What is the workup for elevated normetanephrine (NMN) and total metanephrines (MN)?

Workup for Elevated Normetanephrine and Total Metanephrines

For elevated normetanephrine and total metanephrines, immediately assess the degree of elevation: if ≥4 times the upper limit of normal, proceed directly to imaging to localize pheochromocytoma/paraganglioma; if 2-4 times elevated, repeat testing in 2 months and consider genetic testing; if marginally elevated (1-2 times), repeat in 6 months or perform clonidine suppression testing. 1, 2

Initial Assessment and Confirmation

Rule Out Interfering Factors First

• Confirm that interfering medications were avoided prior to testing, as tricyclic antidepressants and phenoxybenzamine account for 41-45% of false-positive elevations of normetanephrine 3
• Common antihypertensive medications (excluding tricyclics) do not affect plasma free metanephrine measurements when using LC-MS/MS analysis 1
• False positive elevations are usually <4 times the upper limit of normal 1

Verify Collection Method

• If plasma free metanephrines were not collected from an indwelling venous catheter after 30 minutes supine rest, marginally elevated results should prompt repetition under ideal conditions 1, 2
• For equivocal plasma results, perform 24-hour urine collection for fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) 1

Risk Stratification Algorithm

Levels ≥4 Times Upper Limit of Normal

• Proceed immediately to imaging - this degree of elevation is highly consistent with pheochromocytoma/paraganglioma regardless of collection method 1, 2
• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 2
• For suspected head/neck paragangliomas, perform MRI with angiography sequences to assess multifocality and tumor extension 4, 2
• Obtain whole-body anatomic imaging together with PET (preferably with radiolabeled somatostatin analogs) 4

Levels 2-4 Times Upper Limit of Normal

• Repeat biochemical testing in 2 months using ideal collection conditions (indwelling catheter, 30 minutes supine) 1
• Consider genetic testing for hereditary syndromes, especially in younger patients or those with extra-adrenal tumors 1, 2
• Assess for hyperadrenergic symptoms: sustained or intermittent palpitations, tachycardia, diaphoresis, tremors, or new-onset hypertension 1
• If ≥2-fold elevation with hyperadrenergic symptoms, initiate alpha-adrenergic blockade even before definitive imaging 5

Marginally Elevated Levels (1-2 Times Upper Limit)

• Repeat testing in 6 months using ideal collection conditions 1
• Consider clonidine suppression test (100% specificity, 96% sensitivity) - lack of suppression of plasma normetanephrine confirms pheochromocytoma 1, 2, 3
• Plasma normetanephrine remains elevated after clonidine in all but 2 of 48 patients with pheochromocytoma in validation studies 3

Additional Biochemical Testing

Plasma Methoxytyramine

• Measure plasma methoxytyramine when available, as elevated levels indicate higher malignancy risk 1, 2
• Up to 30% of head/neck paragangliomas produce dopamine, indicated by increases in plasma methoxytyramine 4
• Urine methoxytyramine is not useful as it derives from renal DOPA decarboxylation, not tumor production 4

Pattern Analysis

• High plasma normetanephrine-to-norepinephrine or metanephrine-to-epinephrine ratios are strongly predictive of pheochromocytoma 3
• Patients with plasma normetanephrine levels more than double the upper reference limit are rare (2.3%) in head/neck paragangliomas and suggest extra-cranial disease 4

Imaging Localization After Biochemical Confirmation

Anatomic Imaging

• Never proceed to imaging without biochemical confirmation first - unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures 1
• MRI is the preferred modality for adrenal and extra-adrenal pheochromocytomas 2
• For head/neck paragangliomas, MRI with angiography (sensitivity 88.7%, specificity 93.7%) is first-line 4
• Temporal bone CT provides essential information on bone involvement for skull base paragangliomas 4
• Obtain cross-sectional imaging of chest, abdomen, and pelvis to detect metastases 1

Functional Imaging Indications

• Consider functional imaging when high-risk features are present: tumor size ≥5 cm, extra-adrenal paraganglioma, SDHB germline mutation, or plasma methoxytyramine >3-fold above upper limit 1
• FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation 1
• Whole-body PET with radiolabeled somatostatin analogs is preferred for SDHD-related tumors 4

Genetic Testing Considerations

Indications for Genetic Testing

• Extra-adrenal tumors and bilateral adrenal tumors warrant genetic testing 1
• Patients with levels 2-4 times upper limit should be considered for genetic testing, especially if young 1, 2
• SDHD pathogenic variants show autosomal dominant transmission and require specialized surveillance 4

Surveillance for Hereditary Syndromes

• Begin surveillance at age 6-8 years for hereditary paraganglioma/pheochromocytoma syndromes 1
• Begin surveillance at age 2 years for von Hippel-Lindau syndrome 1
• SDHB mutations require more intensive surveillance due to higher risk of malignancy and aggressive behavior 1, 2

Preoperative Medical Management

Alpha-Adrenergic Blockade

• Alpha-adrenergic blockade is mandatory prior to any intervention in patients with elevated normetanephrine to prevent life-threatening cardiovascular complications 5
• Start phenoxybenzamine 7-14 days preoperatively with gradually increasing dosages until blood pressure targets are achieved (mean effective dose 140-270 mg/day) 5
• Doxazosin (α1-selective blocker) is an alternative with similar efficacy and may cause less orthostatic hypotension 5
• Never start beta-blockers before alpha-blockade - this can precipitate hypertensive crisis due to unopposed alpha-stimulation 1, 5

Adjunctive Therapy

• Add beta-blockers only after adequate alpha-blockade if tachycardia develops 5
• Metyrosine can reduce catecholamine biosynthesis by 35-80% as add-on therapy 5
• Calcium channel blockers can be used as adjuncts to alpha-blockade 2

Supportive Measures

• High-sodium diet and 1-2 liters IV saline 24 hours prior to surgery 5
• Compression stockings to reduce orthostatic hypotension 5

Long-Term Surveillance Protocol

Post-Treatment Monitoring

• Measure plasma/urine metanephrines 2-8 weeks postoperatively to confirm complete resection 5, 2
• Perform imaging at 3-6 months post-treatment 5
• Annual blood pressure measurements, clinical assessment, and biochemical testing lifelong 5, 2
• Whole-body MRI every 2-3 years to detect new tumors, metastases, or progression 5, 2

High-Risk Surveillance

• PASS score ≥4, large primary tumor, or SDHB mutation requires extended and lifelong monitoring 1
• Patients with SDHB mutations require more intensive surveillance due to 30-40% malignancy risk 1, 2

Critical Pitfalls to Avoid

• Never perform fine needle biopsy of suspected pheochromocytoma - this can precipitate fatal hypertensive crisis 1, 2
• Never use beta-blockers as monotherapy before alpha-blockade 1, 5
• Avoid contrast-enhanced CT when MRI is available due to hypertensive crisis risk 1, 2
• Do not dismiss marginally elevated results without proper repeat testing under ideal conditions 1
• Patients with dopamine-only producing tumors (isolated methoxytyramine elevation) do not require alpha-blockade as they are typically normotensive or hypotensive 5

Interdisciplinary Management

• All decisions in patients with pheochromocytoma/paraganglioma should be discussed and managed by an expert interdisciplinary tumor team 2
• Consider referral to specialized centers with experience in these rare tumors 4