What is the recommended management approach for pheochromocytoma, including biochemical confirmation, tumor localization, pre‑operative α‑blockade (and β‑blockade if needed), surgical resection, and postoperative follow‑up?

Management of Pheochromocytoma

All patients with suspected pheochromocytoma must undergo biochemical confirmation with plasma free metanephrines or 24-hour urinary fractionated metanephrines before any intervention, followed by anatomical imaging, preoperative alpha-blockade for 7-14 days, laparoscopic surgical resection, and lifelong postoperative surveillance. 1

Biochemical Confirmation

Initial diagnostic testing:

• Measure plasma free metanephrines (sensitivity 96-100%, specificity 89-98%) or 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) as first-line tests 1, 2, 3
• For plasma testing, ideally collect from an indwelling venous catheter after 30 minutes supine rest to minimize false positives 1
• Confirm interfering medications were avoided prior to testing 1

Interpretation algorithm based on metanephrine levels:

• ≥4 times upper limit of normal: Proceed immediately to imaging—this confirms pheochromocytoma/paraganglioma 1, 4
• 2-4 times upper limit: Repeat testing in 2 months and consider genetic testing, especially in younger patients 1, 4
• 1-2 times upper limit (marginally elevated): Repeat in 6 months or perform clonidine suppression test (100% specificity, 96% sensitivity) if clinical suspicion remains high 1, 4

Additional biomarkers:

• Measure plasma methoxytyramine when available—elevated levels (>3-fold upper limit) indicate higher malignancy risk and warrant functional imaging 1

Tumor Localization

Anatomical imaging:

• First-line: MRI of abdomen and pelvis is preferred over CT due to risk of hypertensive crisis with IV contrast 1, 2
• Include chest CT to evaluate for metastatic disease 1
• Never perform fine needle biopsy of suspected pheochromocytoma—this can precipitate fatal hypertensive crisis 1, 4

Functional imaging indications (high-risk features):

• Tumor size ≥5 cm 1
• Extra-adrenal paraganglioma 1
• SDHB germline mutation 1
• Plasma methoxytyramine >3-fold above upper limit 1
• MIBG-negative cases or multifocal tumors 5

Imaging modality selection:

• For sporadic nonmetastatic pheochromocytoma: 123I-MIBG scintigraphy is sufficient and as sensitive as PET imaging 5
• For head/neck paragangliomas: 18F-FDOPA PET has highest sensitivity approaching 100% 5
• For metastatic disease with SDHB mutations: 18F-FDG PET is particularly sensitive (83% per lesion in SDHB-positive patients) 5

Genetic Testing

Indications for genetic testing:

• Family history of pheochromocytoma or associated syndromes (MEN2, VHL, NF1, hereditary paraganglioma) 1
• Young age at diagnosis (≤40 years) 5
• Bilateral or multifocal disease 1
• Extra-adrenal location (paraganglioma) 1

Key genetic considerations:

• Approximately 25-33% of pheochromocytomas are hereditary with germline mutations (NF1, VHL, SDHD, SDHB, RET) 1, 3
• SDHB mutations carry 31-71% malignancy risk and require extended lifelong monitoring 5, 1
• SDHD mutations show maternal imprinting—only paternal inheritance causes disease 4

Preoperative Alpha-Blockade

Essential preoperative preparation:

• Alpha-adrenergic blockade must be started 7-14 days before surgery to prevent hypertensive crisis 1, 4, 2
• Phenoxybenzamine: Start 10 mg twice daily, increase every other day to 20-40 mg 2-3 times daily until optimal blood pressure control 1
• Alternative alpha-blockers (prazosin, doxazosin) are equally effective with no significant difference in operative outcomes 6

Beta-blockade considerations:

• Never initiate beta-blockade alone before alpha-blockade—this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 4
• Add beta-blockers only after adequate alpha-blockade if needed to control tachycardia or tachyarrhythmias 7

Surgical Resection

Surgical approach:

• Laparoscopic adrenalectomy is the treatment of choice and usually curative 5, 2, 3
• For bilateral MEN2-related pheochromocytomas: Consider cortical-sparing (subtotal) adrenalectomy to preserve adrenal function 8
• Open adrenalectomy reserved for suspected malignancy with irregular/inhomogeneous morphology, lipid-poor tumors, or tumors >3 cm secreting multiple hormones 5

Postoperative Follow-Up

Immediate postoperative assessment:

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 1
• Normal urine assays 2 weeks postoperatively ensure complete tumor removal 7

Long-term surveillance protocol:

• Follow-up every 3-4 months for 2-3 years, then every 6 months 1
• Lifelong surveillance is mandatory—recurrence or malignancy can occur up to 41 years after initial resection 7

High-risk patients requiring intensive monitoring:

• PASS score ≥4 5
• Large primary tumor (≥5 cm) 5, 1
• SDHB gene mutation 5, 1
• Extra-adrenal tumors 1

Surveillance for hereditary syndromes:

• Begin at age 2 years for von Hippel-Lindau syndrome 4
• Begin at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes 4

Critical Pitfalls to Avoid

• Never perform adrenal biopsy before biochemically excluding pheochromocytoma—this is absolutely contraindicated and can cause fatal hypertensive crisis 1, 4
• Never use IV contrast CT until pheochromocytoma is definitively excluded—this can trigger catecholamine crisis 4
• Biochemical evidence of catecholamine excess usually precedes clinical manifestations when tumors recur 7
• Unrecognized pheochromocytomas can cause life-threatening complications including syncope, cardiac arrest, myocardial infarction, cardiomyopathy, stroke, or sudden death 4