What is the recommended diagnostic workup and management for a patient with suspected pheochromocytoma?

Diagnostic Workup for Suspected Pheochromocytoma

Measure plasma free metanephrines as the first-line diagnostic test, which has 96-100% sensitivity and reliably excludes pheochromocytoma when normal. 1, 2

Initial Biochemical Testing

• Plasma free metanephrines (normetanephrine and metanephrine) are the single best screening test with 99% sensitivity and 89% specificity, making them superior to all other biochemical tests 1, 3
• Ideally collect plasma from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positives 1
• 24-hour urinary fractionated metanephrines are an acceptable alternative (sensitivity 86-97%, specificity 86-95%), particularly useful for pediatric patients or when plasma collection is impractical 1
• All patients with suspected pheochromocytoma must undergo biochemical confirmation before any intervention, as unrecognized tumors can cause life-threatening hypertensive crises 1

Interpretation of Biochemical Results

• If levels are ≥4 times the upper limit of normal, proceed immediately to imaging as this confirms pheochromocytoma/paraganglioma 1, 2
• If levels are 2-4 times upper limit of normal, repeat testing in 2 months and consider genetic testing, especially in younger patients 1
• If marginally elevated (1-2 times upper limit), repeat testing in 6 months or perform clonidine suppression test if clinical suspicion remains high 1
• The clonidine suppression test has 100% specificity and 96% sensitivity for distinguishing true pheochromocytoma from false positives when biochemical results are equivocal 1, 3

Common Causes of False Positives

• Obesity, obstructive sleep apnea, and tricyclic antidepressants can elevate catecholamine metabolites 1
• False positive elevations are usually <4 times the upper limit of normal 1
• Common antihypertensive medications (including alpha-blockers like doxazosin) do not interfere with plasma free metanephrine measurements when using LC-MS/MS analysis 1

Imaging Studies

• MRI is preferred over CT for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast 4, 1, 2
• Only proceed to imaging after biochemical confirmation is obtained 1
• Obtain cross-sectional imaging of chest, abdomen, and pelvis to detect metastases 1
• FDG-PET is superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutations 4

Indications for Functional Imaging

Consider functional imaging (FDG-PET or MIBG) when any high-risk features are present: 1

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

Critical Safety Considerations

• Never perform fine needle biopsy of suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis 4, 1
• Avoid contrast-enhanced CT until pheochromocytoma is definitively excluded 1
• Never initiate beta-blockade alone before alpha-blockade, as 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, 2
• Consider genetic testing for: family history of pheochromocytoma, young age at diagnosis (<30 years), bilateral or multifocal disease, extra-adrenal location (paraganglioma) 1, 2
• Test for germline mutations in: RET (MEN2), VHL, NF1, SDHB, SDHD, SDHC 1, 2
• SDHB mutations carry higher risk of malignancy and require more intensive lifelong surveillance 4, 1, 2

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Management of Confirmed Pheochromocytoma

Alpha-adrenergic blockade must be started 7-14 days preoperatively with gradually increasing dosages until blood pressure targets are achieved, followed by surgical resection. 1, 2, 3

Preoperative Medical Management

• Initiate alpha-blockade 7-14 days before surgery to prevent hypertensive crisis 1, 2, 3
• Phenoxybenzamine is typically started at 10 mg twice daily, increased every other day to 20-40 mg 2-3 times daily until optimal blood pressure control 2
• Doxazosin (alpha-1 selective blocker) is an alternative option 1
• Add beta-blockers only after adequate alpha-blockade is established to control tachyarrhythmias 3
• Monotherapy with beta-blockers is absolutely contraindicated as it can precipitate hypertensive crisis 3
• Calcium channel blockers can be used as adjuncts for refractory hypertension 3

Surgical Treatment

• Laparoscopic adrenalectomy is the preferred surgical approach and is curative in 90% of cases 3
• Pheochromocytomas <5 cm can be removed laparoscopically; larger tumors require open surgery 5
• Complete surgical extirpation (R0 resection) is the only curative treatment 3
• For pregnant patients diagnosed in the first 24 weeks of gestation, perform laparoscopic adrenalectomy after 10-14 days of alpha-blockade 3

Post-Surgical Follow-Up

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 1
• Follow-up every 3-4 months for 2-3 years, then every 6 months 1
• All patients require lifelong surveillance due to 10-15% recurrence risk and 10-12% malignancy rate 3
• Continue surveillance for at least 10 years minimum 3

High-Risk Features Requiring Intensive Surveillance

Patients with the following features need more aggressive monitoring: 4, 1, 2

• SDHB mutations (highest malignancy risk)
• Extra-adrenal tumors (paragangliomas)
• Tumor size >5 cm
• PASS (Pheochromocytoma of the Adrenal gland Scaled Score) ≥4
• Elevated plasma methoxytyramine

Management of Malignant Disease

• Malignancy is defined only by presence of metastases at sites where chromaffin cells are normally absent (liver, bone, lymph nodes) 4, 1, 2
• Approximately 10% of pheochromocytomas are malignant 2, 3
• For malignant disease with metastases, treatment options include radiotherapy, chemotherapy, and alpha-methyl-metatyrosine to inhibit catecholamine synthesis 6, 7
• FDG-PET is the preferred imaging modality for detecting metastatic disease 4

Special Populations

• For NF1 patients over age 30 with hypertension, particularly if pregnant or with paroxysmal symptoms, screen for pheochromocytoma 3
• For pediatric patients with hereditary syndromes, begin surveillance at age 6-8 years for HPP syndromes and age 2 years for von Hippel-Lindau syndrome 1
• Head and neck paragangliomas (parasympathetic origin) typically do not produce catecholamines and present with mass effect symptoms (hearing loss, pulsatile tinnitus, hoarseness) 1