What is the diagnostic workup and management of pheochromocytoma?

Pheochromocytoma: Diagnostic Workup and Management

All patients with suspected pheochromocytoma must undergo biochemical confirmation with plasma free metanephrines (sensitivity 96-100%, specificity 89-98%) before any imaging or intervention, followed by surgical resection after 7-14 days of alpha-adrenergic blockade, as this is the only curative treatment and prevents life-threatening hypertensive crises. 1, 2, 3

Diagnostic Workup

When to Screen for Pheochromocytoma

Screen patients presenting with any of the following clinical scenarios:

• Classic triad of headache, palpitations, and sweating in episodic fashion (90% specificity, 94% sensitivity when all three present) 2
• Paroxysmal or resistant hypertension (present in 95% of cases; 50% sustained, 50% episodic) 2, 4
• Adrenal incidentaloma discovered on imaging 4
• Family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations) - approximately 30-35% are hereditary 2, 4
• Neurofibromatosis Type 1 patients over age 30 with hypertension, especially if pregnant or with paroxysmal symptoms 4
• Young-onset hypertension (<30 years) 2

Biochemical Testing Algorithm

First-line test: Plasma free metanephrines (normetanephrine and metanephrine) collected from an indwelling venous catheter after 30 minutes supine rest 1, 2

• Sensitivity: 96-100%
• Specificity: 89-98% 2
• Avoid interfering medications (tricyclic antidepressants) but common antihypertensives do not interfere with LC-MS/MS analysis 2

Alternative: 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) - preferred for pediatric patients not yet continent or when plasma collection is impractical 1, 2

Interpretation of Biochemical Results

≥4 times upper limit of normal:

• Proceed directly to imaging for tumor localization 1, 2
• This degree of elevation is diagnostic for pheochromocytoma/paraganglioma 2

2-4 times upper limit of normal:

• Repeat testing in 2 months 2
• Consider genetic testing for hereditary syndromes, especially in younger patients 2
• If strong clinical suspicion persists, perform clonidine suppression test (100% specificity, 96% sensitivity) 1, 2

1-2 times upper limit of normal (marginally elevated):

• Repeat testing in 6 months using proper collection technique 2
• Consider clonidine suppression test if clinical suspicion remains high 2
• False positives can occur with obesity, obstructive sleep apnea, or improper collection technique 2

Equivocal plasma results with strong clinical suspicion:

• Perform 24-hour urine collection for fractionated metanephrines and catecholamines 1, 2
• Consider clonidine suppression test 1, 2

Additional Biochemical Markers

• Plasma methoxytyramine: Measure when available, as elevated levels indicate higher malignancy risk 1, 2
• Particularly important for head/neck paragangliomas (30% produce dopamine) 2

Imaging Localization

Only proceed to imaging after biochemical confirmation - never perform imaging or biopsy before biochemical exclusion due to risk of fatal hypertensive crisis 2

Anatomic imaging:

• CT or MRI of abdomen and pelvis for initial localization 1
• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 2
• Chest CT to evaluate for thoracic metastases 1
• Brain MRI if concern for cerebral metastases 1

Functional imaging indications (at least one required):

• Tumor size ≥5 cm 1, 2
• Extra-adrenal paraganglioma 1
• SDHB germline mutation 1
• Plasma methoxytyramine >3-fold above upper limit 1
• Suspected metastatic disease 1

Functional imaging options:

• FDG-PET/CT - superior for detecting malignant tumors, especially with SDHB mutations 1, 2
• DOTATATE-PET/CT - preferred for SDHD-related tumors 1, 2
• MIBG scintigraphy - useful for assessing radionuclide therapy eligibility 1

Pathology and Risk Assessment

Histological features:

• No single marker predicts malignancy - diagnosis requires metastases at sites where chromaffin tissue is normally absent (liver, bone, lungs, lymph nodes) 1
• Immunohistochemistry: Chromogranin A, tyrosine hydroxylase, synaptophysin for PPGL identification 1
• Ki-67 labeling index useful for prognosis 1

High-risk features for metastasis:

• Tumor size ≥5 cm 1
• Extra-adrenal location 1
• SDHB mutation 1, 2
• Plasma methoxytyramine >3-fold elevation 1
• PASS score ≥4 2

Genetic Testing

Indications for genetic testing:

• Extra-adrenal tumors 2
• Bilateral adrenal tumors 2
• Age <30 years at diagnosis 2
• Family history of pheochromocytoma or related syndromes 2, 4
• SDHB mutations (40% of metastatic cases) 1

Surveillance for hereditary syndromes:

• VHL syndrome: Begin at age 2 years 2
• HPP syndromes (SDHx mutations): Begin at age 6-8 years 2
• SDHD mutations: Show maternal imprinting - only paternal inheritance causes disease 2

Management

Preoperative Medical Preparation

Critical principle: Alpha-blockade must be established 7-14 days before surgery to prevent fatal hypertensive crises 1, 3

Blood pressure targets:

• Supine BP <130/80 mmHg 1, 3
• Standing systolic BP >90 mmHg 1, 3

Alpha-adrenergic blockade (first-line):

