What is the diagnosis and treatment approach for a 20-50 year old adult with suspected pheochromocytoma, without known genetic syndromes or underlying medical conditions?

Pheochromocytoma: Diagnosis and Treatment

Diagnostic Approach

Measure plasma free metanephrines or 24-hour urinary fractionated metanephrines as the first-line biochemical test in any adult with suspected pheochromocytoma, as these provide the highest diagnostic accuracy with sensitivity of 96-100% and specificity of 89-98%. 1, 2

When to Suspect Pheochromocytoma

Screen for pheochromocytoma in the following clinical scenarios:

• Classic triad: Headache, palpitations, and sweating ("cold sweat") occurring together—this combination has 90% diagnostic specificity and 93.8% sensitivity 1, 2
• Resistant hypertension: Blood pressure >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic (prevalence up to 4% in this population) 1, 2
• Early-onset hypertension: Age <30 years 1, 2
• Paroxysmal hypertension: Episodic blood pressure spikes with significant variability 1, 2
• Adrenal incidentaloma: Any adrenal mass displaying >10 HU on non-contrast CT 2
• Family history: Known genetic syndromes (MEN2, VHL, NF1, hereditary paraganglioma syndromes) 1, 2

Biochemical Testing Algorithm

Step 1: Initial Testing

• Measure plasma free metanephrines (sensitivity 96-100%, specificity 89-98%) OR 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) 1, 2
• Critical 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
• Ensure interfering medications are avoided (tricyclic antidepressants can cause false elevations), though common antihypertensive medications do not affect results when using LC-MS/MS analysis 1

Step 2: Interpretation Based on Elevation Level

• ≥4 times upper limit of normal: Proceed immediately to imaging—this confirms pheochromocytoma/paraganglioma 1, 2
• 2-4 times upper limit of normal: Repeat testing in 2 months and consider genetic testing, especially in younger patients 1
• 1-2 times upper limit of normal (marginally elevated): Repeat testing in 6 months OR perform clonidine suppression test 1

Step 3: Confirmatory Testing for Equivocal Results

• Clonidine suppression test: Use when results are equivocal but clinical suspicion remains high—this test has 100% specificity and 96% sensitivity 1, 3
• 24-hour urine collection: If plasma testing is equivocal (<4-fold elevation), obtain 24-hour urine for fractionated metanephrines and catecholamines 1
• Plasma methoxytyramine: When available, measure this to assess malignancy risk—elevated levels indicate higher risk of aggressive disease 1

Imaging Localization

Only proceed to imaging after biochemical confirmation is obtained—never perform imaging or biopsy before excluding pheochromocytoma biochemically, as unrecognized tumors can cause life-threatening hypertensive crises. 1, 2

First-Line Anatomical Imaging:

• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast administration 4, 3, 2
• Obtain imaging of abdomen and pelvis initially 2
• Include chest CT to evaluate for metastatic disease 1

Functional Imaging Indications:

Consider functional imaging (FDG-PET preferred, or MIBG scintigraphy) when high-risk features are present 4, 1:

• Tumor size ≥5 cm 1
• Extra-adrenal paraganglioma 1
• SDHB germline mutation 1
• Plasma methoxytyramine >3-fold above upper limit 1
• Initial imaging negative but biochemistry positive 1

Critical Pitfall: FDG-PET is superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutations 4, 1

Genetic Testing Considerations

Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance. 1, 2

Indications for genetic testing:

• Family history of pheochromocytoma or associated syndromes 1, 2
• Young age at diagnosis 2
• Bilateral or multifocal disease 1
• Extra-adrenal location (paraganglioma) 1, 2

Key genetic mutations and their implications:

• SDHB mutations: Associated with highest malignancy risk (34-60% 5-year survival), require lifelong intensive surveillance 4, 1, 2
• SDHD mutations: Show maternal imprinting—only paternal inheritance causes disease 1
• Begin surveillance at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes, or age 2 years for von Hippel-Lindau syndrome 1

Treatment Approach

Preoperative Medical Management

Alpha-adrenergic blockade is mandatory before any surgical intervention and must be started 7-14 days preoperatively. 1, 2, 5

Phenoxybenzamine protocol:

• Start with 10 mg twice daily 2
• Increase every other day to 20-40 mg 2-3 times daily until optimal blood pressure control achieved 2
• FDA-approved indication: "to control episodes of hypertension and sweating" in pheochromocytoma 5

Critical Pitfall: Never initiate beta-blockade alone before alpha-blockade—this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 1

If tachycardia is excessive after alpha-blockade, add beta-blocking agent concomitantly 5

Surgical Management

Complete surgical resection (R0 resection) is the only curative treatment and the mainstay of therapy for localized pheochromocytoma. 4, 2

Surgical approach:

• Laparoscopic adrenalectomy: Preferred for tumors <5 cm in diameter 6
• Open surgery: Required for larger tumors (≥5 cm) or suspected malignancy 6
• Adrenal-sparing surgery: Consider when appropriate 7
• Success rate: 90% for benign tumors 6

Absolute contraindications before surgery:

• Fine needle biopsy of suspected pheochromocytoma—this can precipitate fatal hypertensive crisis 4, 1
• Any invasive procedure without adequate alpha-blockade 1

Management of Malignant Disease

Malignancy is defined only by presence of metastases at sites where chromaffin cells are normally absent (e.g., liver, bone). 4

Risk factors for malignancy:

• Tumor size >5 cm 4, 1
• Extra-adrenal location 4
• SDHB mutation 4, 1
• Elevated plasma methoxytyramine >3-fold upper limit 1
• PASS score ≥4 1

Treatment options for metastatic disease:

• 131I-MIBG radionuclide therapy: First-line for patients with good MIBG uptake, progressive disease, or high tumor burden with low number of bone metastases—objective responses in 22-47% of cases 4
• Chemotherapy: CVD (cyclophosphamide, vincristine, dacarbazine) or CVDD regimens—clinical benefit in 40% of patients, tumor size reduction in 25% 4
• Local therapies: Surgical debulking, embolization, or radiofrequency ablation to reduce hormone secretion and prevent complications 4
• Peptide-radiolabeled radiotherapy: Emerging option with radiolabeled somatostatin analogs 4

Post-Surgical Follow-Up

All patients require long-term surveillance due to risk of recurrence, particularly those with high-risk features. 1

Follow-up protocol:

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 1
• Follow-up every 3-4 months for first 2-3 years, then every 6 months 1
• Lifelong monitoring required for patients with: SDHB mutations, extra-adrenal tumors, tumors >5 cm, or PASS score ≥4 1
• After 2 years of disease-free status, intervals may be gradually increased, but continue for at least 10 years 4

Life-Threatening Complications

Eleven percent of patients with unrecognized pheochromocytoma require ICU admission for life-threatening complications. 8

Potential complications include:

• Tako-Tsubo cardiomyopathy 8
• Myocardial infarction 8
• Acute pulmonary edema 8
• Cerebrovascular stroke 8
• Multi-organ failure 8
• Sudden death 1

Patients with larger tumors (>7 cm), higher catecholamine levels (>20-fold upper limit), and younger age are at highest risk for complications. 8