Overview Of VHL
- Definition & Inheritance
- Autosomal dominant tumor suppressor disorder
- Characterized by multiple benign and malignant neoplasms, including hemangioblastomas (central nervous system), retinal angiomas, clear cell renal cell carcinoma, pheochromocytoma, paraganglioma, endolymphatic sac tumors, pancreatic lesions, and epididymal/broad ligament papillary cystadenomas
- High penetrance: ~75% risk for renal cell carcinoma (RCC), retinal angioma, or cerebellar hemangioblastoma
- Types
- Type I: Low risk of pheochromocytoma
- Type II: High risk of pheochromocytoma
- Type IIA: Low risk of RCC
- Type IIB: High risk of RCC
- Type IIC: Pheochromocytomas only
Genetics
- Chromosome & Gene
- Mutation in the VHL tumor suppressor gene on chromosome 3p25–26
- Functions in regulating hypoxia-induced proteins (e.g., HIF pathway)
- 300 germline VHL mutations identified; nearly 100% detection rate in affected families
- Mutation Patterns
- Missense mutations often linked with pheochromocytomas
- Null/truncating mutations often do not present with pheochromocytoma
Pheochromocytoma
- Frequency & Secretion
- ~20% prevalence in VHL syndrome
- Often bilateral and multicentric
- Primarily secrete norepinephrine and normetanephrine
- Management
- Annual biochemical screening (e.g., plasma or urine fractionated metanephrines)
- Resect if identified, following standard pheochromocytoma management (α-blockade, etc.)
Hemangioblastoma
- Location & Features
- Vascular tumors in the cerebellum, spinal cord, or brainstem
- May cause symptoms by mass effect or hemorrhage
- Typically benign; do not metastasize
- Surveillance & Treatment
- Periodic brain/spine imaging (MRI) every 1–2 years
- Intervention (surgery or stereotactic radiotherapy) if lesions are large, symptomatic, or rapidly growing
Clear Cell Renal Cell Carcinoma (RCC)
- Risk & Presentation
- ~75% of VHL patients develop RCC; a leading cause of death in VHL
- Typically multicentric and bilateral
- Surveillance & Management
- Annual imaging (CT, MRI, or ultrasound)
- Early detection → nephron-sparing resection or ablative therapies
- Goal: preserve renal function while preventing metastatic disease
Retinal Angiomas
- Clinical Features
- May be multifocal and bilateral
- Can lead to hemorrhage, retinal detachment, vision loss
- Surveillance & Treatment
- Annual ophthalmologic examination
- Treatment with laser photocoagulation or cryotherapy for vision-threatening lesions
Pancreatic Lesions
- Types
- Simple cysts (common)
- Serous cystadenomas
- Pancreatic neuroendocrine tumors (can be malignant)
- Surveillance
- Imaging (often combined with renal imaging)
- Neuroendocrine tumors may secrete hormones (insulin, glucagon, etc.) or be nonfunctional
Other Lesions
- Endolymphatic Sac Tumors
- Arise in the temporal bone → can cause hearing loss, vertigo, tinnitus
- Papillary Cystadenomas
- Occur in the epididymis (men) and broad ligament (women); usually benign, bilateral, and asymptomatic
Clinical Screening & Management
- Genetic Testing
- Indicated for: bilateral pheochromocytoma, early-onset pheochromocytoma, or typical VHL tumors (hemangioblastoma, etc.)
- Positive family history → test all at-risk relatives
- Biochemical Testing
- Annual screening for catecholamine-secreting tumors (pheochromocytoma) with plasma/urine metanephrines
- Imaging Surveillance
- Brain/spine MRI every 1–2 years for hemangioblastoma
- Annual abdominal imaging (kidneys, pancreas) to catch RCC or pancreatic lesions early
- Annual eye exam for retinal angioma
- Therapeutic Interventions
- Early, nephron-sparing surgery for RCC if lesion meets size/progression criteria
- Resection of symptomatic hemangioblastomas or endolymphatic sac tumors
- Surgical removal of pheochromocytomas after appropriate preoperative medical management