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Von Hippel-Lindau disease

Definition

Von Hippel-Lindau disease (VHL) is a rare (1/36,000 live births) dominantly inherited cancer syndrome caused by a tumor suppressor gene defect predisposing to multiple hemangioblastomas (HB) of the CNS and retina, renal cell carcinomas (RCC), pheochromocytomas, pancreatic islet cell tumors and cysts in the kidneys and pancreas. Also, several other less common lesions have been described, such as epididymal cystadenomas, and endolymphatic sac tumors. Diagnosis of VHL is based on VHL gene mutation analysis and/or clinical manifestations over long-term follow-up. A patient with HB of the CNS or retina is classified as having VHL if the patient has a germline mutation, family history of VHL, or other VHL-related neoplasms (HBs of the CNS or retina, RCC, pheochromocytoma).

Historical Aspects

In 1911, Eugen von Hippel, a German ophthalmologist, defined retinal HBs as a cystic capillary angiomatosis of congenital origin. In 1926-1927, Arvid Lindau a Swedish pathologist, disclosed the relationship between HBs of the CNS and retina and visceral lesions. In 1992, Hans Grossniklaus showed that HBs of the retina are histologically identical to their counterparts in the CNS. In 1993, Farida Latif identified the VHL tumor suppressor gene, which together with modern imaging of the CNS and abdomen, have improved the diagnosis of VHL also in asymptomatic carriers.

Genetics of VHL

VHL is caused by a defect in the VHL tumor suppressor gene in chromosome 3p25-p26. The function of the VHL gene is not fully understood, but loss of the gene product (pVHL) appears to have multiple functions, but in particular, regulates the activity of hypoxia inducible factors (HIF). In the absence of pVHL, HIFs appear to be constitutively active leading to increased expression of several target genes including vascular endothelial growth factor (VEGF). VEGF is a small peptide growth factor that binds to cell surface tyrosine kinase receptors (VEGFR1&2) on endothelial cells promoting their growth and migration. VEGF and its receptors are highly expressed by HBs and appear to play a prominent role in the growth of these tumors.

VHL is an autosomal dominant trait with a high penetrance, as almost 100 % of the carriers of a VHL gene defect will develop clinical manifestations by the age of 60 years. Their children have a 50% risk of getting the disease. Half of the VHL cases are familial and half are caused by new mutations, estimated to occur at 4.4x106 gametes per generation. Several mutations have been described, and a VHL gene mutation database has been established. Mutations are heterogeneous in type and position, and VHL shows intra- and interfamilial differences in phenotype.

Hemangioblastomas of the CNS

The hemangioblastoma (HB) is a highly vascular, benign and well-circumscribed, slowly growing solid or cystic neoplasm of the CNS and retina composed of stromal cells, endothelial cells, pericytes, and mast cells. The origin of the stromal cells, believed to be the true neoplastic cells of HB tissue, is still undefined. HB may cause polycytemia by secreting erythropoietin from stromal or mast cells. HB of the CNS is one of the manifestations of von Hippel-Lindau disease (VHL) (see below), but is regarded to be sporadic in approximately 80% of the cases, and then it is typically a single, cystic lesion of the cerebellum, brain stem or upper cervical medulla, presenting at the average age of somewhat over 40 years. Supratentorial HBs are rare. Microsurgery is still the treatment of choice aided, if necessary, by preoperative embolization to reduce vascularity. The intraoperative MRI scanner at BWH is utilized in collaboration with the Surgical Planning Lab to provide detailed real-time imaging information for surgical guidance. It allows accurate localization and targeting as well as confirmation of the extent of resection of the tumors. Stereotactic radiotherapy may be considered in multiple small solid HBs in VHL. Internal organ cysts in the HB patients do not necessarily indicate VHL as they are common in other wise healthy subjects increasing in incidence with age.

