What are the diagnostic and management approaches for pheochromocytoma?

Management and Diagnosis of Pheochromocytoma

Diagnostic Approach

Measure plasma free metanephrines as the first-line diagnostic test for suspected pheochromocytoma, as this provides the highest sensitivity (99%) and specificity (89%) of all available biochemical tests. 1, 2

Biochemical Testing Strategy

• Plasma free metanephrines are the single best screening test, with 99% sensitivity and 89% specificity, outperforming all other biochemical markers 2
• Ideally, collect plasma samples from an indwelling venous catheter after the patient has been supine for 30 minutes to minimize false positives 3
• If plasma testing is unavailable or equivocal (less than 4-fold elevation), perform 24-hour urine collection for fractionated metanephrines, which has 97% sensitivity and 69% specificity 4, 2
• Add plasma methoxytyramine measurement to assess malignancy risk—this biomarker provides critical prognostic information 4, 1

Interpreting Biochemical Results

• Levels ≥4 times the upper limit of normal: Proceed directly to imaging—this confirms pheochromocytoma/paraganglioma 3
• Levels 2-4 times upper limit: Repeat testing in 2 months and consider genetic testing, especially in younger patients 3
• Marginally elevated levels: Repeat in 6 months and consider clonidine suppression test (100% specificity, 96% sensitivity) to exclude false positives 3, 5
• False positives typically occur with obesity, obstructive sleep apnea, or tricyclic antidepressants, but are usually <4 times upper limit 3

Imaging Studies

After positive biochemical confirmation, obtain CT or MRI of the abdomen as the initial localization study. 4, 1

Anatomical Imaging

• MRI is preferred over CT for suspected pheochromocytoma due to risk of hypertensive crisis with IV contrast administration 4, 3
• Include chest CT to evaluate for metastatic disease and extra-adrenal paragangliomas 4, 1
• Most pheochromocytomas appear inhomogeneous with irregular margins and irregular enhancement after contrast 4

Functional Imaging Indications

Perform functional imaging when any of these high-risk features are present: 4

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

For patients with established pheochromocytoma requiring functional imaging, FDG-PET is superior to MIBG scintigraphy, particularly in SDHB mutation carriers and malignant tumors 4, 3

Critical Imaging Caveat

• Never perform fine needle biopsy of suspected pheochromocytoma—this is contraindicated due to risk of life-threatening hypertensive crisis 4, 3

Surgical Management

Complete surgical resection (R0 resection) is the only potentially curative treatment and should be performed in all resectable cases. 4, 1

Preoperative Preparation

• Initiate α1-adrenergic blockade at least 10-14 days before surgery—this is mandatory to prevent intraoperative hypertensive crisis 6, 5
• Phenoxybenzamine is FDA-approved for controlling hypertensive episodes and sweating in pheochromocytoma 6
• If tachycardia is excessive after α-blockade, add β-blocker (never before α-blockade to avoid unopposed α-stimulation) 6
• Meticulous perioperative management of blood pressure, glucose, electrolytes, cardiac function, and fluid status is critical 4

Surgical Approach

• Laparoscopic resection is appropriate for tumors <5 cm 7
• Open surgical approach is recommended for masses >5 cm 7
• Locoregional lymphadenectomy is not routinely indicated for pheochromocytoma (unlike adrenocortical carcinoma) 4

Management of Malignant/Metastatic Disease

Malignancy in pheochromocytoma is defined only by the presence of metastases at sites where chromaffin cells are normally absent—histology alone cannot determine malignancy. 4, 7

Risk Factors for Malignancy

The following features indicate high malignancy risk: 4, 7

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

Treatment Options for Inoperable Disease

• Disease and symptom control is the primary treatment goal for inoperable pheochromocytoma 4, 1
• 131I-MIBG radiopharmaceutical therapy for patients with sufficient MIBG uptake on functional imaging 4, 1
• Locoregional ablative procedures in selected cases 4
• Combination chemotherapy (CVD regimen) for rapidly progressive disease 4
• Wait-and-see approach is appropriate for low tumor burden and asymptomatic malignant pheochromocytoma/paraganglioma 4

Cytoreductive Surgery Consideration

• In malignant pheochromocytoma, cytoreductive surgery may be considered even without curative intent 4, 1

Follow-Up Protocol

All patients require long-term surveillance regardless of apparent complete resection, as malignant recurrence can occur years after initial surgery. 4

Post-Surgical Monitoring

• Perform biochemical testing (plasma or urinary metanephrines, normetanephrine, chromogranin A, methoxytyramine) approximately 14 days after surgery to check for residual disease 4, 1, 7
• Repeat biochemical testing every 3-4 months for the first 2-3 years 4, 7
• Subsequently test every 6 months 4, 7
• Continue clinical monitoring for adrenergic symptoms and blood pressure abnormalities 4

High-Risk Surveillance

Lifelong follow-up is mandatory for patients with: 4, 7

• Proven malignant disease
• SDHB mutation
• Extra-adrenal primary disease
• Tumor size >5 cm at diagnosis
• Pheochromocytoma without preoperative hormone secretion

Imaging During Follow-Up

• If new symptoms, pathological biochemical tests, or elevated chromogranin A develop, obtain thorax and abdomen CT plus functional imaging (preferably FDG-PET) 4
• For high-risk patients, perform imaging at least every 6 months during the first year and yearly thereafter, even with negative biochemical tests 4
• Follow-up for inoperable disease: every 2-4 months initially, then adjusted based on disease behavior 4

Genetic Considerations

Approximately 25-33% of pheochromocytomas are hereditary, making genetic evaluation essential in all patients. 1, 8

Genetic Testing Indications

Consider genetic testing particularly when: 1

• Family history of pheochromocytoma/paraganglioma
• Young age at diagnosis
• Bilateral or multifocal disease
• Extra-adrenal location
• Any of the high-risk features mentioned above

Associated Genetic Syndromes

Key hereditary syndromes include: 1, 8

• Multiple Endocrine Neoplasia type 2 (MEN2) - RET mutations
• Von Hippel-Lindau disease (VHL)
• Neurofibromatosis type 1 (NF1)
• Hereditary paraganglioma syndromes (SDHB, SDHD mutations)

SDHB mutations carry the highest risk for malignant behavior and metastatic disease, requiring the most intensive surveillance 4, 3, 7