What are the symptoms and diagnostic approach for pheochromocytoma?

Pheochromocytoma: Clinical Presentation and Diagnostic Approach

Clinical Symptoms

The classic symptom triad of headache, palpitations, and sweating occurring episodically has 90% diagnostic specificity for pheochromocytoma and should immediately trigger biochemical testing. 1, 2

Cardinal Manifestations

• Hypertension occurs in approximately 95% of patients, with 50% presenting with sustained hypertension and 50% with paroxysmal (episodic) hypertension 1, 3
• Severe headaches are present in 72-92% of cases 4
• Sweating (diaphoresis) occurs in 60-70% of patients, often described as "cold sweat" 1, 4
• Palpitations affect 51-73% of patients, typically from sinus tachycardia 1, 4
• Pallor is a common associated finding 1

Additional Clinical Features

• Anxiety or panic attack-like symptoms are common, as catecholamine release mimics panic disorder 1, 3
• Increased blood pressure variability is characteristic and represents an independent cardiovascular risk factor beyond the hypertension itself 1, 3
• Life-threatening complications can occur, including syncope, cardiac arrest, myocardial infarction, cardiomyopathy, hypertensive crisis, stroke, or sudden death 5, 6, 7

Non-Hormone-Producing Paragangliomas

• Head and neck paragangliomas (parasympathetic origin) typically do not produce catecholamines and present with mass effect symptoms 5
• These include hearing loss, pulsatile tinnitus, cough, hoarseness, dysphagia, facial palsy, pain, or abnormal tongue motility 5

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Diagnostic Approach

Plasma free metanephrines (normetanephrine and metanephrine) represent the single best screening test with 99% sensitivity and 89% specificity and should be the initial diagnostic test. 1, 2, 3

Initial Biochemical Testing

• Plasma free metanephrines should ideally be collected from an indwelling IV catheter after the patient has been supine for 30 minutes to minimize false positives 1, 2
• If ideal collection conditions cannot be met and results are marginally elevated, repeat testing under proper conditions 2
• 24-hour urine fractionated metanephrines and catecholamines serve as an acceptable alternative, particularly for pediatric patients or when plasma testing is equivocal, with sensitivity of 86-97% and specificity of 86-95% 1, 2, 3

Interpretation Algorithm Based on Metanephrine Levels

• ≥4 times upper limit of normal: Proceed directly to imaging for tumor localization—this degree of elevation is diagnostic 1, 2
• 2-4 times upper limit of normal: Repeat testing in 2 months and consider genetic testing, especially in younger patients 2
• 1-2 times upper limit of normal (marginally elevated): Repeat testing in 6 months or perform clonidine suppression test 2

Clonidine Suppression Test

• Reserved for equivocal results with strong clinical suspicion, this test has 100% specificity and 96% sensitivity 1, 2
• Helps distinguish true pheochromocytoma from false positive elevations 2

Additional Biomarkers

• Plasma methoxytyramine measurement can assess malignancy risk—elevated levels (>3-fold above upper limit) indicate higher risk of malignant disease 1, 3
• Up to 30% of head/neck paragangliomas produce dopamine, indicated by elevated plasma methoxytyramine 2

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Imaging Localization

Only proceed to imaging after biochemical confirmation—never perform imaging or invasive procedures before excluding pheochromocytoma, as this can precipitate fatal hypertensive crisis. 2

Initial Imaging

• Abdominal CT or MRI for adrenal and abdominal tumors 3
• MRI is preferred over contrast-enhanced CT due to risk of hypertensive crisis with IV contrast 2
• Extend imaging to chest, abdomen, pelvis, and neck if initial abdominal imaging is negative but biochemistry is positive 2

Functional Imaging Indications

Consider functional imaging (PET with radiolabeled somatostatin analogs or MIBG scintigraphy) when high-risk features are present: 2, 3

• Tumor size ≥5 cm
• Extra-adrenal paraganglioma
• SDHB germline mutation
• Plasma methoxytyramine >3-fold above upper limit
• Suspected metastatic disease

Head/Neck Paragangliomas

• MRI with angiography sequences is first-line (sensitivity 88.7%, specificity 93.7%) 2
• Temporal bone CT provides essential information on bone involvement for skull base paragangliomas 2
• Whole-body PET with radiolabeled somatostatin analogs is preferred for SDHD-related tumors 2

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Critical Diagnostic Pitfalls

Absolute Contraindications

• Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated—it can precipitate fatal hypertensive crisis 2
• Never initiate beta-blockade alone before alpha-blockade—this causes unopposed alpha-adrenergic stimulation and severe hypertensive crisis 2

False Positive Considerations

• Obesity, obstructive sleep apnea, and tricyclic antidepressants can cause elevated catecholamine metabolites 2
• False positive elevations are usually <4 times the upper limit of normal 2
• Confirm that interfering medications and foods were avoided prior to testing 2
• Common antihypertensive medications (including alpha-1 blockers like doxazosin) do not interfere with plasma free metanephrine measurements when using LC-MS/MS analysis 2

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High-Risk Populations Requiring Screening

Screen for pheochromocytoma in: 1, 2

• Patients with the classic triad (headache, palpitations, sweating) occurring episodically
• Resistant hypertension (not controlled on ≥3 medications including a diuretic)
• Paroxysmal hypertension with significant blood pressure variability
• Incidentally discovered adrenal mass
• Early-onset hypertension (<30 years of age)
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations)
• Neurofibromatosis Type 1 patients over age 30 with hypertension

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Genetic Testing Considerations

• Approximately 30-35% of pheochromocytomas are hereditary with autosomal dominant inheritance 5, 3
• Genetic testing should be considered, especially with: family history, young age at diagnosis, bilateral or multiple tumors, extra-adrenal location, or SDHB-related features 3
• SDHB mutations are associated with higher malignancy risk and require more intensive lifelong surveillance 2, 3
• SDHD mutations show maternal imprinting—only paternal inheritance causes disease 5

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Clinical Context and Urgency

• The average time from initial symptoms to diagnosis is approximately 3 years, and many cases are completely missed 3
• 75% of fatal cases were not suspected during life, with the tumor causing 55% of deaths 3
• Early diagnosis and proper preoperative management are essential to prevent life-threatening cardiovascular complications 7