• Phenoxybenzamine (non-competitive α-blocker): Start 10 mg twice daily, adjust every 2-4 days 1
• Doxazosin (competitive, selective α1-blocker): Alternative with fewer side effects 1, 3
• Other options: Prazosin, terazosin 3

Beta-blockers (second-line, ONLY after adequate alpha-blockade):

• Never initiate beta-blockers before alpha-blockade - this causes unopposed alpha-stimulation and precipitates hypertensive crisis 2, 3
• Add only after adequate alpha-blockade to control tachyarrhythmias 3

Calcium channel blockers (adjunctive):

• Use as adjuncts to alpha-blockers for refractory hypertension 1, 3
• Can be combined with ARBs (e.g., amlodipine + telmisartan) after adequate alpha-blockade 3
• May be used as presurgical monotherapy in patients with normal-to-mildly elevated BP or severe orthostatic hypotension limiting alpha-blocker use 3

Metyrosine (catecholamine synthesis inhibitor):

• Consider if target BP not reached with alpha-blockers and calcium channel blockers 1

Perioperative fluid management:

• High-sodium diet and 1-2 liters isotonic saline 24 hours before surgery 3
• Compression stockings to prevent orthostatic hypotension 3
• Hydrocortisone 150 mg/day during surgery if glucocorticoid excess present 1

Surgical Management

Laparoscopic adrenalectomy is the preferred approach for most pheochromocytomas (curative in 90% of cases) 4, 3

Indications for open surgery:

• Tumors >6-8 cm 1
• High suspicion of malignancy 3
• Local invasion requiring resection of adjacent organs (vena cava, liver, spleen, colon, pancreas, stomach) 1

Surgical principles:

• Complete R0 resection is the only curative treatment and major predictor of prognosis 1
• Perform surgery only in centers with >10 adrenalectomies for adrenal cancer per year 1
• Locoregional lymphadenectomy improves staging and outcomes for ACC 1

Cytoreductive (R2) resection:

• Consider in malignant pheochromocytoma to improve quality of life and control hormonal hypersecretion 1
• Indicated in ACC with severe symptomatic hormone excess when medical therapy fails and life expectancy >6 months 1

Surgery for recurrence:

• Effective if R0 resection achievable and time to first recurrence >12 months 1

Special Populations

Pregnant patients:

• First 24 weeks: Laparoscopic adrenalectomy after 10-14 days of alpha-blockade 4, 3
• Third trimester: Medical management until fetal viability, then cesarean section with tumor removal in same session 3

Intraoperative Management

Be prepared to treat hypertensive crises with:

• Magnesium sulfate 3
• Phentolamine 3
• Calcium antagonists 3
• Nitroprusside or nitroglycerin 3

Monitor for:

• Hemodynamic instability and orthostatic hypotension (patients often have relative hypovolemia) 3
• Hypoglycemia after tumor removal due to sudden catecholamine decline 3

Management of Malignant/Metastatic Disease

Treatment options for inoperable disease:

• 131I-MIBG radiotherapy (if MIBG-avid) 1
• Combination chemotherapy (CVD: cyclophosphamide, vincristine, dacarbazine) in selected cases 1
• Locoregional ablative procedures 1
• Wait-and-see policy for low tumor burden and asymptomatic disease 1

Systemic therapy for ACC:

• Combination chemotherapy plus mitotane (EDP-M) for fit patients with high tumor volume and rapid progression 1
• Mitotane monotherapy for less fit patients or low tumor burden with slow progression 1

Postoperative Follow-up

Immediate postoperative assessment:

• Biochemical testing 14 days (2-8 weeks) after surgery to confirm complete resection 1, 2
• Monitor for adrenal insufficiency if glucocorticoid excess was present preoperatively 1

Long-term surveillance (lifelong due to 10-15% recurrence risk):

First 2-3 years:

• Clinical assessment and biochemical testing (plasma/urinary metanephrines, chromogranin A, methoxytyramine) every 3-4 months 1, 4

After 2-3 years:

• Testing every 6 months 1, 4
• Continue for minimum 10 years, preferably lifelong 1, 4

Imaging surveillance:

• Repeat imaging if new symptoms (hypertension, adrenergic symptoms, pain) or elevated biochemical markers 1
• For high-risk patients (SDHB mutation, extra-adrenal disease, tumor >5 cm, or no preoperative hormone secretion): imaging every 6 months first year, then yearly regardless of biochemical results 1

Intensified surveillance for high-risk features:

• SDHB mutations (40% of metastatic cases, higher malignancy risk) 1, 2
• Extra-adrenal location (30% of childhood cases, up to 40% malignant) 1, 5
• Tumor size ≥5 cm 1
• PASS score ≥4 2

Critical Pitfalls to Avoid

• Never perform biopsy of suspected pheochromocytoma - can precipitate fatal hypertensive crisis 2
• Never initiate beta-blockers before alpha-blockade - causes unopposed alpha-stimulation and severe hypertension 2, 3
• Never proceed to imaging or intervention without biochemical confirmation - unrecognized tumors cause life-threatening crises 2
• Avoid contrast-enhanced CT until pheochromocytoma excluded - use MRI preferentially 2
• Do not assume benign disease - all PPGLs have malignant potential per WHO classification 1
• Do not discontinue surveillance - lifelong follow-up mandatory due to recurrence risk even decades later 1, 4