What is the recommended approach for screening and managing a patient with a suspected or known family history of pheochromocytoma?

Screening for Pheochromocytoma

Measure plasma free metanephrines as the first-line screening test in patients with suspected pheochromocytoma, as this provides the highest sensitivity (96-100%) and reliably excludes the tumor when normal. 1, 2

Who Should Be Screened

Screen for pheochromocytoma 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
• Early-onset hypertension (age <30 years) 1, 2
• Paroxysmal hypertension with classic triad: headache, palpitations, and sweating ("cold sweat"), which has 90% diagnostic specificity when occurring together 1, 2
• Significant blood pressure variability or pallor 1, 2
• Family history of pheochromocytoma or associated genetic syndromes (MEN2, VHL, NF1, hereditary paraganglioma syndromes) 1, 2
• Adrenal incidentalomas displaying >10 HU on non-contrast CT or with signs/symptoms of catecholamine excess 2

The classic triad of headache, palpitations, and sweating in a hypertensive patient has 93.8% specificity and 90.9% sensitivity, with an exclusion value of 99.9% when absent. 1

Biochemical Testing Algorithm

First-Line Test

Measure plasma free metanephrines (normetanephrine and metanephrine) as the initial biochemical test, with sensitivity of 96-100% and specificity of 89-98%. 1, 2, 3

Optimal collection technique: Collect from an indwelling venous catheter after the patient has been lying supine for 30 minutes to limit false positive results. 1 However, if this ideal approach is bypassed, marginally elevated results should prompt repetition under ideal conditions. 1

Alternative test: 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) may be used, particularly for pediatric patients who are continent of urine or for testing low-risk patients. 1, 2

Interpretation Based on Metanephrine Levels

Levels ≥4 times upper limit of normal:

• Results are consistent with pheochromocytoma/paraganglioma 1, 2
• Proceed immediately to imaging to localize the lesion 1, 2

Levels 2-4 times upper limit of normal:

• Repeat testing in 2 months 1
• Consider genetic testing for hereditary syndromes, especially in younger patients 1

Marginally elevated levels (1-2 times upper limit):

• Repeat testing in 6 months 1
• Consider clonidine suppression test (100% specificity, 96% sensitivity) to exclude false positivity 4, 1

Equivocal plasma results:

• Perform 24-hour urine collection for fractionated metanephrines and catecholamines 1, 3

Important Caveats About False Positives

Common causes of false-positive elevations (usually <4 times upper limit of normal):

• Tricyclic antidepressants account for 41% of false-positive normetanephrine elevations 5
• Phenoxybenzamine causes 44-45% of false-positive norepinephrine elevations 5
• Obesity, obstructive sleep apnea 1

Critical point: Confirm that interfering agents were avoided prior to testing. 1 However, common antihypertensive medications (including alpha-1 selective blockers like doxazosin) do not affect plasma free metanephrine measurements when using LC-MS/MS analysis. 1

Imaging Studies

Only proceed to imaging after biochemical confirmation, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures. 1

First-Line Anatomical Imaging

• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 2, 3
• Image abdomen and pelvis initially 2, 3
• Include chest CT to evaluate for metastatic disease 2, 3

Functional Imaging Indications

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

• Tumor size ≥5 cm 1, 3
• Extra-adrenal paraganglioma 1, 3
• SDHB germline mutation 1, 3
• Plasma methoxytyramine >3-fold above upper limit 1, 3

For head/neck paragangliomas specifically: MRI with angiography sequences (sensitivity 88.7%, specificity 93.7%) is first-line. 1

Genetic Testing and Family Screening

When to Consider Genetic Testing

Approximately 25-33% of patients with pheochromocytoma have germline mutations. 2 Consider genetic testing in:

• Family history of pheochromocytoma/paraganglioma 2, 3
• Young age at diagnosis 2, 3
• Bilateral or multifocal disease 2, 3
• Extra-adrenal location (paraganglioma) 2, 3

Family Screening Protocols

For first-degree relatives (FDR) of mutation carriers:

SDHD and SDHAF2 mutations (maternally imprinted):

• If variant inherited from father: Annual biochemical screening, whole-body MRI every 2 years, clinical check-up every 2 years 4
• If variant inherited from mother: One-time biochemical screening and one whole-body MRI; if normal, no further surveillance 4

SDHB mutations:

• FDR: Annual biochemical screening, whole-body MRI every 2 years, clinical check-up every 2 years 4
• Second-degree relatives: One baseline MRI and biochemical analysis; if normal, no continued surveillance 4

SDHA, SDHC, TMEM127, MAX mutations:

• FDR: Annual biochemical screening, whole-body MRI every 2-3 years, clinical check-up every 2-3 years 4
• Second-degree relatives: One-time screening; if normal, no further surveillance 4

Age to begin surveillance:

• Start at age 15 years or older for most hereditary syndromes 4
• Start at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes 1
• Start at age 2 years for von Hippel-Lindau syndrome 1

Critical Pitfalls to Avoid

Never perform fine needle biopsy of a suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis. 1

Never initiate beta-blockade alone in a patient with suspected pheochromocytoma before alpha-blockade, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation. 1

SDHB mutations require heightened vigilance: These are associated with higher risk of aggressive behavior and metastatic disease, requiring more intensive and lifelong surveillance. 1, 2, 3