Hemangioblastomas of the retina

The retina consists of 10 layers and contains blood vessels in its inner layers. After photoreception by the rods and cones, the bipolar cells in the inner nuclear layer transmit their signals to the ganglion cells, the axons of which form the optic nerve. The central area of the retina (macula lutea) has the highest visual acuity in its cone-rich center, i.e. the fovea (diameter 150 m-6). HB of the retina originates from the inner, mid-peripheral retina, and is histologically identical to HB of the CNS. Mature HBs resembling 'sugar-powdered' raspberries and the adjoining dilated, tortuous arterioles and venules (feeder vessels) are distinctive enough to permit visual diagnosis after pupillary dilatation with indirect ophthalmoscopy, Goldmann 3-mirror contact lens or non-contact lens fundus examination. Incipient HBs are small, reddish or grayish dots, without abnormal adjoining vessels. In retinal HBs, fluorescein angiography (FA) shows an arteriovenous shunt with leakage of dye due to incompetent capillary walls.

HBs of the retina can be asymptomatic for years, and may even regress spontaneously. Usually, however, symptoms such as flashing and floaters occur and there is progressive visual impairment due to leakage from the incompetent capillary walls of HBs. This leads to secondary changes in the vitreous and retina such as premature posterior vitreous detachment, retinal break, vitreous hemorrhage, lipid exudates and edema in the macula, or preretinal fibrosis. In advanced cases, total retinal detachment may occur either due to accumulation of fluid between the photoreceptor layer and the retinal pigment epithelium causes by excessive leakage from large HBs, vitreous traction causes by vitreous strands and epiretinal membranes and/or retinal breaks. Early lesions are often easy to eradicate, and they carry the lowest risk of complications. Therefore, retinal HBs should usually be treated even when small and asymptomatic with laser or cryocoagulation for a better prognosis of vision. About one third to one half of patients with retinal HB(s) have VHL. Internal organ cysts in patients with retinal HBs do not necessarily indicate VHL. The appearance of retinal HB(s) do not differ between VHL and non-VHL

Manifestations of VHL

Multiple HBs of the CNS are a typical manifestation of VHL. HBs of the CNS occur about 10 years earlier than their sporadic counterparts, at the average age of about 30 years. Of the patients with HBs of the CNS, approximately 20% have VHL. In VHL, as compared to sporadic cases, HBs of the CNS are more often located in the brainstem and spinal cord. Analogous to cerebellar HBs that often produce cysts, spinal cord HBs may induce syringomyelia. When symptomatic, HBs of the CNS cause disruption of neurological functions, or symptoms due to raised intracranial pressure, often caused by the adjoining cyst. Magnetic resonance imaging (MRI) enables the detection of even incipient asymptomatic HBs of the CNS in VHL.

A 21- year-old VHL patient with multiple HBs of the CNS.

a. MRI.
b. Superselective angiography showing one in the cervical
spinal cord.
c. The same lesion after preoperative embolization.

Retinal HB is the first manifestation in about half of the VHL patients, and is usually bilateral and multifocal, or becomes so over the years. The mean age at presentation is 25 years and the estimated cumulative probability to develop retinal HBs exceeds 70% by the age of 60 years. There is no general influence of germline mutation in the severity of retinal HBs.VHL occurs in only 2% of RCC patients, whereas in VHL patients RCC develops in up to 45% of the patients. Compared to sporadic RCC, in VHL patients RCC is characterized by appearing 25 years earlier (i.e. at the average age of 35 years), an association with renal cysts, multifocal and bilateral tumors, and low grade histology. The incidence of metastatic disease for VHL patients with RCC has been reported to be 20%. The distribution of metastases is similar to that of sporadic cases of RCC including liver, lung and bones. Abdominal computed tomography (CT) with contrast, using 5-mm contiguous sections represents preferable radiographic assessment of the kidney. CT helps in differentiating simple cysts (smooth borders and a homogeneous attenuation similar to water) and complex cysts (mostly cystic but containing some solid elements) from solid masses (attenuation higher than water and enhanced with contrast). Renal ultrasonography (US) is a useful screening method, but does not offer comparable anatomic detail. For patients with advanced renal insufficiency or contrast allergy, MRI before and after gadolinium yields equivalent results to CT. Renal arteriography is important for surgical planning when a partial nephrectomy is anticipated. Earlier, nephrectomies were often performed, but lately nephron-sparing surgery (lesionectomy or partial nephrectomy), whenever possible, has been recommended as primary treatment. The prognosis of RCC is better in VHL patients than in sporadic ones, and metastases are claimed to appear in VHL less frequently than in sporatic non-familial cases. Single tumors should be excised when their diameter exceeds 3 cm. In smaller tumors laparoscopic cryotherapy or radiofrequency ablation may be considered.

