von Hippel-Lindau Disease

Synonyms: VHL

This is a rare condition associated with familial cancers. It predisposes to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal haemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumours. It is one of several neurocutaneous syndromes called phacomatoses.

It is due to a mutation of the VHL tumour suppressor gene at chromosome site 11q13, 3p26-p25. Variation in the cyclin D1 gene on chromosome 11q13 may modify the phenotype.¹

The disease has much in common with multiple endocrine neoplasia that is also a genetic disease with failure of a tumour suppressor gene on chromosome 11.

• The inheritance pattern is autosomal dominant.
• The point prevalence of heterozygotes in East Anglia is 1 in 53,000, with an estimated birth incidence of 1 in 36,000 live births.
• A small percentage of cases are new mutations.
• A VHL register exists in Northwest England.³

There are various classifications of the disease, such as:

• Type 1 is without phaeochromocytoma and type 2 is with phaeochromocytoma
• Type 2A has phaeochromocytomas and retinal/CNS haemangioblastomas, but no renal cell carcinoma
• Type 2B has phaeochromocytomas and retinal/CNS haemangioblastomas with renal cell carcinoma
• Type 2C is with isolated pheochromocytoma without haemangioblastoma or renal cell carcinoma

Diagnostic criteria⁴

Diagnostic criteria have been proposed. Few patients have all features and about half have only one.

• With a family history of retinal or central nervous system haemangioblastoma, only 1 such tumour or visceral lesion (renal tumours, pancreatic cysts or tumours, pheochromocytoma, papillary cystadenomas of the epididymis) is required to make the diagnosis.
• For isolated cases without a clear family history, 2 or more haemangioblastomas or 1 haemangioblastoma and a visceral lesion is required.

Renal and epididymal cysts are too common in the general population to be reliable markers of the disease.

Possible clinical features are listed below. Note that most of these cysts and tumours may be asymptomatic for long periods, and often are detected on screening.

• Retinal haemangioblastoma - may present with visual symptoms (see below).
• Cerebellar, spinal and medullary haemangioblastoma - cause cerebellar or spinal neurological features. Early symptoms are back pain, headaches, dizziness, and limb sensory or motor symptoms.
• Phaeochromocytoma - may present with hypertension.
• Renal cysts and carcinoma - renal cell carcinoma may present as haematuria.
• Pancreatic cysts or tumours - often asymptomatic, may cause pain.
• Papillary cystadenoma of the epididymis - presenting as scrotal swelling.
• Endolymphatic sac tumours (rare) - cause hearing and vestibular symptoms.

Presenting features and ages³

In one UK study:

• Onset of symptoms was at a mean age of 26 years. Cerebellar haemangioblastoma was the commonest presentation.
• The diagnosis of VHL was at a mean age of 31 years.
• The mean age for diagnosis of renal cell carcinoma was 38 years.
• Retinal angiomas were diagnosed at a mean age of 21 years.
• Few patients develop tumours before the age of 10 (though screening from early childhood is recommended).⁴
• Pheochromocytoma, if present, often develops at an early age, under 5 years.⁴

Retinal haemangioblastomas^4,5

They are the commonest lesions and the earliest to be detected. They affect between 45 and 60% of people with the syndrome and about half are bilateral. They usually develop between childhood and 30 years of age, though can occur later.

Retinal screening:

• New lesions may develop within 2 years, so screening at least annually from early childhood is important.
• The lesions are usually asymptomatic if peripheral but if they become large or if they are central, they can cause profound visual loss.
• Screening requires direct or indirect ophthalmoscopy. Fluorescein angioscopy can detect small lesions. Periodic tonometry to exclude glaucoma is also recommended. If the lesion is large enough to be seen on CT or MRI, it is already at an advanced stage and vision is severely impaired.

Treatment:

• Treatment involves aggressive use of laser photocoagulation and is often successful in preventing blindness if the retinal lesion is diagnosed and treated early.
• If they have enlarged and bled, photocoagulation will not recover vision but it may delay further vision loss.
• Cryotherapy has been used for large lesions.

Ophthalmic complications:

• Arteriovenous shunting and leaky capillaries lead to exudation of fluid.
• Complications due to haemorrhage include retinal detachment, macular oedema, glaucoma, cataract, uveitis, and sympathetic ophthalmitis.
• Glaucoma, large tumours or severe pain may require enucleation.

Haemangioblastomas of the central nervous system⁴

• As with retinal lesions, these usually develop in childhood or <30 years. Annual MRI from age 10 years is recommended.
• They are most often in the cerebellum, spine or medulla.
• The lesions are usually cystic but may be solid and occasionally they produce erythropoetin causing polycythaemia. Between 5 and 20% have a high haematocrit and may need periodic venesection.
• Symptoms are often subtle or intermittent and this may delay diagnosis.
  • Cerebellar tumours present with headache, positional vertigo, vomiting, wide based gait (cerebellar ataxia), slurred speech, nystagmus, dysmetria, and IX cranial nerve palsy.
  • Spinal tumours may present with backache and limb symptoms.
• Paroxysmal hypertension has been reported without pheochromocytoma.
• Haemangioblastomas of the medulla account for around 5% of tumours.
• Tumours may cause syringomyelia and syringobulbia.

Screening:

• Routine screening of the CNS should include MRI images of the brain and spinal cord. Meticulous attention to technique is required.

