What is pheochromocytoma, its clinical features, diagnosis, and treatment?

Pheochromocytoma: Definition, Clinical Features, Diagnosis, and Treatment

Definition

Pheochromocytoma is a rare catecholamine-producing neuroendocrine tumor arising from chromaffin cells of the adrenal medulla, with a prevalence of 0.01-0.2% in the general hypertensive population but up to 4% in resistant hypertension. 1, 2 Extra-adrenal tumors arising from sympathetic or parasympathetic paraganglia are termed paragangliomas. 3 Approximately 35% of cases are hereditary, associated with genetic syndromes including multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1), and succinate dehydrogenase (SDH) mutations. 2, 4

Clinical Features

Hypertension Patterns

• Approximately 95% of patients present with hypertension: 50% have sustained hypertension (particularly with high norepinephrine production) and 50% have paroxysmal (episodic) hypertension. 2, 5
• Increased blood pressure variability is characteristic and represents an independent risk factor for cardiovascular morbidity and mortality beyond elevated blood pressure alone. 2, 5

Classic Symptom Triad

• The classic triad of headache, palpitations, and sweating occurring episodically has 90% diagnostic specificity. 1, 5
• Additional symptoms include pallor, diaphoresis ("cold sweat"), tachycardia, and anxiety or panic attacks. 2, 5
• These symptoms result from episodic or sustained catecholamine release acting on alpha and beta-adrenergic receptors throughout the body. 5

Diagnostic Delay and Pitfalls

• Despite advances in diagnostics, there is typically a 3-year delay from initial symptoms to diagnosis. 1, 2
• Many cases are completely missed, with the tumor causing 55% of deaths and 75% of cases not suspected during life. 2
• Symptoms can closely mimic panic attacks, leading to misdiagnosis. 5

Diagnosis

When to Suspect Pheochromocytoma

Screen patients with:

• Early-onset hypertension (<30 years) 1
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 1
• Paroxysmal hypertension with classic symptoms 1
• Significant blood pressure variability 1
• Family history of pheochromocytoma or hereditary syndromes 1

Biochemical Testing Algorithm

Initial screening: Measure plasma free metanephrines (normetanephrine and metanephrine), which have the highest sensitivity (96-100%) and specificity (89-98%). 1, 2

Interpretation Based on Elevation Level:

• ≥4 times upper limit of normal: Results consistent with pheochromocytoma/paraganglioma—proceed immediately to imaging for tumor localization. 1
• 2-4 times upper limit of normal: Repeat testing in 2 months and consider genetic testing for hereditary syndromes, especially in younger patients. 1
• Marginally elevated: Repeat testing in 6 months and consider clonidine suppression test (100% specificity, 96% sensitivity) to exclude false positivity. 3, 1

Alternative Testing:

• 24-hour urine fractionated metanephrines and catecholamines are acceptable alternatives with high sensitivity (86-97%) and specificity (86-95%), particularly useful for pediatric patients or when plasma testing is equivocal. 1, 2
• Plasma methoxytyramine measurement helps assess malignancy risk. 1, 2

Important Testing Considerations:

• Plasma free metanephrines should ideally be collected from an indwelling venous catheter after the patient has been lying supine for 30 minutes to limit false positives. 1
• Common antihypertensive medications do not affect plasma free metanephrine measurements when using LC-MS/MS analysis. 1
• False positive elevations (usually <4 times upper limit) can occur with obesity, obstructive sleep apnea, or tricyclic antidepressants. 1

Imaging Studies

After biochemical confirmation, perform abdominal CT or MRI for tumor localization. 2

• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast. 1
• If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck, and consider functional imaging. 1
• For patients with established pheochromocytoma, FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation. 1
• Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated due to risk of hypertensive crisis. 1

Genetic Testing

• Genetic testing should be offered to all patients with pheochromocytoma/paraganglioma, as up to 35% are hereditary. 3, 2
• SDHB mutations are associated with higher risk of aggressive behavior, metastatic disease, and require more intensive surveillance. 1

Treatment

Preoperative Medical Management

All patients with pheochromocytoma must receive preoperative alpha-adrenergic blockade for at least 10-14 days before surgery. 3

Alpha-Blockade Options:

• Phenoxybenzamine (non-competitive, non-selective α1- and α2-blocker): Standard dose is 10 mg twice daily with adjustments every 2-4 days. 3, 6 FDA-indicated for pheochromocytoma to control episodes of hypertension and sweating. 6
• Doxazosin (competitive, selective α1-blocker): May be as effective with fewer side effects, started 7-14 days preoperatively with gradually increasing dosages. 3

Blood Pressure Targets:

• <130/80 mmHg in supine position 3
• Systolic BP preferably >90 mmHg in upright position 3

Additional Medications:

• If target BP not reached, add calcium channel blockers (nifedipine slow release) or metyrosine. 3
• Metyrosine inhibits tyrosine hydroxylase (the rate-limiting step in catecholamine biosynthesis), reducing catecholamine production by 35-80%. 7
• Beta-adrenergic blockade is indicated for tachyarrhythmias but must NEVER be started before alpha-blockade to avoid unopposed alpha-stimulation and hypertensive crisis. 3

Perioperative Preparation:

• High-sodium diet and 1-2 liters of saline 24 hours prior to surgery to reduce risk of postoperative hypotension. 3
• Use compressive stockings. 3
• Hydrocortisone administration during and after surgery for patients with glucocorticoid excess. 3

Surgical Management

Complete surgical resection (R0 resection) is the only potentially curative treatment and should be performed only in specialized centers with >10 adrenalectomies for adrenal cancer per year. 3, 2

Surgical Approach:

• Open surgery with transperitoneal access is the standard for localized (stage I-II) and locally advanced (stage III) disease when complete resection is achievable. 3
• Laparoscopic adrenalectomy is safe and effective for pheochromocytoma in selected centers with consolidated experience, strictly respecting oncologic surgical principles. 3
• R0 resection (margin-free complete resection) is a major predictor of prognosis and provides the only means to achieve long-term survival. 3

Intraoperative Management:

• Hypertension during surgery may be treated with magnesium sulfate, intravenous phentolamine (α-blocker), calcium antagonist, nitroprusside, or nitroglycerin. 3
• Tachycardia can be treated with intravenous β-adrenergic blockers. 3

Management of Advanced Disease

• Cytoreductive (R2) resection in malignant pheochromocytoma may improve quality of life and survival by reducing tumor burden and controlling hormonal hypersecretion. 3
• Surgery for recurrence after primary treatment might be effective in improving survival if R0 resection is achievable and time to first recurrence was >12 months. 3

Malignancy Risk Factors:

• Tumor size ≥5 cm 2
• Extra-adrenal location (paraganglioma) 2
• SDHB germline mutation 1, 2
• Elevated plasma methoxytyramine (>3 times upper limit of normal) 2
• PASS score ≥4 1

Postoperative Follow-up

• Biochemical testing (plasma or urine metanephrines and plasma methoxytyramine) should be performed approximately 8-14 days post-operatively to check for residual disease. 3, 2
• Imaging at 3-6 months post-treatment. 3
• Long-term follow-up includes clinical evaluation, biochemical testing, and chest/abdominal CT scans as clinically indicated. 2
• Patients with SDHB mutations require lifelong monitoring due to higher malignancy risk. 1