What is the protocol for diagnosing and managing pheochromocytoma?

Pheochromocytoma Diagnosis Protocol

The diagnostic protocol for pheochromocytoma begins with measurement of plasma free metanephrines, which provides the highest sensitivity (99%) and specificity (89%) for diagnosis, followed by anatomical imaging with CT or MRI of the abdomen and chest, and consideration of functional imaging in select cases. 1, 2, 3

Initial Biochemical Testing

Plasma free metanephrines should be the first-line biochemical test for all patients with suspected pheochromocytoma, as this provides superior diagnostic accuracy compared to all other biochemical markers. 2, 3

• Plasma free metanephrines demonstrate 99% sensitivity and 89% specificity, making them the single best test for excluding or confirming pheochromocytoma. 3
• Blood should ideally be collected from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positives. 4
• If plasma testing is unavailable or equivocal, 24-hour urinary fractionated metanephrines serve as an acceptable alternative with 97% sensitivity and 69% specificity. 1, 2, 3

Additional Biochemical Markers

• Plasma methoxytyramine measurement provides useful information to assess the likelihood of malignancy and should be obtained when available. 1, 2
• If initial plasma metanephrines show less than fourfold elevation, perform follow-up 24-hour urine collection for catecholamines and metanephrines. 1, 4

Interpretation of Biochemical Results

Results ≥4 times the upper limit of normal are diagnostic and warrant immediate imaging to localize the tumor. 4

• Elevations of 2-4 times the upper limit require repeat testing in 2 months and consideration of genetic testing. 4
• Marginally elevated levels should prompt repeat testing in 6 months and consideration of clonidine suppression testing. 4
• False positive elevations are usually <4 times the upper limit of normal and may occur with obesity, obstructive sleep apnea, or tricyclic antidepressant use. 4

Clonidine Suppression Test

For equivocal results with strong clinical suspicion, clonidine suppression testing demonstrates 100% specificity and 96% sensitivity. 4

Anatomical Imaging

Once biochemical diagnosis is established, proceed with CT or MRI of the abdomen to localize the tumor, plus chest CT to evaluate for metastatic disease. 1, 2

• CT and MRI are equally effective for differential diagnosis of adrenal masses. 1
• MRI is preferred when there is concern about hypertensive crisis with IV contrast administration. 4
• Most pheochromocytomas show inhomogeneous appearance with irregular margins and irregular enhancement after contrast. 1
• Cross-sectional imaging of chest, abdomen, and pelvis is mandatory before planning surgery to detect metastases. 1

Critical Caveat

Guided biopsies of potentially resectable primary adrenal tumors are contraindicated as they are potentially harmful and can precipitate hypertensive crisis. 1, 4

Functional Imaging

Functional imaging should be considered in specific clinical scenarios to complement anatomical imaging. 1, 2

• Meta-iodobenzylguanidine (MIBG) scintigraphy is helpful to detect multifocal disease and confirm diagnosis. 2, 5
• FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutations. 4
• If initial anatomical imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck, and consider functional imaging. 4

Genetic Testing Considerations

Genetic testing should be considered in all patients, as approximately one-third of cases are hereditary. 2, 4

High-Risk Features Requiring Genetic Testing:

• Family history of pheochromocytoma/paraganglioma 2
• Young age at diagnosis 2
• Bilateral or multifocal disease 2
• Extra-adrenal location (paraganglioma) 2
• Tumor size ≥5 cm 1
• SDHB mutations are associated with higher risk of malignancy and require more intensive surveillance. 4

Preoperative Management

Meticulous perioperative management of hormonal, glucose, electrolytes, cardiac and fluid/blood pressure abnormalities is critical. 1

• Alpha-1 blockade should be initiated at least 10-14 days before surgery. 6, 7
• Phenoxybenzamine is indicated to control episodes of hypertension and sweating in pheochromocytoma. 6
• If tachycardia is excessive, beta-blocking agents may be used concomitantly, but only after adequate alpha-blockade. 6

Surgical Treatment

Complete surgical extirpation (R0 resection) is the mainstay of potentially curative treatment for localized pheochromocytoma. 1, 2

• Laparoscopic resection is appropriate for tumors <5 cm in diameter. 8
• Larger tumors should be removed by open surgery. 8
• Cytoreductive surgery might be considered in malignant pheochromocytoma. 1, 2

Postoperative Follow-Up

Biochemical testing should be performed approximately 14 days following surgery to check for remaining disease. 1, 2

• Repeat biochemical testing every 3-4 months for 2-3 years, then every 6 months thereafter. 1
• Long-term clinical follow-up includes monitoring for adrenergic symptoms and blood pressure levels. 1
• Patients with high-risk features (extra-adrenal primary disease, tumor size >5 cm, SDHB mutations) require lifelong follow-up. 1, 4
• Imaging with thorax and abdomen CT should be repeated at least every 6 months during the first year and yearly afterward in high-risk patients. 1

Management of Malignant Disease

Malignancy is defined only by the presence of metastatic lesions at sites where chromaffin cells are normally absent. 1, 2

• Disease and symptom control is the main treatment goal for inoperable pheochromocytoma. 1, 2
• Treatment options include radiopharmaceuticals (131I-MIBG), locoregional ablative procedures, and/or combination chemotherapy (CVD) in selected cases. 1
• Wait and see policy is recommended in low tumor burden and asymptomatic malignant pheochromocytoma. 1