Management of Von Hippel-Lindau Disease
The management of Von Hippel-Lindau (VHL) disease requires a comprehensive surveillance program with early genetic testing and regular multiorgan screening to detect tumors before they cause significant morbidity or mortality.
Diagnosis and Genetic Testing
VHL disease is confirmed through genetic identification of a pathogenic variant in the VHL gene, which is considered the gold standard for diagnosis 1. Genetic testing should be performed in:
- First-degree relatives of individuals with pathogenic VHL variants
- Any child diagnosed with VHL-associated manifestations including:
- Retinal angioma/hemangioblastoma
- CNS hemangioblastoma
- Clear cell renal cell carcinoma (RCC)
- Pheochromocytoma or paraganglioma
- Endolymphatic sac tumor (ELST)
- Multiple pancreatic cysts or neuroendocrine tumors
- Multiple renal cysts
Surveillance Protocol
Children (0-4 years)
- Annual pediatric examination
- Annual ophthalmoscopy in dilation
Children (5-14 years)
- Continue annual pediatric examination and ophthalmoscopy
- Annual plasma-metanephrine and normetanephrine tests
- Annual hearing examinations
- MRI of CNS and abdomen between ages 8-14 years
Adolescents and Adults (15+ years)
- Annual ophthalmoscopy in dilation
- Annual neurological examination
- MRI of CNS including inner ear every 1-2 years (annual preferred to reduce intercurrent manifestation risk from 7.2% to 2.7%) 2
- Annual abdominal imaging (ultrasound/MRI)
- Annual plasma-metanephrine, normetanephrine, and chromogranin A tests
- Annual hearing examination
Treatment Approach by Manifestation
Retinal Hemangioblastomas (RHs)
- Extramacular or extrapapillary RHs should be treated promptly upon detection, even when small (≤500 μm) 1
- Laser photocoagulation is highly effective for small RHs (≤1.5 mm), with 100% success rate compared to only 47-73% for larger tumors 1
- Observation is not recommended as most lesions grow at unpredictable rates
CNS Hemangioblastomas
- Early surgical excision is recommended when detected and before significant neurological damage occurs
- CNS hemangioblastomas occur in 60-80% of VHL patients, with spinal hemangioblastomas in 13-50% 3
Renal Cell Carcinoma
- Nephron-sparing surgery is preferred when tumors reach 3 cm
- Regular surveillance allows for early detection and intervention
Pheochromocytomas
- Surgical removal when detected, with appropriate pre-operative alpha-blockade
- Occurs in 10-25% of VHL patients, with earliest reported case at age 2 1
Pancreatic Lesions
- Cysts (21% of patients) typically require monitoring only
- Neuroendocrine tumors (10-17% of patients) may require surgical intervention based on size and growth rate
New Therapeutic Options
Belzutifan, an oral HIF2-α inhibitor, has recently been FDA-approved for treatment of VHL-associated renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas 1, 4. This systemic therapy may:
- Provide safer options for juxtapapillary and macular tumors
- Allow treatment of large tumors where safe and effective options are lacking
- Potentially suppress formation of new tumors
Coordination of Care
A single physician should coordinate the surveillance program and referrals to specialists 5. Patients should be managed by providers with experience in VHL disease, ideally within multidisciplinary centers capable of providing comprehensive surveillance and genetic testing 1.
Common Pitfalls and Challenges
Poor adherence to surveillance: Studies show only 38.9% of mutation carriers continue participating in tumor surveillance programs after five years 6. Being symptomatic at testing is the strongest predictor of adherence (OR = 5; 95% CI 1.2-20.3).
Delayed detection: Without proper surveillance, tumors may remain clinically occult until symptoms become severe, leading to increased morbidity and mortality.
Inadequate coordination: The multisystem nature of VHL requires coordination between multiple specialists, which can be challenging without a designated coordinator.
Failure to treat small lesions: Small extrapapillary or extramacular retinal hemangioblastomas should be treated promptly rather than observed, as they typically grow and become more difficult to treat successfully.
Missing family screening: Genetic testing of family members is essential as early detection significantly improves outcomes.