What is the appropriate evaluation and workup for a patient suspected of having pheochromocytoma?

Evaluation of Pheochromocytoma

Initial Biochemical Testing

Measure plasma free metanephrines as the first-line diagnostic test, which provides the highest sensitivity (96-100%) and negative predictive value for reliably excluding pheochromocytoma when normal. 1, 2

Critical Collection Requirements

• Plasma free metanephrines must be collected after 30 minutes of supine rest, ideally from an indwelling venous catheter, to minimize false positive results 1, 2
• If collected sitting rather than supine, 25% of results will be falsely elevated and require repeat testing 2
• Confirm that interfering medications and foods were avoided prior to testing (though common antihypertensive medications do not affect LC-MS/MS analysis) 1
• Methoxytyramine should be sampled after an overnight fast 2

Alternative Testing Options

• 24-hour urinary fractionated metanephrines are an acceptable alternative with sensitivity of 86-97% and specificity of 86-95%, particularly useful for pediatric patients not yet continent of urine 1, 2
• Analysis should be performed using LC-MS/MS methodology for optimal accuracy 2

Interpretation Algorithm Based on Biochemical Results

Results ≥4 Times Upper Limit of Normal

• Proceed directly to imaging to localize the tumor—this degree of elevation is diagnostic of pheochromocytoma/paraganglioma 1, 2
• MRI of the abdomen is preferred over CT due to risk of hypertensive crisis with IV contrast 3, 2

Results 2-4 Times Upper Limit of Normal

• Repeat testing in 2 months 1
• Consider genetic testing for hereditary syndromes, especially in younger patients 1

Marginally Elevated Results (1-2 Times Upper Limit)

• Repeat testing in 6 months using proper collection technique (indwelling catheter, 30 minutes supine) 1
• Consider clonidine suppression test if clinical suspicion remains high 1

Equivocal Results with Strong Clinical Suspicion

• Perform 24-hour urine collection for fractionated metanephrines and catecholamines if plasma testing shows less than fourfold elevation 1, 2
• The clonidine suppression test has 100% specificity and 96% sensitivity for distinguishing true pheochromocytoma from false positives 1

Imaging Localization (After Biochemical Confirmation)

Anatomical Imaging

• MRI is preferred for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast for CT 3, 2
• CT is less expensive and acceptable if pheochromocytoma is biochemically excluded 3
• Obtain cross-sectional imaging of chest, abdomen, and pelvis to detect metastases 1

Functional Imaging Indications

Consider functional imaging when any of these high-risk features are present: 1, 2

• Tumor size ≥5 cm

• Extra-adrenal paraganglioma location

• SDHB germline mutation

• Plasma methoxytyramine >3-fold above upper limit

• For patients with established pheochromocytoma, FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation 3

• Whole-body PET with radiolabeled somatostatin analogs is preferred for SDHD-related tumors 1

Special Population Considerations

Genetic Testing Indications

• Extra-adrenal tumors and bilateral adrenal tumors warrant genetic testing 1
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations) 1, 4
• Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance 1, 4

Pediatric Surveillance

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

SDHB Mutation Carriers

• Measure all three metanephrines including methoxytyramine, as these tumors have higher malignancy risk (up to 70%) 2
• Require more intensive lifelong surveillance due to higher risk of aggressive behavior and metastatic disease 3, 1, 4

Clinical Indicators for Screening

Classic Presentation

• The triad of episodic headache, palpitations, and sweating in a hypertensive patient has 93.8% specificity and 90.9% sensitivity for pheochromocytoma 1
• Sustained hypertension occurs in 50% of patients related to norepinephrine secretion 4
• Paroxysmal hypertension with classic symptoms warrants immediate biochemical testing 1

High-Risk Scenarios Requiring Screening

• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 1
• Early-onset hypertension (<30 years) 1
• Adrenal incidentaloma (must systematically rule out pheochromocytoma before any biopsy or intervention) 1
• Hypertensive crisis during anesthesia or radiologic procedures 4
• Patients with NF1 over age 30, pregnant, or with paroxysmal hypertension 1

Critical Safety Considerations

Absolute Contraindications

• Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated due to risk of precipitating fatal hypertensive crisis 3, 1, 2
• Never perform contrast-enhanced CT or invasive procedures until pheochromocytoma is definitively excluded 1

Medication Precautions

• Never initiate beta-blockade alone before alpha-blockade in suspected pheochromocytoma, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 1, 4
• If surgery is planned before pheochromocytoma is definitively excluded, alpha-adrenoceptor blockade must be started 7-14 days preoperatively with gradually increasing dosages 1

Follow-Up Protocol

Post-Surgical Surveillance

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 1, 4
• Follow-up every 3-4 months for 2-3 years, then every 6 months 1
• 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

Extended Monitoring Indications

• PASS (Pheochromocytoma of the Adrenal gland Scaled Score) score ≥4 3
• Large primary tumor (>5 cm) 3
• SDHB gene mutation 3