What is the appropriate diagnosis and treatment approach for a patient suspected of having pheochromocytoma?

Diagnosis and Management of Pheochromocytoma

When to Suspect Pheochromocytoma

Screen for pheochromocytoma in patients with resistant hypertension (BP >140/90 mmHg on ≥3 medications including a diuretic), early-onset hypertension (<30 years), paroxysmal hypertension with the classic triad of headache, palpitations, and sweating, or in any patient with an adrenal incidentaloma. 1, 2

Additional high-risk scenarios requiring screening include: 1, 2

• Significant blood pressure variability or pallor
• Family history of pheochromocytoma or genetic syndromes (MEN2, VHL, NF1, hereditary paraganglioma syndromes)
• Adrenal incidentalomas displaying >10 HU on non-contrast CT

The classic triad of headache, palpitations, and sweating in a hypertensive patient has 93.8% specificity and 90.9% sensitivity for pheochromocytoma, with a 99.9% exclusion value when absent. 1 However, at least 5% of patients are normotensive, and the presentation is highly variable, which can lead to diagnostic delays averaging 3 years. 1, 3

Biochemical Diagnosis

Measure plasma free metanephrines as the first-line diagnostic test—this provides the highest sensitivity (96-100%) and negative predictive value, reliably excluding pheochromocytoma when normal. 1, 2

Optimal Collection Technique

• Collect plasma free metanephrines from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positives 1
• If this ideal collection method is not feasible, marginally elevated results should prompt repetition under proper conditions 1

Alternative Testing

• 24-hour urinary fractionated metanephrines are an acceptable alternative with 86-97% sensitivity and 86-95% specificity 1, 2
• Urinary testing may be preferred for pediatric patients not yet continent of urine 1

Interpretation Algorithm Based on Metanephrine Levels

For levels ≥4 times the upper limit of normal: Proceed immediately to imaging—this degree of elevation is diagnostic for pheochromocytoma/paraganglioma. 1, 2

For levels 2-4 times the upper limit of normal: 1

• Repeat testing in 2 months using proper collection technique
• Consider genetic testing, especially in younger patients
• Confirm interfering medications were avoided

For marginally elevated levels (1-2 times upper limit): 1

• Repeat testing in 6 months with optimal collection conditions
• Consider clonidine suppression test (100% specificity, 96% sensitivity) if strong clinical suspicion persists 1, 4

Important Caveats About False Positives

• Hypertensive patients may have elevated catecholamine metabolites with obesity, obstructive sleep apnea, or tricyclic antidepressant use 1
• False positive elevations are usually <4 times the upper limit of normal 1
• Common antihypertensive medications (including alpha-1 blockers like doxazosin) do not interfere with plasma free metanephrine measurements when using LC-MS/MS analysis 1

Additional Biomarkers

• Measure plasma methoxytyramine when available—elevated levels indicate higher malignancy risk 1, 2
• If plasma testing is equivocal, perform 24-hour urine collection for catecholamines and metanephrines 1

Imaging Localization

Never proceed to imaging without biochemical confirmation first, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures. 1

First-Line Anatomical Imaging

MRI is preferred over CT due to the risk of hypertensive crisis with IV contrast administration. 5, 1, 2

• Obtain MRI of the abdomen and pelvis as first-line imaging 1, 2
• Include chest CT to evaluate for metastatic disease 1, 2
• If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck 1

Functional Imaging Indications

Consider functional imaging (preferably PET with radiolabeled somatostatin analogs) when any of these high-risk features are present: 1, 2

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

FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation. 1

Critical Safety Considerations

Never perform fine needle biopsy of a suspected pheochromocytoma before biochemical exclusion—this can precipitate fatal hypertensive crisis. 5, 1

Never initiate beta-blockade alone before alpha-blockade in suspected pheochromocytoma—this can cause severe hypertensive crisis due to unopposed alpha-adrenergic stimulation. 1

Genetic Testing

Consider genetic testing in all patients, as approximately 25-33% have germline mutations. 2

Specific indications for genetic testing include: 1, 2

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

For pediatric patients with suspected hereditary syndromes: 1

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

Preoperative Management

All patients require alpha-adrenergic blockade for 10-14 days before surgery to prevent life-threatening hypertensive crises and arrhythmias. 5, 2, 6

Alpha-Blockade Protocol

• Start phenoxybenzamine 10 mg twice daily, increasing every 2-4 days 5, 6
• Target blood pressure: <130/80 mmHg supine, systolic >90 mmHg upright 5
• Alternative: doxazosin (competitive, selective α1-antagonist) may be as effective with fewer side effects 5

Additional Preoperative Measures

• If target blood pressure not reached, add calcium channel blockers (nifedipine slow release) or metyrosine 5
• Beta-blockade is indicated only for tachyarrhythmias and must never be started before alpha-blockade 5
• Prevent postoperative hypotension with saline infusion the day before surgery 5
• Administer hydrocortisone during surgery (150 mg/day) if glucocorticoid excess is present 5

Intraoperative Management

Hypertension during surgery may be treated with: 5

• Magnesium sulfate
• Intravenous phentolamine (α-adrenoreceptor antagonist)
• Calcium antagonist
• Nitroprusside or nitroglycerin

Tachycardia can be treated with intravenous esmolol (β-adrenergic receptor blocker). 5

Special Considerations in Pregnancy

Pheochromocytoma in pregnancy is extremely dangerous with 50% maternal and fetal mortality if undiagnosed. 5

Management Based on Gestational Age

First 24 weeks of gestation: 5

• Laparoscopic adrenalectomy after 10-14 days of alpha-adrenergic blockade
• This approach reduces maternal mortality to <5% and fetal mortality to 15%

Third trimester: 5

• Manage with alpha-adrenergic blockade until fetus is viable
• Caesarean section with tumor removal in the same session is recommended

Surgical Treatment

Complete surgical resection (R0 resection) is the mainstay of curative treatment and is successful in 90% of cases. 5, 2

• Pheochromocytomas <5 cm can be removed laparoscopically 3
• Larger tumors should be removed by open surgery 3
• Locoregional lymphadenectomy improves tumor staging and oncologic outcomes 5

Malignancy Risk Assessment

Malignancy is defined only by the presence of metastatic lesions at sites where chromaffin cells are normally absent (approximately 10-15% of cases). 2, 3

Risk factors for malignancy include: 1, 2

• Tumor size ≥5 cm
• Extra-adrenal paraganglioma
• SDHB germline mutation
• Elevated plasma methoxytyramine (>3x upper limit)
• PASS (Pheochromocytoma of the Adrenal gland Scaled Score) ≥4

Patients with these features require life-long monitoring. 1

Post-Surgical Follow-Up

All patients require long-term surveillance due to risk of recurrence (17% develop recurrent or new tumors, 9% malignant). 5, 1

Follow-Up Protocol

• 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
• Patients with SDHB mutations, extra-adrenal tumors, or tumors >5 cm require more intensive surveillance 1, 2

Treatment of Malignant/Metastatic Disease

For unresectable or metastatic disease: 5

• 131I-MIBG therapy is first-line for patients with good uptake on diagnostic scans (objective responses in 22-47% of cases) 5
• Cyclophosphamide-based regimens (CVD or CDD) for patients with low MIBG uptake or rapidly progressive disease (clinical benefit in 40% of patients) 5
• Cytoreductive surgery may improve quality of life and survival by controlling hormonal hypersecretion 5
• Peptide-radiolabeled radiotherapy is an emerging option 5