Treatment:

• Surgical removal of symptomatic lesions.
• Small, asymptomatic tumours should be carefully monitored for symptoms. Surgery may not be needed for such tumours, because their growth pattern tends to be intermittent and variable.⁶
• Inoperable cases may benefit from external beam radiation and stereotactic radiosurgical ablation or gamma knife treatment.

Phaeochromocytoma and adrenal tumours

• The incidence of pheochromocytoma varies between families.
• Many pheochromocytomas are asymptomatic and do not elevate serum catecholamine levels.
• The diagnosis and management of pheochromocytoma is described elsewhere.

Renal cysts and tumours⁴

Occurence:

• Renal cysts usually develop later than CNS or retinal tumours, at age 20-50 years.
• Renal involvement is multicentral and bilateral in most cases.
• Large and multiple cysts can mimic adult polycystic kidney disease, including causing chronic renal failure.
• Between 25 and 45% of patients with the syndrome have renal cell carcinoma (RCC).

Screening:

• Screening is with CT or MRI which can detect tumours just 2cm in diameter, compared with 3cm for ultrasound.
• Patients with RCC, or a family history of it, require annual CT/MRI screening.

Treatment:

• Previously, nephrectomy was required; bilateral nephrectomy necessitated long term dialysis.
• 'Nephron sparing surgery' is now used, involving either removal of the tumour, or partial nephrectomy.
• Other, new options are cryosurgery or percutaneous radiofrequency ablation of the tumours.

Cystic disease of the pancreas⁴

Features:

• Pancreatic lesions include pancreatic cysts, serous microcystic adenomas and adenocarcinomas. The pancreatic cyst is the commonest of these lesions but its frequency varies considerably between families.
• Pancreatic involvement usually comes to light between the ages of 20 and 40 during screening studies or work ups for other abnormalities.

Features:

• Most islet cell tumours are slow growing and asymptomatic; but they may grow rapidly, cause biliary obstruction, or metastasise to the liver or bone.
• Endocrinopathies that have been reported with these tumours including pancreatic polypeptide, vasoactive intestinal polypeptide (VIP), calcitonin, insulin and glucagon, gastrin and somatostatin.

Treatment:

• Tumours require surgery. It may be possible to shell out the tumour and avoid pancreatectomy.
• Pancreatic supplements or insulin may be required if the pancreas becomes non-functioning.

Papillary cystadenoma of the epididymis and broad ligament¹

• Papillary cystadenomas of the epididymis affects between approximately 10 and 25% of men with VHL.
• Epididymal cysts are very common in the general population but when they are bilateral it is suggestive of VHL.
• A histologically identical lesion to that in males is very occasionally found in the broad ligament, the embryological counterpart in women.

Endolymphatic sac tumours¹

Clinical features:

• The endolymphatic sac is at the end of endolymphatic duct within the dura of the posterior fossa. Its function is unknown but it may be involved with the production and resorption of endolymph from the cochlea and semicircular canals.
• Tumours can grow outward into the cerebellum or cerebellopontine angles. They can also erode the vestibular aqueduct to involve the inner ear structures, the semicircular canals and cochlea where they impair balance and hearing.
• Involvement of the acoustic nerve and facial nerve can cause deafness and facial weakness.
• These tumours do not metastasise but they are locally aggressive and may require surgery. Early surgery may preserve hearing.

Other lesions

Just because a lesion occurs in a patient with a disease does not mean that the disease is the cause. Once reports enter "the literature" it is difficult to expunge them, even if they turn out later to be unrelated to the disease. Some of the better documented other lesions include omental cysts, skeletal haemangiomas, ovarian cysts and angiomas, medullary and papillary carcinoma of the thyroid, pituitary adenoma, dermal haemangiomas and pigmented naevi.

With a condition that affects so many systems, it is essential that one person coordinates the management of the patient and perhaps holds the database for the whole family. The best person to do so is probably a clinical geneticist.

Genetic testing

The VHL gene mutation can be identified in some cases. Family members can be screened by direct mutation testing, if the mutation is identified, and by DNA linkage analysis, if feasible.⁴ However, in some cases, a negative genetic test does not completely exclude VHL disease because genetic recombination is possible. If VHL cannot be excluded then periodic screening for clinical disease is necessary.⁸

Screening requirements for patients and at-risk relatives^7,9

General points

• If a genetic test cannot exclude VHL, then there should be imaging and ophthalmologic testing, which must be continued at least to age 60.
• For patients known to carry the VHL gene, or for patients at risk, a number of screening regimens involving clinical, laboratory, imaging and ophthalmoscopic tests have been proposed. There is a need for periodic testing throughout most, if not all, of the patient's life.
• Any new symptoms should be investigated immediately without waiting for the next scheduled testing.
• An example of a screening protocol is the Cambridge routine (below). There are different protocols from other centres.^8,10

Renal cell carcinoma and cerebellar haemangioblastomas are the most common causes of death. Mean age of death has been reported as 41 or 49 years.^3,11 However, the outlook for renal cell carcinoma has improved with nephron sparing treatment.⁴

The most significant complications of VHL are CNS haemangioblastomas and complications of their treatment, and renal cell carcinoma.

The risk of malignancy rises with age.¹¹ Screening of elderly people with the gene will find some manifestation of the disease in nearly all.

The syndrome is named after Eugen von Hippel, who described the retinal tumours (1904), and Arvid Lindau, who described their association with other tumours (1926).