What is the diagnostic approach for a patient suspected of having pheochromocytoma?

Diagnostic Investigation of Pheochromocytoma

First-Line Biochemical Testing

Measure plasma free metanephrines as the initial 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

• Plasma free metanephrines should ideally be collected from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positive results 1, 2
• If the ideal collection method is not feasible, testing can proceed, but marginally elevated results should prompt repetition under proper conditions 1
• 24-hour urinary fractionated metanephrines are an acceptable alternative with sensitivity of 86-97% and specificity of 86-95%, and may be preferred for pediatric patients not yet continent of urine 1, 2

Clinical Scenarios Requiring Screening

Screen for pheochromocytoma in the following high-risk presentations:

• Classic triad: Headache, palpitations, and sweating ("cold sweat") in a hypertensive patient—this combination has 90% diagnostic specificity and 93.8% sensitivity 1, 4
• Resistant hypertension: Blood pressure >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic (prevalence up to 4% in this population) 1, 4
• Early-onset hypertension: Age <30 years at diagnosis 1, 4
• Paroxysmal hypertension with episodic symptoms despite treatment 1
• Adrenal incidentaloma displaying >10 HU on non-contrast CT or any signs of catecholamine excess 4
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations) 1, 4

Interpretation Algorithm Based on Metanephrine Levels

Levels ≥4 Times Upper Limit of Normal

• Results are consistent with pheochromocytoma/paraganglioma 1, 4, 2
• Proceed immediately to imaging to localize the lesion 1, 2
• No need for repeat biochemical testing 1

Levels 2-4 Times Upper Limit of Normal

• Perform 24-hour urine collection for fractionated metanephrines and catecholamines if plasma testing was initial test 1, 2
• Repeat testing in 2 months 1
• Consider genetic testing for hereditary syndromes, especially in younger patients 1

Marginally Elevated (1-2 Times Upper Limit)

• Repeat testing in 6 months using proper collection technique (indwelling catheter, 30 minutes supine) 1, 2
• Consider clonidine suppression test, which has 100% specificity and 96% sensitivity 1, 2, 5
• Assess for hyperadrenergic symptoms (sustained or intermittent palpitations, tachycardia, diaphoresis, tremors) 1

Important Considerations for False Positives

• False positive elevations are usually <4 times the upper limit of normal 1
• Common causes of false positives include obesity, obstructive sleep apnea, and tricyclic antidepressants 1
• Common antihypertensive medications (including alpha-1 selective blockers like doxazosin) do not affect plasma free metanephrine measurements when using LC-MS/MS analysis 1
• Confirm that interfering medications and foods were avoided prior to testing 1, 2

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 Anatomical Imaging

• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 1, 4, 2
• Obtain imaging of abdomen and pelvis initially 4
• Include chest imaging to evaluate for metastatic disease 4

When Initial Imaging is Negative

• Extend imaging to include chest and neck 1, 2
• Consider functional imaging with FDG-PET or MIBG scintigraphy 1, 2

Functional Imaging Indications

Consider functional imaging when any high-risk features are present:

• Tumor size ≥5 cm 1, 4
• Extra-adrenal paraganglioma 1, 4
• SDHB germline mutation 1, 4
• Plasma methoxytyramine >3-fold above upper limit 1
• FDG-PET is superior to MIBG for detecting malignant tumors, particularly with SDHB mutations 1, 2

Additional Biomarkers

• Measure plasma methoxytyramine when available, as elevated levels indicate higher malignancy risk 1, 2
• Up to 30% of head/neck paragangliomas produce dopamine, indicated by increases in plasma methoxytyramine 1

Critical Safety Considerations

Absolute contraindications:

• Never perform fine needle biopsy of suspected pheochromocytoma before biochemical exclusion—this can precipitate fatal hypertensive crisis 1, 2
• Never initiate beta-blockade alone before alpha-blockade in suspected pheochromocytoma—this can cause severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 1

Genetic Testing Indications

Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance 1, 4

Consider genetic testing in:

• Family history of pheochromocytoma or hereditary syndromes 1, 4
• Young age at diagnosis 4
• Bilateral or multifocal disease 1, 4
• Extra-adrenal location (paraganglioma) 1, 4

Key genetic considerations:

• SDHB mutations are associated with higher malignancy risk and require more intensive lifelong surveillance 1, 4, 2
• SDHD mutations show maternal imprinting—only paternal inheritance causes disease 1

Pediatric Surveillance Protocols

• 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
• Urine fractionated metanephrines may be more practical for pediatric patients once continent of urine 1

Common Diagnostic Pitfalls

• Failing to ensure proper patient preparation (30 minutes supine rest, indwelling catheter) leads to false positives 1, 2
• Relying solely on imaging without biochemical confirmation is dangerous 2
• Not considering extra-adrenal locations when adrenal imaging is negative results in missed diagnoses 2
• Performing procedures or administering contrast before excluding pheochromocytoma can trigger catecholamine crisis 1