What is the diagnostic approach for pheochromocytoma?

How to Diagnose Pheochromocytoma

Measure plasma free metanephrines as the first-line diagnostic test, which has the highest sensitivity (96-100%) and specificity (89-98%) for detecting pheochromocytoma. 1, 2, 3

Initial Biochemical Testing

First-Line Test

• Plasma free metanephrines (normetanephrine and metanephrine) should be your initial test of choice, as they outperform all other biochemical markers including plasma catecholamines, urinary catecholamines, and urinary vanillylmandelic acid 1, 2, 3
• Plasma free metanephrines are produced continuously within tumor cells independent of catecholamine release, making them superior for detecting tumors even during asymptomatic periods 4
• Collect plasma samples from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positives from stress-induced catecholamine release 1, 2

Alternative Testing

• Urinary fractionated metanephrines (24-hour collection) are an acceptable alternative with sensitivity of 86-97% and specificity of 86-95%, particularly useful for pediatric patients who are continent of urine 1, 2
• Urinary testing may be more practical in outpatient settings where proper plasma collection conditions cannot be guaranteed 1

Interpreting Biochemical Results

Results ≥4 Times Upper Limit of Normal

• Proceed immediately to imaging as this level is highly consistent with pheochromocytoma/paraganglioma 1, 2
• No additional confirmatory biochemical testing is needed 1

Results 2-4 Times Upper Limit of Normal

• Repeat testing in 2 months 1, 2
• Consider genetic testing for hereditary syndromes, especially in younger patients 1
• If repeat testing confirms elevation, proceed to imaging 1

Results 1-2 Times Upper Limit of Normal (Marginally Elevated)

• Perform clonidine suppression testing if clinical suspicion remains high, which has 100% specificity and 96% sensitivity 1, 2
• Alternatively, repeat testing in 6 months 1, 2
• Consider 24-hour urine collection for catecholamines and metanephrines as confirmatory testing 2, 5

Critical Preanalytical Considerations

Patient Preparation

• Ensure proper patient positioning (supine for 30 minutes) before plasma collection 1, 2
• Review medications for potential interferents—tricyclic antidepressants can cause false elevations 1
• Note: Common antihypertensive medications including alpha-1 blockers like doxazosin do NOT interfere with plasma free metanephrine measurements when using LC-MS/MS analysis 1

Common Causes of False Positives

• Obesity, obstructive sleep apnea, and certain medications can cause elevations typically <4 times the upper limit of normal 1
• Sulfasalazine and other drugs may cause method-specific analytical interference 6
• If results are discordant or unexpected, consider re-analysis using LC-MS/MS methodology 6

Imaging After Biochemical Confirmation

Initial Anatomical Imaging

• MRI is preferred over CT for suspected pheochromocytoma due to the risk of hypertensive crisis with IV contrast administration 7, 2, 5
• Begin with MRI or CT of the abdomen and pelvis to evaluate adrenal glands and common extra-adrenal locations 2, 5

When Initial Imaging is Negative

• Extend imaging to include chest and neck to capture extra-adrenal paragangliomas 2, 5
• Consider functional imaging with 123I-MIBG scintigraphy, 18F-FDOPA PET, or 18F-FDG PET 2, 5
• Combined anatomical and functional imaging (SPECT/CT or PET/CT) significantly improves diagnostic accuracy 5

Functional Imaging Strategy

• For apparently sporadic non-metastatic disease, 123I-MIBG scintigraphy is first-line functional imaging 5
• Reserve PET tracers for MIBG-negative cases, multifocal tumors, or patients taking drugs that interfere with MIBG accuracy 5
• For head and neck paragangliomas, 18F-FDOPA PET has sensitivity approaching 100% 5
• For SDHB-related metastatic disease, 18F-FDG PET is the imaging modality of choice 5

Additional Diagnostic Considerations

Plasma Methoxytyramine

• Measure plasma methoxytyramine when available to assess the likelihood of malignant disease 2, 5
• This marker is particularly useful in high-risk patients with familial syndromes 1

Genetic Testing

• Consider genetic testing in patients with confirmed pheochromocytoma, as approximately one-third of cases are hereditary 1
• SDHB mutations are associated with higher risk of aggressive behavior and metastatic disease, requiring more intensive surveillance 2, 5

Critical Pitfalls to Avoid

Never Perform Fine Needle Biopsy

• Biopsy of suspected pheochromocytoma is absolutely contraindicated due to the risk of precipitating a life-threatening hypertensive crisis 7, 2, 5

Don't Skip Biochemical Testing

• Always obtain biochemical confirmation before proceeding to imaging 2, 5
• Relying solely on imaging without biochemical confirmation is a common diagnostic error 2, 5

Don't Overlook Extra-Adrenal Locations

• Approximately 10-15% of pheochromocytomas are extra-adrenal (paragangliomas) 5
• If adrenal imaging is negative but biochemical evidence is positive, expand imaging to chest, neck, and pelvis 2, 5

Don't Ignore Atypical Presentations

• Pheochromocytomas can present with sustained hypertension (up to 50% of cases) rather than paroxysmal symptoms 1
• Classic triad of headache, palpitations, and sweating has 90% specificity but is not always present 1

Special Populations

Pediatric Patients

• For suspected hereditary paraganglioma/pheochromocytoma syndromes, begin surveillance at age 6-8 years 1, 2
• For von Hippel-Lindau syndrome, begin surveillance at age 2 years 1, 2
• Urine fractionated metanephrines may be more practical once children are continent of urine 1

Patients with Resistant Hypertension

• Pheochromocytoma may be present in up to 4% of patients with resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 1
• Screen patients with early-onset hypertension (<30 years), resistant hypertension, paroxysmal hypertension with classic symptoms, or significant blood pressure variability 1