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
  • 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

  1. Genetic Testing
    • Indicated for: bilateral pheochromocytoma, early-onset pheochromocytoma, or typical VHL tumors (hemangioblastoma, etc.)
    • Positive family history → test all at-risk relatives
  2. Biochemical Testing
    • Annual screening for catecholamine-secreting tumors (pheochromocytoma) with plasma/urine metanephrines
  3. 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
  4. 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

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