What is the recommended diagnostic workup and management for a patient with paroxysmal hypertension, palpitations, headache, sweating, or unexplained tachyarrhythmias, especially when symptoms are triggered by stress, posture change, or medications, suggestive of pheochromocytoma?

Diagnostic Workup and Management of Suspected Pheochromocytoma

Initial Biochemical Testing

Measure plasma free metanephrines or 24-hour urinary fractionated metanephrines as the first-line diagnostic test in any patient presenting with the classic triad of headache, palpitations, and sweating along with hypertension. 1

• Plasma free metanephrines are the single best screening test with sensitivity of 96-100% and specificity of 89-98% 1, 2
• 24-hour urinary fractionated metanephrines offer sensitivity of 86-97% and specificity of 86-95%, and may be preferred for pediatric patients or those unable to undergo ideal plasma collection 2
• The classic triad (headache, palpitations, sweating) has 93.8% specificity and 90.9% sensitivity for pheochromocytoma, with 99.9% negative predictive value when absent 1, 2

Optimal Collection Technique

• For plasma testing: Ideally collect from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positives 1, 2
• If bypassing ideal collection conditions, marginally elevated results should prompt repetition under proper conditions 2

Pre-Test Preparation

• Discontinue interfering medications including tricyclic antidepressants, sympathomimetics, decongestants, and certain neuropsychiatric agents before testing 1
• Common antihypertensive medications do not affect plasma free metanephrine measurements when using LC-MS/MS analysis 2
• Alpha-1 selective blockers like doxazosin do not interfere with testing and can be continued 2

Who Should Be Screened

Screen for pheochromocytoma in the following clinical scenarios:

• Paroxysmal hypertension with episodic severe headaches, profuse sweating, palpitations, and pallor 1
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic), where prevalence reaches up to 4% 1, 2
• Early-onset hypertension in patients <30 years of age 1
• Incidentally discovered adrenal mass 3
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations) 2, 3
• Unexplained tachyarrhythmias or symptoms triggered by stress, posture change, or medications 1

Interpretation Algorithm Based on Metanephrine Levels

Levels ≥4 Times Upper Limit of Normal

• Results are consistent with pheochromocytoma/paraganglioma 1, 2
• Proceed immediately to imaging to localize the lesion 1, 2
• No further biochemical testing needed 2

Levels 2-4 Times Upper Limit of Normal

• Repeat testing in 2 months 2
• Consider genetic testing for hereditary syndromes, especially in younger patients 2
• If repeat testing confirms elevation, proceed to imaging 2

Marginally Elevated Levels (1-2 Times Upper Limit)

• Repeat testing in 6 months using ideal collection conditions 2
• Consider clonidine suppression test if clinical suspicion remains high (100% specificity, 96% sensitivity) 1, 2
• Assess for false positive causes: obesity, obstructive sleep apnea, or medication effects 2

Equivocal Plasma Results with Strong Clinical Suspicion

• Perform 24-hour urine collection for fractionated metanephrines and catecholamines 2, 3
• Clonidine suppression test can distinguish true pheochromocytoma from false positives 1, 2

Imaging After Biochemical Confirmation

Once biochemically confirmed, obtain MRI of abdomen/pelvis as the preferred modality over CT due to risk of hypertensive crisis with IV contrast. 1, 2

• MRI has sensitivity of 88.7% and specificity of 93.7% for localization 2
• If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck 2
• Never perform fine needle biopsy of suspected pheochromocytoma—this is absolutely contraindicated due to risk of fatal hypertensive crisis 2, 3

Functional Imaging Indications

Consider functional imaging (MIBG, FDG-PET, or radiolabeled somatostatin analog PET) when high-risk features are present:

• Tumor size ≥5 cm 2
• Extra-adrenal paraganglioma 2
• SDHB germline mutation 2
• Plasma methoxytyramine >3-fold above upper limit 2
• Suspected metastatic disease 2

FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation. 2

Critical Management Pitfalls to Avoid

Never Initiate Beta-Blockade Alone

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, 2

Avoid Procedures That Trigger Catecholamine Release

• No contrast-enhanced CT until pheochromocytoma is excluded (use MRI preferentially) 2
• No fine needle biopsy of adrenal masses before biochemical exclusion 2, 3
• No invasive procedures until diagnosis is definitively excluded 2

Preoperative Management

If pheochromocytoma is confirmed and surgery is planned, alpha-adrenergic blockade must be started 7-14 days preoperatively. 1, 2, 3

• Start with alpha-blockade (e.g., doxazosin) with gradually increasing dosages until blood pressure targets are achieved 2, 3
• Only add beta-blockers after adequate alpha-blockade to control tachyarrhythmias 3
• Ensure volume expansion during preoperative preparation 3
• Calcium channel blockers can be used as adjuncts for refractory hypertension 3

Genetic Testing Considerations

Consider genetic testing in approximately 25-33% of cases, particularly with the following features: 1

• Family history of pheochromocytoma/paraganglioma 1, 2
• Young age at diagnosis 1
• Bilateral or multifocal disease 1
• Extra-adrenal location 1, 2
• SDHB mutations (associated with higher malignancy risk) 1, 2

Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance 2

Surgical Treatment

• Laparoscopic adrenalectomy is the preferred surgical approach and is curative in 90% of cases 3
• 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 and Surveillance

All patients require lifelong surveillance due to 10-15% recurrence risk and 10-12% malignancy rate. 3

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 2
• Follow-up every 3-4 months for 2-3 years, then every 6 months 2
• Continue surveillance for at least 10 years minimum 3
• Patients with SDHB mutations require more intensive lifelong surveillance due to higher risk of malignancy and aggressive behavior 2
• Those with extra-adrenal tumors, tumors >5 cm, or PASS score ≥4 require extended monitoring 2