What is the clinical approach to diagnose pheochromocytoma in a patient presenting with symptoms such as hypertension, headaches, palpitations, and sweating?

Clinical Diagnosis of Pheochromocytoma

Screen for pheochromocytoma using plasma free metanephrines or 24-hour urinary fractionated metanephrines as the first-line biochemical test in patients presenting with the classic triad of headache, palpitations, and sweating along with hypertension, as this combination has 93.8% specificity and 90.9% sensitivity for the diagnosis. 1, 2

When to Suspect Pheochromocytoma

Consider screening in the following clinical scenarios:

• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic), where prevalence reaches up to 4% 1, 2
• Paroxysmal or sustained hypertension with episodic symptoms including severe headaches, profuse sweating ("cold sweat"), palpitations, and pallor 1
• Early-onset hypertension in patients <30 years of age 1, 2
• Significant blood pressure lability or orthostatic hypotension despite hypertension 1
• Adrenal incidentaloma discovered on imaging, particularly if >10 HU on non-contrast CT 2, 3
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, hereditary paraganglioma syndromes) 1, 2
• Physical examination findings including café-au-lait spots, neurofibromas, or other stigmata of neurofibromatosis 1

Biochemical Testing Algorithm

First-Line Testing

Measure plasma free metanephrines (sensitivity 96-100%, specificity 89-98%) OR 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) as the initial diagnostic test. 1, 2, 3

For plasma free metanephrines, ideally collect from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positives. 2 However, if this ideal collection method is not feasible, proceed with standard venipuncture, but repeat under ideal conditions if results are marginally elevated 2.

Pre-Test Preparation

Before testing, confirm that interfering agents were avoided 2, 4:

• Discontinue tricyclic antidepressants (can cause false elevations) 1, 2
• Avoid sympathomimetics, decongestants, and certain neuropsychiatric agents 1
• Note: Alpha-1 selective blockers like doxazosin do NOT need to be discontinued 2, 4

Interpretation Based on Degree of Elevation

If levels are ≥4 times the upper limit of normal: Results are consistent with pheochromocytoma/paraganglioma—proceed immediately to imaging to localize the lesion 2, 3, 4

If levels are 2-4 times the upper limit of normal: Repeat testing in 2 months and consider genetic testing for hereditary syndromes, especially in younger patients 2, 4

If levels are marginally elevated (1-2 times upper limit): Repeat testing in 6 months using ideal collection conditions (indwelling catheter, 30 minutes supine), or consider clonidine suppression test 2

Confirmatory Testing for Equivocal Results

If initial plasma testing is equivocal, perform 24-hour urine collection for fractionated metanephrines and catecholamines. 2, 4 The clonidine suppression test has 100% specificity and 96% sensitivity and should be considered when results remain equivocal with strong clinical suspicion 1, 2.

Physical Examination Findings

Look for specific signs during examination 1:

• Hypertension (present in >90% of cases; 50% sustained, 50% paroxysmal) 5, 6
• Orthostatic hypotension despite elevated blood pressure 1
• Skin findings: café-au-lait spots, neurofibromas (suggesting neurofibromatosis type 1) 1
• Tachycardia and fine tremor during symptomatic episodes 1
• Pallor during hypertensive episodes 1

Imaging After Biochemical Confirmation

Never proceed to imaging without biochemical confirmation first, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures. 2

Once biochemically confirmed:

• MRI of abdomen/pelvis is preferred over CT due to risk of hypertensive crisis with IV contrast 1, 2, 3
• Include chest imaging to evaluate for metastatic disease 2, 3
• Consider functional imaging (FDG-PET or somatostatin receptor PET/CT) for high-risk features: tumor ≥5 cm, extra-adrenal location, SDHB mutation, or plasma methoxytyramine >3-fold above upper limit 2, 3, 4

Critical Pitfalls to Avoid

Never initiate beta-blockade alone before alpha-blockade in suspected pheochromocytoma, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation. 2

Never perform fine needle biopsy of a suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis. 2, 3

Avoid IV contrast CT in favor of MRI when pheochromocytoma is suspected, as contrast can trigger catecholamine release 2, 3

Genetic Testing Considerations

Consider genetic testing in approximately 25-33% of cases with: 2, 3

• Family history of pheochromocytoma/paraganglioma
• Young age at diagnosis (<30 years)
• Bilateral or multifocal disease
• Extra-adrenal location (paraganglioma)
• SDHB mutations (associated with higher malignancy risk requiring intensive surveillance) 2, 3, 4

Preoperative Management

If pheochromocytoma is confirmed and surgery is planned, alpha-adrenergic blockade must be started 7-14 days preoperatively. 2, 3, 7 Phenoxybenzamine is typically initiated at 10 mg twice daily and increased every other day to 20-40 mg 2-3 times daily until optimal blood pressure control is achieved 3, 7. If tachycardia is excessive, beta-blockade may be added only after adequate alpha-blockade is established 7.