What is the appropriate work‑up for a suspected pheochromocytoma?

Work-up for Pheochromocytoma

Initial Biochemical Testing

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

Collection Method

• Ideally 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
• If bypassing ideal collection conditions, marginally elevated results should prompt repetition under proper conditions 1
• Confirm that interfering medications and foods were avoided prior to testing (though common antihypertensives do not affect LC-MS/MS analysis) 1

Alternative Testing Options

• 24-hour urinary fractionated metanephrines are an acceptable alternative with high sensitivity (86-97%) and specificity (86-95%), particularly useful for pediatric patients or when plasma collection is impractical 1
• Plasma methoxytyramine should be measured when available, as elevated levels indicate higher malignancy risk 1, 2

Interpretation of Biochemical Results

Results ≥4 Times Upper Limit of Normal

• Proceed directly to imaging to localize the lesion, as this degree of elevation is consistent with pheochromocytoma regardless of collection method 1

Results 2-4 Times Upper Limit of Normal

• Repeat testing in 2 months using ideal collection conditions (indwelling catheter, 30 minutes supine) 1
• Consider genetic testing for hereditary syndromes, especially in younger patients 1

Results 1-2 Times Upper Limit of Normal (Marginally Elevated)

• Repeat testing in 6 months using ideal collection conditions 1
• Consider clonidine suppression test if clinical suspicion remains high (100% specificity, 96% sensitivity) 1
• False positive elevations are common with obesity, obstructive sleep apnea, or tricyclic antidepressants, and are usually <4 times upper limit 1

Equivocal Plasma Results with Strong Clinical Suspicion

• Perform 24-hour urine collection for fractionated metanephrines and catecholamines 1, 3
• Consider clonidine suppression test to distinguish true pheochromocytoma from false positives 1

Anatomical Imaging After Biochemical Confirmation

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

First-Line Imaging

• CT or MRI of abdomen and pelvis to capture adrenal and extra-adrenal locations 2, 3
• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 1
• Obtain concurrent chest CT to evaluate for metastatic disease 4

Extended Imaging for Negative Initial Results

• If initial abdominal imaging is negative but biochemistry is positive, extend imaging to include chest and neck 1, 3
• Consider functional imaging with 123I-MIBG, 18F-FDOPA-PET, or 18F-FDG-PET 1, 3

Functional Imaging Indications

Functional imaging is indicated when any of the following high-risk features are present: 1

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

Functional Imaging Modalities

• For apparently sporadic non-metastatic pheochromocytoma: 123I-MIBG scintigraphy as first-line functional imaging 3
• For SDHB-related metastatic disease: 18F-FDG PET is the imaging modality of choice 3
• For head/neck paragangliomas: 18F-FDOPA PET with sensitivity approaching 100% 3
• For MIBG-negative cases or multifocal tumors: Reserve PET tracers 3

Genetic Testing Considerations

• Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance 1
• Extra-adrenal tumors and bilateral adrenal tumors are indications for genetic testing 1
• SDHB mutations are associated with higher malignancy risk (at least 40% of metastatic cases) and require more intensive lifelong surveillance 2, 1
• SDHD mutations show maternal imprinting—only paternal inheritance causes disease 1

Critical Pitfalls to Avoid

• Never perform fine needle biopsy of a suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis 1, 3, 4
• 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
• Do not rely solely on CT imaging without biochemical confirmation 3
• Do not overlook extra-adrenal locations when adrenal imaging is negative 3
• Avoid contrast-enhanced CT or invasive procedures until pheochromocytoma is definitively excluded 1

Clinical Indications for Screening

Screen for pheochromocytoma in patients with: 1

• Early-onset hypertension (<30 years)
• Resistant hypertension (BP >140/90 mmHg despite ≥3 antihypertensives including diuretic)
• Paroxysmal hypertension with classic triad (headache, palpitations, sweating—93.8% specificity, 90.9% sensitivity)
• Significant blood pressure variability
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations)
• Adrenal incidentaloma (must systematically rule out before any biopsy or intervention)