What is the best approach to managing a patient suspected of having pheochromocytoma?

Management of Suspected Pheochromocytoma

All patients suspected of having pheochromocytoma must undergo immediate biochemical confirmation with plasma free metanephrines (the single best test with 99% sensitivity and 89% specificity) before any intervention, as unrecognized tumors can cause life-threatening hypertensive crises. 1

Initial Diagnostic Workup

Biochemical Testing Strategy

• Measure plasma free metanephrines (normetanephrine and metanephrine) as the first-line test, ideally collected from an indwelling IV cannula after 30 minutes supine to minimize false positives 1, 2
• If plasma testing shows ≥4 times the upper limit of normal, proceed directly to imaging as this confirms pheochromocytoma 1, 2
• If plasma levels are <4 times elevated but still abnormal, perform 24-hour urine collection for fractionated metanephrines and catecholamines 1, 2
• For equivocal results with strong clinical suspicion, use clonidine suppression testing (100% specificity, 96% sensitivity) 1, 2

High-Risk Populations Requiring Screening

Screen patients with any of the following 1, 2:

• Resistant hypertension (uncontrolled on ≥3 medications including a diuretic)
• Paroxysmal hypertension with classic triad: headache, palpitations, and sweating (90% specificity when episodic) 1, 2
• Incidentally discovered adrenal mass
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations)
• NF1 patients over age 30 with hypertension, especially if pregnant or with paroxysmal symptoms 1

Imaging Localization

After Biochemical Confirmation Only

• Never perform imaging or biopsy before biochemical confirmation - this can precipitate fatal hypertensive crisis 3, 2
• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 3, 4
• Obtain CT/MRI of abdomen and chest CT to assess for metastases 3, 1
• If anatomical imaging is negative despite positive biochemistry, extend imaging to chest and neck and consider functional imaging 2

Functional Imaging Indications

Consider 123I-MIBG scintigraphy or PET with radiolabeled somatostatin analogs for 3, 2:

• Tumor size ≥5 cm
• Extra-adrenal paraganglioma
• SDHB germline mutation (higher malignancy risk)
• Plasma methoxytyramine >3-fold above upper limit
• Suspected metastatic disease

Preoperative Medical Management

Alpha-Blockade Protocol

Begin alpha-adrenergic blockade 7-14 days before surgery with gradually increasing doses until blood pressure targets are achieved 1, 2, 5

• Phenoxybenzamine is FDA-approved for controlling hypertensive episodes and sweating in pheochromocytoma 5
• Never use beta-blockers alone before adequate alpha-blockade - this causes unopposed alpha-stimulation and severe hypertensive crisis 2
• If tachycardia is excessive after alpha-blockade, add beta-blocker only after adequate alpha control 5

Critical Perioperative Considerations

Meticulous management of hormonal, glucose, electrolyte, cardiac, and fluid/blood pressure abnormalities is essential to prevent perioperative complications 3

Surgical Treatment

Definitive Management

• Complete surgical extirpation (R0 resection) is the only curative treatment and is curative in 90% of cases 3, 1
• Laparoscopic adrenalectomy is the preferred surgical approach for localized disease 1
• Cytoreductive surgery may be considered for metastatic pheochromocytoma to reduce hormone secretion and prevent complications 3

Absolute Contraindications

Never perform fine needle biopsy of suspected pheochromocytoma - this is absolutely contraindicated due to risk of precipitating fatal hypertensive crisis 3, 2

Management of Malignant/Metastatic Disease

Treatment Options for Unresectable Disease

For patients with confirmed metastatic disease (malignancy defined by presence of metastases) 3:

• 131I-MIBG radiotherapy is first-line for patients with good MIBG uptake, progressive disease, or high tumor burden with low bone metastases (objective responses in 22-47% of cases) 3
• CVD chemotherapy (cyclophosphamide, vincristine, dacarbazine) for patients with low MIBG uptake or rapidly progressive disease (clinical benefit in 40%, tumor reduction in 25%) 3
• Locoregional ablative procedures (embolization, radiofrequency ablation) for symptom control 3
• Watch-and-wait approach is appropriate for asymptomatic patients with low tumor burden 3

Genetic Testing and Surveillance

Genetic Evaluation

• Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance 2
• All patients require genetic testing, especially those with 1, 2:
  • Extra-adrenal tumors
  • Bilateral adrenal tumors
  • Age <30 years at diagnosis
  • Family history of pheochromocytoma

High-Risk Genetic Mutations

• SDHB mutations carry highest malignancy risk and require intensive lifelong surveillance 3, 2
• Begin surveillance at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes 2
• Begin surveillance at age 2 years for von Hippel-Lindau syndrome 2

Long-Term Follow-Up

Post-Surgical Surveillance

All patients require lifelong surveillance due to 10-15% recurrence risk and 10-12% malignancy rate 1:

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 2
• Follow-up every 3-4 months for first 2-3 years, then every 6 months 2
• Continue surveillance for at least 10 years minimum, with lifelong surveillance favored for malignant disease 3, 1
• Monitor with plasma metanephrines and imaging (abdominal CT/MRI, chest CT) 3

Patients Requiring Intensive Surveillance

More frequent monitoring for 3, 2:

• SDHB mutations
• PASS score ≥4 (Pheochromocytoma of the Adrenal gland Scaled Score)
• Large primary tumor
• Extra-adrenal paragangliomas
• Tumors >5 cm

Common Pitfalls to Avoid

• Never proceed with adrenal biopsy or contrast-enhanced CT until pheochromocytoma is biochemically excluded 3, 2
• Avoid misinterpreting borderline biochemical results - levels <4 times upper limit require repeat testing or clonidine suppression test 2, 6
• Do not overlook interfering medications that cause false positive metanephrines (tricyclic antidepressants, but NOT alpha-blockers like doxazosin) 2
• Never start beta-blockers before alpha-blockade in confirmed or suspected cases 2
• Do not assume benign disease - 10-12% are malignant, defined only by presence of metastases 3, 1