What is the recommended diagnostic workup, pre‑operative preparation, surgical treatment, and follow‑up for a patient with suspected pheochromocytoma?

Pheochromocytoma: Diagnostic Workup, Preoperative Preparation, Surgical Treatment, and Follow-Up

Diagnostic Workup

Measure plasma free metanephrines as the first-line biochemical test for suspected pheochromocytoma, as this provides the highest sensitivity (96-100%) and negative predictive value, reliably excluding the tumor when normal. 1

When to Suspect Pheochromocytoma

Screen for pheochromocytoma in the following clinical scenarios:

• Classic triad: Headache, palpitations, and sweating ("cold sweat") occurring together—this has 90% diagnostic specificity 1
• Early-onset hypertension (<30 years of age) 1
• Resistant hypertension (BP >140/90 mmHg despite ≥3 antihypertensive medications including a diuretic)—prevalence up to 4% in this population 1
• Paroxysmal hypertension with episodic symptoms 1
• Adrenal incidentaloma with >10 HU on non-contrast CT 2
• Family history of pheochromocytoma or genetic syndromes (MEN2, VHL, NF1, hereditary paraganglioma syndromes) 1, 2

Biochemical Testing Algorithm

Step 1: Initial Screening

• Measure plasma free metanephrines (sensitivity 96-100%, specificity 89-98%) OR 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) 1
• For plasma testing, ideally collect from an indwelling venous catheter after 30 minutes supine rest to minimize false positives 1
• Confirm interfering medications were avoided (tricyclic antidepressants can cause false elevations, but alpha-blockers like doxazosin do not interfere) 1

Step 2: Interpretation Based on Elevation Level

• ≥4 times upper limit of normal: Proceed immediately to imaging—this confirms pheochromocytoma/paraganglioma 1
• 2-4 times upper limit: Repeat testing in 2 months and consider genetic testing 1
• 1-2 times upper limit (marginally elevated): Repeat testing in 6 months OR perform clonidine suppression test if clinical suspicion remains high 1

Step 3: Confirmatory Testing for Equivocal Results

• Clonidine suppression test has 100% specificity and 96% sensitivity for distinguishing true pheochromocytoma from false positives 1
• If plasma testing is equivocal (<4-fold elevation), perform 24-hour urine collection for fractionated metanephrines and catecholamines 1
• Measure plasma methoxytyramine when available—elevated levels indicate higher malignancy risk 1

Imaging Studies

Never perform imaging before biochemical confirmation, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures. 1

Anatomical Imaging:

• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 3
• Obtain chest, abdomen, and pelvis imaging to detect metastases 1
• If initial abdominal imaging is negative but biochemistry is positive, extend imaging to chest and neck 1

Functional Imaging Indications:

Proceed to functional imaging when any high-risk feature is present 1:

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

Functional Imaging Modalities:

• 18F-FDG PET is superior to MIBG for detecting malignant tumors, particularly in SDHB mutation carriers 3, 2
• 123I-MIBG scintigraphy is sufficient for sporadic, non-metastatic pheochromocytoma 2
• 18F-FDOPA PET offers highest sensitivity (≈100%) for head-and-neck paragangliomas 2

Critical Diagnostic Pitfalls

Never perform fine needle biopsy of a suspected pheochromocytoma—this is absolutely contraindicated due to risk of precipitating fatal hypertensive crisis. 3, 1, 4

• Do not use beta-blockade alone before alpha-blockade, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation 1
• Avoid contrast-enhanced CT until pheochromocytoma is definitively excluded 1

Genetic Testing

Approximately 25-35% of pheochromocytomas are hereditary with autosomal dominant inheritance. 1, 5

Offer genetic testing to:

• All patients diagnosed at ≤40 years of age 2
• Patients with family history of pheochromocytoma/paraganglioma 1
• Bilateral or multifocal disease 2
• Extra-adrenal location (paraganglioma) 2

Key genetic mutations and their implications:

• SDHB mutations: 31-71% malignancy risk, require lifelong intensive surveillance 2
• SDHD mutations: Show maternal imprinting—only paternal inheritance causes disease 1
• VHL, MEN2, NF1: Associated syndromes requiring specific surveillance protocols 1

Preoperative Preparation

Alpha-adrenergic blockade is mandatory and must be started 7-14 days before surgery to prevent intraoperative hypertensive crisis. 3, 1, 5

Pharmacological Preparation Protocol

• Start phenoxybenzamine 10 mg twice daily 2
• Increase every other day to 20-40 mg 2-3 times daily until optimal blood pressure control achieved 2
• Add beta-blockade only AFTER adequate alpha-blockade is established 1
• Ensure adequate volume expansion during preoperative period 3

Perioperative Management

Meticulous perioperative management of hormonal, glucose, electrolytes, cardiac and fluid/blood pressure abnormalities is a critical component of patient care. 3

Surgical Treatment

Complete surgical extirpation (R0 resection) is the mainstay of potentially curative treatment for localized and locally advanced pheochromocytoma. 3

Surgical Approach

• Laparoscopic adrenalectomy is the preferred treatment and is usually curative 2
• Open adrenalectomy is reserved for lesions suspicious for malignancy (irregular/inhomogeneous morphology, lipid-poor appearance, or size >3 cm with multi-hormonal secretion) 2
• In metastatic disease, cytoreductive surgery might be considered for symptom control 3

Malignancy Risk Factors

Malignancy is defined only by presence of metastases at sites where chromaffin cells are normally absent (e.g., liver, bone). 3

High-risk features for malignancy include 3, 1:

• Tumor size >5 cm
• Extra-adrenal location (paragangliomas have up to 40% malignancy rate) 6
• SDHB mutation
• PASS (Pheochromocytoma of the Adrenal gland Scaled Score) ≥4 1, 2

Follow-Up

All patients require long-term surveillance due to risk of malignant recurrence, with lifelong follow-up recommended for high-risk patients. 3, 1

Post-Surgical Surveillance Protocol

Immediate Post-Operative:

• Repeat biochemical testing (plasma or urinary metanephrines) 14 days post-surgery to confirm complete resection 3, 1

First 2-3 Years:

• Biochemical testing every 3-4 months 3
• Clinical assessment of adrenergic symptoms and blood pressure levels 3

After 2-3 Years:

• Biochemical testing every 6 months 3
• Continue for at least 10 years 3

High-Risk Patients (SDHB mutation, extra-adrenal primary, tumor >5 cm):

• Imaging every 6 months during first year, then yearly regardless of negative biochemical tests 3
• Lifelong surveillance is mandatory 3, 2
• Include chromogranin A and methoxythyramine measurements 3

Surveillance for Malignant/Metastatic Disease

For proven malignant disease:

• Follow-up every 3-6 months during first year 3
• Use FDG-PET for imaging, especially in SDHB mutation carriers 3, 2

For inoperable disease with low tumor burden and asymptomatic presentation:

• "Wait and see" policy is recommended 3
• Disease and symptom control is the main treatment goal 3

Treatment Options for Inoperable Disease

• 131I-MIBG radiopharmaceuticals for symptom control 3
• Locoregional ablative procedures in selected cases 3
• Combination chemotherapy (CVD) for symptomatic disease 3