Description
Von Hippel-Lindau (VHL) disease is a rare, autosomal dominant, multisystem disorder characterised by the formation of tumours and cysts in multiple organs. It commonly causes haemangioblastomas in the brain, spinal cord, and retina; clear cell renal cell carcinoma; pheochromocytomas in the adrenal glands; and cysts in organs such as the kidneys, pancreas, and testicles.
Pathogenesis
Von Hippel-Lindau (VHL) disease is a result of germline mutations in the VHL tumour suppressor gene located on the short arm of chromosome 3 (3p25-26). The VHL gene plays a key role in cellular response to oxygen levels, controlling the degradation of hypoxia-inducible factors (HIFs).
In a normoxic environment, the VHL protein binds to HIF, leading to its ubiquitination and subsequent degradation. When the VHL gene is mutated, its protein loses this ability, resulting in HIF accumulation even under normoxic conditions.
Elevated HIF levels promote the transcription of numerous genes, including those involved in angiogenesis (such as VEGF), cell proliferation, and metabolism. Consequently, this leads to the development of highly vascularised tumours and cysts, characteristic of VHL disease.
Epidemiology, Risk Factors & Associations
The disease is relatively rare, affecting 1 in 36,000 live births globally. It follows an autosomal dominant inheritance pattern meaning offspring of an affected parent have a 50% chance of inheriting the VHL gene mutation.
Clinical Features
VHL disease manifests in a range of clinical phenotypes, the most typical features include:
- Haemangioblastomas (60-80% of patients)1: These benign (WHO grade I) vascular tumours commonly occur in the cerebellum (50% of cases), brain stem (25%), and spinal cord (15-20%). May also occur in the retina, typically bilaterally and is often the first feature of VHL disease. Can cause a range of neurological symptoms depending on their size and location, including headaches, ataxia, and vision impairment.
- Clear cell renal cell carcinoma (24-45%): Presents as multiple and bilateral lesions. Often asymptomatic until they become large and start to cause symptoms such as pain, haematuria, or a palpable mass.
- Pheochromocytomas (10-20%): These neuroendocrine tumours of the adrenal medulla are often bilateral. Can cause hypertension, palpitations, sweating, and anxiety due to the overproduction and release of catecholamines.
- Pancreatic lesions (35-70%): These lesions include simple cysts, serous cystadenomas, and neuroendocrine tumours. Pancreatic neuroendocrine tumours (10% of patients) have the potential to be functional and secrete hormones such as insulin or glucagon, leading to symptoms related to hormone excess.
- Endolymphatic sac tumours (10-15%): These are rare, low-grade malignancies arising from the endolymphatic sac in the inner ear. May cause symptoms like hearing loss, tinnitus, vertigo, or facial palsy.
- Epididymal papillary cystadenomas (25-60% of male patients): These benign tumours occur in the epididymis, causing palpable scrotal masses in male patients. Often asymptomatic but can occasionally cause discomfort or pain.
- Broad ligament cystadenomas (up to 20% of female patients): These benign tumours are found in the broad ligament of the uterus in females and are often asymptomatic.
- Pulmonary and hepatic cysts (around 50% and 60%, respectively): These cysts are often asymptomatic and detected incidentally on imaging studies. In rare cases, pulmonary cysts can cause spontaneous pneumothorax.
Complications
The complications of VHL are related to the various types of tumours.
They can include neurological symptoms from haemangioblastomas such as headaches, ataxia, and dizziness, and high blood pressure and palpitations from pheochromocytomas. Renal cell carcinomas can lead to chronic kidney disease.
Subtypes
There are two main types of VHL disease:
- Type 1: Characterised by a low risk of pheochromocytoma but a high risk of renal cell carcinoma.
- Type 2: Associated with a high risk of pheochromocytoma. It is further subdivided into types:
- 2A (low risk of renal cell carcinoma)
- 2B (high risk of renal cell carcinoma)
- 2C (pheochromocytoma only).
Pathological Features
Morphology
- Haemangioblastomas typically show a proliferation of thin-walled, dilated blood vessels.
- Renal cell carcinomas have a clear-cell phenotype, characterised by cells with a clear cytoplasm due to their high glycogen content.
- Pheochromocytomas show nests of cells separated by a rich vascular network.
Histopathology
- Haemangioblastomas typically show large, vacuolated stromal cells which stain positive for inhibin A, and negative for epithelial markers.
- The clear cells of the renal cell carcinomas are polygonal and are organised in a solid, tubular, or papillary pattern.
Biochemistry
- There is often an increase in erythropoietin due to increased HIF, leading to secondary polycythemia.
- Pheochromocytomas lead to increased catecholamines.
Genetics
Mutations in the VHL gene are found in the majority of cases. There are over 800 different mutations reported in the VHL gene.
Radiological Features
CT
Clear cell renal cell carcinomas present as hypodense masses before contrast administration and enhance vividly after contrast administration.
MRI
- Haemangioblastomas: These lesions typically appear as well-defined cystic masses with mural nodule(s) and are hyperintense on T2-weighted images and enhance brightly with contrast.
- Clear cell renal cell carcinomas: These tumours often show a high signal intensity on T2-weighted images and demonstrate enhancement after contrast administration.
Ultrasound
- Cysts in the kidney and pancreas.
Grading and Staging
There is no specific grading or staging system for VHL disease as it is a systemic condition and management is focused on individual tumours.
Differential Diagnosis
Differential diagnosis may include other phakomatoses like
- Neurofibromatosis: Characterised by café-au-lait spots, neurofibromas, and Lisch nodules in the iris.
- Tuberous Sclerosis: Presents with hypopigmented macules (ash leaf spots), shagreen patches, and angiofibromas.
- Sturge-Weber syndrome: Characterised by a facial port-wine stain, glaucoma, and seizures.
The presence of multiple tumours in various organs helps distinguish VHL.
Management
Management of VHL requires a multidisciplinary approach with regular screening for new tumours. Surgical intervention may be needed for larger tumours, and targeted therapies are being investigated. Genetic counselling is also an important part of management.
References