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

Pheochromocytoma: Diagnosis and Treatment

Diagnostic Approach

Patients suspected of having pheochromocytoma should undergo plasma free metanephrines as the first-line test (99% sensitivity, 89% specificity), collected ideally from an indwelling venous catheter after 30 minutes supine to minimize false positives, followed by imaging only after biochemical confirmation, and never undergo biopsy due to risk of fatal hypertensive crisis. 1, 2

Who Should Be Screened

Screen for pheochromocytoma in the following clinical scenarios:

• Resistant hypertension (uncontrolled on ≥3 medications including a diuretic) 1, 2
• Classic triad: Headache, palpitations, and sweating occurring episodically (90% specificity when present together) 1, 2
• Paroxysmal hypertension with any of the classic symptoms 1, 3
• Incidentally discovered adrenal mass 1
• Neurofibromatosis Type 1 patients over age 30 with hypertension 1
• Family history of pheochromocytoma or hereditary syndromes (MEN 2, VHL, NF) 1, 4

Biochemical Testing Protocol

Primary screening test:

• Plasma free metanephrines (normetanephrine and metanephrine) - 99% sensitivity, 89% specificity 1, 2
• Collect from indwelling IV catheter after patient supine for 30 minutes 2
• If ideal collection not feasible, marginally elevated results require repeat testing under proper conditions 2

Interpretation algorithm:

• ≥4 times upper limit of normal: Proceed directly to imaging - consistent with pheochromocytoma 2
• 2-4 times upper limit: Repeat testing in 2 months; consider genetic testing 2
• 1-2 times upper limit: Repeat in 6 months or perform clonidine suppression test (100% specificity, 96% sensitivity) 2

Alternative/confirmatory testing:

• 24-hour urine fractionated metanephrines if plasma testing equivocal (<4-fold elevation) - 86-97% sensitivity, 86-95% specificity 1, 2
• Plasma methoxytyramine when available to assess malignancy risk 2

Imaging Localization

Critical caveat: Never proceed to imaging without biochemical confirmation first - unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures 2

Imaging sequence:

1. MRI preferred over CT due to risk of hypertensive crisis with IV contrast 5
2. Abdominal/pelvic imaging to localize primary tumor 2
3. Chest CT to evaluate for metastases 2

Functional imaging indications (high-risk features):

• FDG-PET is superior to MIBG, particularly for SDHB mutations and malignant tumors 5
• Consider when: tumor ≥5 cm, extra-adrenal location, SDHB mutation, or plasma methoxytyramine >3-fold elevated 2

Absolute contraindication: Fine needle biopsy - can precipitate fatal hypertensive crisis 5, 2

Treatment Approach

Surgical Management

Complete surgical resection (R0 resection) is the only curative treatment and is successful in 90% of cases. 5, 3

Surgical approach:

• Laparoscopic adrenalectomy is the preferred method 5
• Open surgery for tumors >5 cm 3
• Cytoreductive surgery may be considered in advanced disease 5

Preoperative Medical Management

Mandatory preoperative preparation - meticulous management of hormonal, cardiac, and blood pressure abnormalities is critical 5

Alpha-blockade protocol:

• Initiate 7-14 days before surgery with gradually increasing dosages until blood pressure targets achieved 1, 2, 6
• Common agents: doxazosin (alpha-1 selective blocker) 2

Beta-blockade:

• Add only AFTER adequate alpha-blockade to control tachyarrhythmias 1
• Never use beta-blockers alone - can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 1, 2

Adjunctive therapy:

• Calcium channel blockers for refractory hypertension 5

Medical Management for Inoperable Disease

For patients with contraindications to surgery or malignant disease:

• Metyrosine (tyrosine hydroxylase inhibitor) - FDA-approved for preoperative preparation, contraindicated surgery, or malignant pheochromocytoma 7
  • Reduces catecholamine biosynthesis by 35-80% 7
  • Dose: 1-4 grams daily 7

Malignant pheochromocytoma treatment options:

• 131I-MIBG radiotherapy for tumors with adequate uptake 5
• Combination chemotherapy (CVD: cyclophosphamide, vincristine, dacarbazine) - 40% clinical benefit, 25% tumor size reduction 5
• Systemic chemotherapy considered first-line for low 123I-MIBG uptake, rapidly progressive disease, or high bone metastasis burden 5

Watch-and-wait approach:

• Reasonable for low tumor burden and asymptomatic malignant pheochromocytoma/paraganglioma 5

Genetic Testing and Risk Stratification

Approximately 40% of pheochromocytomas are hereditary - genetic testing recommended for all patients 6, 4

High-risk genetic features:

• SDHB mutations: Higher malignancy risk, more aggressive behavior, requires intensive lifelong surveillance 5, 2
• Extra-adrenal location: 10-12% malignancy rate 1
• Tumor size >5 cm: Higher malignancy risk 5, 2

Hereditary syndromes requiring screening:

• MEN 2a/2b: Screen first-degree relatives even if asymptomatic 8, 4
• Von Hippel-Lindau: Begin surveillance at age 2 years 2
• Neurofibromatosis Type 1: Screen patients >30 years with hypertension 1, 4

Follow-Up and Surveillance

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

Post-surgical surveillance protocol:

• Repeat biochemical testing 14 days post-surgery to confirm complete resection 2
• Every 3-4 months for 2-3 years, then every 6 months 2
• Continue for minimum 10 years, lifelong surveillance favored for malignant disease 5, 1
• Include abdominal imaging (CT or MRI), chest CT, and biochemical monitoring 5

High-risk patients (SDHB mutations, extra-adrenal tumors, tumors >5 cm) require more intensive monitoring 2

Critical Pitfalls to Avoid

• Never perform biopsy of suspected pheochromocytoma before biochemical exclusion 5, 2
• Never use beta-blockers alone without prior alpha-blockade 1, 2
• Never proceed to imaging without biochemical confirmation 2
• Avoid contrast-enhanced CT until pheochromocytoma excluded (use MRI instead) 5, 2
• Confirm interfering medications avoided before biochemical testing (tricyclic antidepressants can cause false positives) 2