What is the appropriate initial evaluation and management for patients presenting with pheochromocytoma or paraganglioma?

Initial Evaluation and Management of Pheochromocytoma and Paraganglioma

The appropriate initial evaluation for patients with suspected pheochromocytoma or paraganglioma (PPGL) should include biochemical testing for catecholamine excess through plasma or urinary metanephrines, followed by cross-sectional imaging, and preoperative alpha-adrenergic blockade for at least 10-14 days before surgical intervention, which remains the definitive treatment. 1

Diagnostic Approach

Biochemical Testing

• Measure plasma free metanephrines or urinary fractionated metanephrines as the screening test of choice (sensitivity 96-100%, specificity 89-98% for plasma; sensitivity 86-97%, specificity 86-95% for urine) 2
• Consider additional tests such as methoxytyramine and chromogranin A 1
• Levels >4 times the upper limit of normal are highly suggestive of PPGL 2
• For borderline elevations, clonidine-suppression testing can be used to rule out false positives (100% specificity, 96% sensitivity) 2

Imaging Studies

• Proceed with imaging only after biochemical evidence of PPGL has been obtained 2
• Start with CT of the abdomen (preferred) or MRI as an alternative 2
• Extend imaging from skull to pelvis, particularly in patients with genetic predisposition 1
• Consider functional imaging with 123I-MIBG or FDG-PET for suspected metastatic disease 2
• Whole-body imaging is essential in patients with:
  • Age ≤40 years 2
  • Extra-adrenal tumors 2
  • Tumors >5 cm 2
  • Genetic mutations (especially SDHB, SDHD) 2, 1

Genetic Testing

• Consider genetic testing for all patients, particularly those who are:
  • Young
  • Have multiple tumors
  • Have a family history of PPGL or related syndromes 1, 3
• SDHB mutation carriers have a significantly higher risk of malignancy (31-71%) 1

Management Protocol

Preoperative Medical Management

1. Alpha-adrenergic blockade:

   • Start at least 10-14 days before surgery 1
   • Options include:
     • Non-selective α-blocker (phenoxybenzamine) 4
     • Selective α1-blocker (doxazosin) 1
   • Target blood pressure: <130/80 mmHg supine, systolic >90 mmHg standing 1

2. Beta-blockers:

   • Add only after adequate alpha-blockade if tachyarrhythmias develop 1, 4
   • Never use beta-blockers alone as they can worsen hypertension due to unopposed alpha-receptor stimulation 5

3. Volume expansion:

   • High-sodium diet
   • 1-2 liters saline infusion 24 hours before surgery
   • Use of compressive stockings to prevent orthostatic hypotension 1

Surgical Management

• Complete surgical extirpation (R0 resection) is the mainstay of potentially curative treatment 2
• For multiple tumors, resect functional (catecholamine-secreting) tumors first 1
• Consider minimally invasive surgery for adrenal pheochromocytomas when possible 1
• For paragangliomas >5-6 cm, an open approach may be required to assess locoregional nodal disease 1
• Include locoregional lymphadenectomy to improve staging and outcomes 2, 1

Important Cautions

• Never perform biopsy of suspected PPGL due to risk of hypertensive crisis and tachyarrhythmia 1
• Have medications readily available during surgery to treat hypertensive crisis:
  • Magnesium sulfate
  • Phentolamine
  • Nitroprusside 1

Follow-up Protocol

• Measure plasma/urine metanephrines by 8 weeks post-treatment 1
• Perform imaging at 3-6 months post-surgery 1
• Long-term follow-up for at least 10 years, with lifelong surveillance recommended for:
  • Patients with genetic syndromes
  • Extra-adrenal primary disease
  • Tumor size >5 cm
  • SDHB mutations 2, 1
• Follow-up frequency:
  • Every 3-4 months for 2-3 years
  • Then every 6 months thereafter 2

Clinical Presentation Pitfalls

• The classic triad of headaches, palpitations, and sweating is not always present:
  • Only 50% of patients have palpitations
  • Only 34.4% have sweating
  • Only 31.3% have headaches 6
• 65.6% of patients are hypertensive at presentation, but hypertension can be paroxysmal or sustained 2, 6
• Consider PPGL in patients with resistant hypertension, as prevalence may be up to 4% in this population 2
• Delayed diagnosis is common (average 3-year delay) 2

By following this structured approach to evaluation and management, the morbidity and mortality associated with these rare but potentially lethal neuroendocrine tumors can be significantly reduced.