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

Diagnostic Approach to Pheochromocytoma

Initial Biochemical Testing

Measure plasma free metanephrines as the first-line diagnostic test for suspected pheochromocytoma, as this provides the highest sensitivity (96-100%) and specificity (89-98%). 1, 2, 3

• Plasma free metanephrines must be collected after the patient has been lying supine for 30 minutes, ideally from an indwelling venous catheter, to minimize false positive results 1, 2, 3

• If proper collection conditions cannot be met initially, marginally elevated results should prompt repetition under ideal conditions 1

• 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, 2, 3

• Use LC-MS/MS methodology for analysis, as common antihypertensive medications do not interfere with this method 1, 3

Interpretation Algorithm Based on Metanephrine Levels

For levels ≥4 times the upper limit of normal, proceed immediately to imaging as this is diagnostic of pheochromocytoma/paraganglioma. 1, 2, 3

• For levels 2-4 times the upper limit of normal, repeat testing in 2 months and consider genetic testing for hereditary syndromes, especially in younger patients 1, 2

• For marginally elevated levels (1-2 times upper limit), repeat testing in 6 months and consider clonidine suppression test to exclude false positivity 1, 2

• False positive elevations are usually <4 times the upper limit of normal and can occur with obesity, obstructive sleep apnea, or tricyclic antidepressants 1

Follow-Up Testing for Equivocal Results

If plasma testing shows less than fourfold elevation with strong clinical suspicion, perform a 24-hour urine collection for fractionated metanephrines and catecholamines. 4, 1, 2, 3

• The clonidine suppression test has 100% specificity and 96% sensitivity for distinguishing true pheochromocytoma from false positive results in equivocal cases 1, 2, 3

• Plasma methoxytyramine measurement can help assess the likelihood of malignant disease, particularly in patients with SDHB mutations 1, 2

Imaging After Biochemical Confirmation

MRI is the preferred imaging modality for suspected pheochromocytoma due to the risk of hypertensive crisis with IV contrast used in CT. 1, 2, 3

• Only proceed to imaging after biochemical confirmation, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures 1

• If initial abdominal imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck, and consider functional imaging 1, 2

• For patients with established pheochromocytoma, FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation 1, 2

• Functional imaging with MIBG or FDOPA-PET is indicated for high-risk features: tumor size ≥5 cm, extra-adrenal paraganglioma, SDHB germline mutation, or plasma methoxytyramine >3-fold above upper limit 4, 1

Clinical Scenarios Warranting Screening

Screen for pheochromocytoma in hypertensive patients with the classic triad of headache, palpitations, and sweating, which has 93.8% specificity and 90.9% sensitivity. 1

• Early-onset hypertension (<30 years of age) 1

• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 1

• Paroxysmal hypertension with classic symptoms 1

• Significant blood pressure variability 1

• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations) 1

• Hypertensive NF1 patients over 30 years of age, pregnant, or with paroxysmal hypertension 4

Special Population Considerations

For pediatric patients with suspected hereditary syndromes, begin surveillance with plasma metanephrines at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes, or age 2 years for von Hippel-Lindau syndrome. 1, 2, 3

• Patients with SDHB mutations require more intensive lifelong surveillance due to higher malignancy risk (up to 70%) 1, 3

• 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

Critical Pitfalls to Avoid

Never perform fine needle biopsy of a suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis. 1, 2, 3

• 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

• Avoid contrast-enhanced CT or any invasive procedures until pheochromocytoma is definitively excluded 1

• If sampling is performed sitting rather than supine, 25% of results will be falsely elevated and require repeat testing 3

• Confirm that interfering medications and foods were avoided prior to testing 1, 2

Post-Surgical Follow-Up

Repeat biochemical testing 14 days post-surgery to confirm complete resection, then 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

• A PASS score ≥4, large primary tumor, and/or SDHB gene mutation should alert the clinician to carry out lifelong monitoring 1