Von Hippel-Lindau (VHL) Syndrome

Overview

Genetics & Molecular Basis

• Gene: VHL tumor suppressor gene, mapped to chromosome 3p25
• Encodes two protein isoforms: pVHL30 (213 aa, 30 kD) and pVHL19 (19 kD, lacking 53 amino acids)
• Follows the two-hit hypothesis - biallelic loss is required for tumor development
• Normal function of pVHL: Under normoxic conditions, pVHL binds and ubiquitinates the alpha-subunits of hypoxia-inducible factor (HIF), targeting them for degradation
• Effect of VHL loss: HIF-alpha subunits accumulate, translocate to the nucleus, form heterodimers with HIF-beta, and activate hypoxia-response genes including:
  • VEGF (angiogenesis - explains the vascular tumors)
  • Erythropoietin (EPO) - causes paraneoplastic polycythemia
  • PDGFB, TGF-alpha, GLUT1, Carbonic anhydrase IX
• pVHL also plays roles in microtubule stability and primary cilia integrity (explaining cyst formation)

Classification (Genotype-Phenotype Correlation)

Clinical Features (Organ by Organ)

1. CNS Hemangioblastomas (60-80% of patients)

• Most common site: cerebellum (~50%), followed by spinal cord and brainstem; cerebral hemispheres <5%
• Benign but slow-growing; behavior is unpredictable with phases of growth and quiescence
• Histology: thin-walled capillary vessels + stromal cells with vacuolated, lipid-rich cytoplasm (PAS-positive); stain positive for inhibin (diagnostic marker); mast cells present and may produce EPO
• Appear as a mural nodule within a large fluid-filled cyst
• Symptoms: headache (most common), ataxia, nausea/vomiting, nystagmus; spinal lesions cause back/neck pain, sensory loss, weakness, and syringomyelia
• 84% of VHL patients develop at least one cerebellar hemangioblastoma by age 60
• Imaging: contrast-enhanced MRI (pre + post T1-weighted with thin posterior fossa cuts)

Contrast MRI: bilateral cerebellar hemangioblastomas (bright nodules with cysts) - Bradley and Daroff's Neurology

2. Retinal Hemangioblastomas / Angiomas

• Most common presenting feature of VHL
• Histopathologically identical to CNS hemangioblastomas
• Typically bilateral; can occur as young as age 1
• Lead to vision loss in 35-55% of cases via arteriovenous shunting, fluid extravasation, hemorrhage, retinal detachment, glaucoma, macular edema
• Treatment: laser photocoagulation for most; VEGF inhibitors (ranibizumab) or tyrosine kinase inhibitors (sunitinib) for severe exudative lesions

3. Renal Cell Carcinoma (RCC)

• Most common malignant tumor in VHL and leading cause of death
• Lifetime risk up to 70%; mean age at presentation ~40 years (younger than sporadic RCC)
• Almost always clear cell type; typically multifocal and bilateral
• Surveillance: abdominal MRI with and without contrast every 2 years from age 16
• Surgery indicated when tumor reaches 3 cm (risk of metastasis increases)
• Kidney-sparing surgery or ablation preferred

4. Pheochromocytoma (PCC)

• Occurs in 7-20% of patients; mean age ~28 years
• Can be bilateral and extraadrenal
• May be the only clinical manifestation in some patients
• Symptoms: episodic/sustained hypertension, severe headache, flushing with profuse sweating; can cause hypertensive crisis, stroke, MI, heart failure
• Diagnosis: excessive catecholamines in serum and urine
• Screening: annually from age 5
• Important: always screen for PCC before any elective surgery

5. Renal Cysts

• Present in >50% of patients; simple cysts from distal tubular epithelium (vs. RCC from proximal tubular epithelium)
• Rarely cause renal failure

6. Pancreatic Lesions

• Pancreatic cysts (most common): usually asymptomatic unless obstructing bile duct
• Pancreatic islet cell tumors: typically non-secretory, occur in 5-10%; surgery when >3 cm
• Serous microcystic adenomas, rarely adenocarcinoma
• Islet cell tumors frequently co-occur with PCC (both from neural crest cells)

7. Endolymphatic Sac Tumors (ELSTs)

• Arise from membranous labyrinth of inner ear
• Bilateral ELSTs are pathognomonic of VHL
• Cause: tinnitus, vertigo, hearing loss
• Occur in ~10% of patients

8. Epididymal Cystadenomas

• May be palpable and cause discomfort; often asymptomatic

Diagnostic Criteria

• At-risk relatives with family history
• Isolated retinal or CNS HB
• PCC or ELST
• Clear cell RCC before age 50, bilateral or multifocal RCC

Surveillance Summary

Treatment

• CNS hemangioblastomas: surgical resection when symptomatic; laser ablation for retinal lesions
• RCC: kidney-sparing surgery or ablation at 3 cm threshold
• PCC: surgery (pre-op catecholamine blockade mandatory)
• Targeted therapies: Tyrosine kinase inhibitors (sunitinib) show promise across multiple VHL-associated lesions; ongoing trials for RCC, pancreatic lesions, PCCs, CNS/retinal HBs
• HIF-2alpha inhibitor belzutifan (approved 2021 by FDA) is a newer targeted therapy specifically for VHL-related tumors