical Context for Testing

High-Risk Populations Requiring Screening

• Early-onset hypertension (<30 years) 3
• Resistant hypertension (BP >140/90 despite ≥3 medications including diuretic) 3
• Paroxysmal hypertension with classic triad: headache, palpitations, and diaphoresis (90% specificity when all three present) 3
• Adrenal incidentaloma (must systematically rule out pheochromocytoma before any biopsy or intervention) 1
• Family history of pheochromocytoma or hereditary syndromes 3

Critical Safety Point

Never perform fine needle biopsy of a suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis. 1, 3

Imaging Localization

Only proceed to imaging after biochemical confirmation. 1

Imaging Modality Selection

• MRI is preferred over CT due to risk of hypertensive crisis from IV contrast 3, 4
• Obtain cross-sectional imaging of chest, abdomen, and pelvis to detect metastases 1
• If initial imaging is negative despite positive biochemistry, extend imaging to chest and neck 3

Functional Imaging Indications

Consider functional imaging when any of the following high-risk features are present 1:

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

For metastatic disease, FDG-PET is superior to MIBG scintigraphy, particularly in SDHB mutation carriers. 3

Genetic Testing

Approximately one-third of pheochromocytomas are hereditary, making genetic evaluation important. 5

• Consider genetic testing for patients with: 3
  • Age <30 years at diagnosis
  • Extra-adrenal tumors
  • Bilateral adrenal tumors
  • Family history of pheochromocytoma
  • Metanephrines 2-4 times upper limit of normal

Common Pitfalls and False Positives

Medications and Conditions Causing Elevation

• Tricyclic antidepressants can elevate catecholamine metabolites 3
• Obesity and obstructive sleep apnea may cause mild elevations 3
• However, alpha-1 selective blockers (like doxazosin) do NOT interfere with metanephrine measurements 3

Key Distinguishing Feature

False positive elevations are typically <4 times the upper limit of normal, whereas true pheochromocytomas usually produce much higher elevations. 3

Management Considerations

Preoperative Preparation

• Alpha-adrenoceptor blockade must be initiated 7-14 days before surgery with gradually increasing doses until blood pressure targets are achieved 3
• This is mandatory even if pheochromocytoma is not definitively excluded but surgery is planned 3

Medical Management

• Metyrosine (tyrosine hydroxylase inhibitor) is FDA-approved for preoperative preparation and management when surgery is contraindicated or for malignant pheochromocytoma 6
• It reduces catecholamine biosynthesis by 35-80% within 2-3 days 6

Post-Surgical Follow-Up

All patients require long-term surveillance due to risk of malignant recurrence, particularly those with SDHB mutations, extra-adrenal tumors, or tumors >5 cm. 1, 3

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 1
• Follow-up every 3-4 months for 2-3 years, then every 6 months 1
• Patients with SDHB mutations, extra-adrenal disease, or PASS score ≥4 require lifelong monitoring 1, 3