Von Hippel–Lindau disease

General information

Von Hippel–Lindau disease is one of the most common autosomal dominant inherited genetic diseases that cause familial cancers, and is characterized by certain types of central nervous system tumours (cerebellar and spinal haemangioblastomas and retinal angiomas), in conjunction with bilateral renal carcinomas and phaechromocytoma (Neumann and Wiestler 1991). The prevalence is approximately 1 in 40 000. Von Hippel described angiomas of the retina in 1904 and Lindau described cerebellar and spine angiomas in 1926.

Genetic

Von Hippel–Lindau (VHL) disease is caused by loss of a tumour suppressor gene situated on the short arm of chromosome 3 (3p25–26) proximal to the locus for the RAF-1 oncogene (Seizinger et al. 1988). The gene for von Hippel–Lindau disease has been cloned (Latif et al. 1993).

Tumour suppressor genes work on the ‘two-hit’ hypothesis, that tumours will only develop after both copies of the VHL gene are damaged. In families with VHL, one damaged gene has been inherited. So far more than 140 different mutations have been identified in the VHL gene. The second ‘hit’ to the allele with the normally functioning gene can occur anytime during life. Recent mutation studies have demonstrated that the tumour suppressor genes are also mutated in the more common sporadic haemangioblastoma and renal carcinoma (Gnarra et al. 1994; Kanno et al. 1994).

Patients with VHL are at risk of:

  • retinal haemangioblastomas (angiomas) (57 per cent),
  • central nervous system haemangioblastomas,
  • renal cell carcinoma (23 per cent),
  • phaeochromocytomas (19 per cent),
  • or simple cysts of the kidney, pancreas liver, etc.

Retinal angiomas (haemangioblastomas) occur in one-quarter to one-half of patients, and are bilateral in one-third of patients with retinal haemangioblastoma. Retinal haemangioblastomas can cause progressive unilateral or bilateral blindness, from glaucoma, haemorrhage, retinal detachment, or sympathetic ophthalmitis.

Symptoms and signs can occur in infancy or in late life. On ophthalmoscopy haemangioblastomas appear as red masses of any size, fed by dilated tortuous arteries.

Central nervous system haemangioblastomas can occur in the:

  • cerebellum (54 per cent),
  • brainstem (20 per cent),
  • spinal cord (15 per cent),
  • cerebrum (rarely).

Haemangioblastomas account for 1–2.5% of all intracranial tumours and 10% of posterior fossa tumours in children. Central nervous system haemangioblastomas may be multiple and imaging of the whole of the CNS is recommended. Approximately 30–40% of patients with haemangioblastoma have VHL, while the remainder have sporadic haemangioblastoma. However, the likelihood of haemangioblastoma being associated with VHL approaches 50–60% if diagnosis is made in children or young adults (<30 years of age) and where the haemangioblastoma is of the spinal cord (>80% associated with VHL). These tumours are commonly associated with secondary polycythaemia due to secretion of erythropoietin by the tumour.

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Fig.1

Renal lesions are frequently asymptomatic, but may present with haematuria, fever, or pain. Renal carcinoma will develop in 20–25% of patients.

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Fig.2

Pancreatic lesions can cause abdominal pain and may be associated with diabetes mellitus.

Phaeochromocytomas are associated with cerebellar haemangioblastomas and may be unilateral or bilateral. They usually are associated with systemic hypertension.

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Fig.3

Diagnostic criteria

Diagnostic criteria for VHL are:

  • evidence of more than one haemangioblastoma in the central nervous system or retina;
  • two types of tumours commonly found in VHL in the same patient (e.g. cerebellar haemangioblastoma and renal carcinoma); or
  • a typical tumour related to VHL and a family history of VHL.

Indirect ophthalmoscopy and fluorescein angiography can detect lesions before they are symptomatic. Cerebellar tumours are usually well defined, with a cystic or multiloculated component with a mural nodule, and the wall enhances with contrast on cranial CT or MRI. MRI is the best technique to examine the posterior fossa and the spine. Spinal and cerebellar tumours are commonly solid and enhance with contrast. Renal, adrenal, and pancreatic lesions are best identified by MRI of the abdomen. Urinary catecholamines and metadrenaline are elevated in phaeochromocytoma. Cerebellar haemangioblastomas may resemble renal clear-cell metastasis on histology. The diagnosis is usually clarified by immunohistochemical studies which are positive for epithelial membrane antigen in renal cell carcinoma and negative in haemangioblastoma (neuron-specific enolase and GFAP positive).

DNA-based diagnostic testing is now available for von Hippel–Lindau disease in cases where there is diagnostic doubt or in cases where early presymptomatic diagnosis is desired in VHL families (Kley et al. 1995).

Screening of patients and at-risk relatives includes annual clinical assessment, including indirect ophthalmoscopy, from the age of 5 years (with fluorescein angiography if there are any suspicious areas):

  • annual urinary metadrenaline from the age of 10 years;
  • biennial cranial imaging (MRI ideally) from the age of 15 years; and
  • biennial abdominal scanning (CT or MRI) to examine, adrenals, kidneys, and pancreas.

The identification of an intracranial haemangioblastoma should stimulate the search for spinal haemangioblastomas, even in patients without spinal symptoms. Before surgery is contemplated in patients with possible haemangioblastoma, blood and urine tests to exclude a phaeochromocytoma, and abdominal CT or MRI scanning to look for renal or adrenal tumours or cysts, should be performed.

Prognosis

Prognosis depends on the site and size of the haemangioblastomas or other associated tumours. Peripheral lesions in patients with retinal haemangioblastoma will usually be treated at an early stage by photocoagulation or cryotherapy (Annesley et al. 1977).

Treatment

Surgical intervention for haemangioblastoma involving the central nervous system is not usually advisable for lesions less than 3 cm in diameter. Tumours of the brainstem and spinal cord carry a high postoperative morbidity from haemorrhage. Haemangiomas of the cerebellum are more easily accessible, and sometimes preoperative embolization can reduce the risk of haemorrhage. Operations on cystic cerebellar lesions appear to have fewer complications than operations on solid lesions (Lamiell et al. 1989). Complete resection of the haemangioblastoma can be curative; however, recurrences or new tumours are common.

Renal tumours in VHL grow at a slower rate and are less aggressive than those with sporadic renal small cell carcinoma. Most surgeons practice renal-sparing surgery because there is a very high chance that further tumours will develop in the same kidney or the opposite kidney at a later date.

Phaeochromocytomas should be resected when diagnosed.