What are the management and treatment options for Von Hippel-Lindau (VHL) disease?

Management and Treatment Options for Von Hippel-Lindau (VHL) Disease

The management of Von Hippel-Lindau disease requires a comprehensive multidisciplinary surveillance program with prompt treatment of detected lesions, including belzutifan for VHL-associated tumors that don't require immediate surgery and early surgical intervention for other manifestations. 1, 2

Surveillance Recommendations

General Surveillance

• Coordination: A single physician should coordinate the surveillance program and referrals to specialists 2
• Setting: Patients should be managed by providers with experience in VHL disease, ideally within multidisciplinary centers 1, 2

Age-Specific Surveillance Protocol

Infancy to 5 years

• Annual pediatric examinations
• Annual ophthalmoscopy in dilation 2

5 to 14 years

• Continue annual ophthalmoscopy
• Annual plasma-metanephrine and plasma-normetanephrine tests
• Annual hearing examinations
• MRI of CNS and abdomen between ages 8-14 2

15 years and older

• Annual ophthalmologic examination with dilated retinal evaluation 1, 2
• Annual comprehensive physical examination with blood pressure assessment
• Annual plasma-free metanephrines or 24-hour urine fractionated metanephrines
• Biennial audiogram for endolymphatic sac tumor detection
• Biennial MRI brain with and without contrast
• Biennial MRI spine with contrast
• Annual abdominal MRI for renal cell carcinoma and pancreatic neuroendocrine tumor screening 2

Pregnancy Management

• Ocular screening before planned pregnancy
• Ocular examinations every 6-12 months during pregnancy 1, 2

Treatment Approaches

Ocular Manifestations

• Extramacular or extrapapillary retinal hemangioblastomas should be treated promptly upon detection, even when small 1, 2
• Laser photocoagulation is highly effective for small retinal hemangioblastomas (≤1.5 mm) 2
• Juxtapapillary tumors require special consideration due to their proximity to the optic disc 2

Central Nervous System Hemangioblastomas

• Early surgical excision is recommended when detected and before significant neurological damage occurs 2
• These occur in 60-80% of VHL patients, with spinal hemangioblastomas in 13-50% 2

Renal Manifestations

• Nephron-sparing surgery is preferred when tumors reach 3 cm 2
• Regular surveillance allows for early detection and intervention 2

Pharmacological Treatment

• Belzutifan: FDA-approved oral HIF2-α inhibitor for treatment of:
  • VHL-associated renal cell carcinoma
  • Pancreatic neuroendocrine tumors
  • CNS hemangioblastomas
  • May provide safer options for juxtapapillary and macular tumors
  • Allows treatment of large tumors
  • Potentially suppresses formation of new tumors 2

Genetic Testing and Diagnosis

• Genetic testing should be performed in:

  • First-degree relatives of individuals with pathogenic VHL variants
  • Any child diagnosed with VHL-associated manifestations 2

• Clinical diagnosis criteria include:

  • One or more retinal hemangioblastomas with family history of VHL
  • Two or more retinal hemangioblastomas even in asymptomatic patients 1

Common Pitfalls and Caveats

1. Diagnostic uncertainty: Ophthalmologists often face uncertainty in cases of:

   • Solitary retinal hemangioblastoma without family history
   • Retinal hemangioblastoma with additional lesions that are missed or difficult to differentiate
   • At-risk individuals without retinal hemangioblastomas who haven't undergone full evaluation 1

2. Examination challenges: Young children may require examination under anesthesia if detailed office examination is not possible 1

3. Follow-up concerns: For patients with poor compliance or poor reporting of symptoms (such as children), early treatment is favored over observation 1

4. Imaging limitations: Ultra-widefield photography and fluorescein angiography may be helpful adjuncts but cannot replace detailed dilated funduscopic examination 1

5. Life expectancy impact: Despite advances in clinical diagnosis and management, life expectancy for VHL patients remains low at 40-52 years 3

The evidence strongly supports a structured surveillance approach with early intervention for detected lesions, with belzutifan offering a promising pharmacological option for certain VHL-associated tumors that don't require immediate surgery.