Pheochromocytomas are catecholamine-producing tumors of the adrenal medulla occurring in 20-35% of VHL patients at the median age of 30 years. About 20% of all pheochromocytomas are related to VHL. In VHL, these tumors tend to be bilateral and multiple, but they are rarely malignant. Pheochromocytomas can be located within or outside the adrenals. Presenting symptoms are palpitations, headache, sweating attacks and hypertension. The diagnosis is based on imaging of the adrenals by US, CT or MRI, and supported by measurement of plasma and urine catecholamines. In extra adrenal lesions, scintigraphy with 123I or 131I-labeled metaiodobezylguanetidine is usually diagnostic. Symptomatic tumors should be enucleated rather than treated by adrenalectomy.

Pancreatic islet cell tumors (can be malignant) and cystadenomas occur in VHL. Therefore, VHL patients should be followed regularly with abdominal CT or MRI scans to detect asymptomatic lesions so that they could be operated before the appearance of islet cell tumor metastases.

VHL predisposes to cysts in the kidneys, pancreas and liver. These cysts tend to be multiple, e.g. in the kidneys bilateral and slowly growing, and they require follow-up because of the possible adjoining malignancy. Renal cysts are usually asymptomatic and do not require treatment as such. In polycystic kidney disease, another autosomal dominant disease, the number of cysts usually exceeds that detected in VHL, and there are no adjoining malignancies. VHL patients with large pancreatic cysts may have mild discomfort, but bile duct obstruction, pancreatitis, and hormonal insufficiency requiring surgical intervention are rarely reported.

Prognosis of VHL

The mean age at death in VHL is 40 to 50 years. RCC had exceeded HBs of the CNS as the primary cause of death (50 and 30%, respectively) due to advances in the microsurgery of HBs of the CNS.

The children of a patient with a VHL gene defect have a 50% risk of getting the disease, and they should be offered the possibility of predictive germline mutation testing to avoid laborious and expensive long-term clinical screening. Furthermore, it has been shown that patients with mutations causing truncation or deletion of the VHL protein developed more often multiple HBs of the CNS and had more often multiple operations than patients with mutations predicted to produce a full length VHL protein. This suggests that truncating mutations induce a more severe disease and thereby might influence the clinical management. Early detection of incidental HB(s) of the CNS may be more favorable at least in terms of radiosurgery. When retinal HBs are small and asymptomatic they are easier to treat with laser or cryocoagulation, and the prognosis of vision is better. Early detection probably ensures also a better prognosis of RCC. Genetic counseling should be offered to all VHL patients, and annual life-long follow-up should be arranged conjointly by an ophthalmologist, a neurosurgeon, and a urologist. Retinal screening of children at risk should start as soon as co-operation permits the detection of even incipient HBs.

Treatment of VHL Manifestions

Hemangioblastomas of the CNS

In VHL, microsurgical treatment of multiple HBs often fails in the long run. Removed tumors tend to recur and new ones develop; some are symptomatic and others incidental. It is often difficult to decide which tumors should be removed, and operative risks should be weighed against the natural course. Furthermore, in VHL, more often than in sporadic cases, HBs are located in the brainstem and spinal cord increasing the risk of morbidity and mortality related to microsurgery of these lesions. The operative mortality for a cerebellar cystic tumor is less than 2%, but it increases considerably for a large solid lesion intrinsic to the caudal brainstem. Stereotactic radiotherapy may be considered in multiple small solid HBs in VHL. Stereotactic radiotherapy may offer a safer means to treat HBs in eloquent brain areas, but overlapping fields in patients with multiple HBs may pose a problem of radiation injury to the adjacent brain.

Hemangioblastomas of the retina

In VHL, the appearance of new and multiple HBs of the retina typically threaten vision. All retinal HBs, even small and asymptomatic, should usually be treated with laser (< 1mm in diameter) or cryocoagulation to prevent loss of vision. However, in papillary or macular HBs, coagulation may cause a central visual field defect, and treatment is often not advised until exudation develops. The feeder vessels and exudates do not require direct treatment, their presence is secondary to the HB, and the treatment of feeders may cause hemorrhage.

Late recurrences may develop mainly due to incomplete primary destruction of the HB, but in VHL new tumors may be mistaken for recurrences. Retinal detachment without vitreous traction may be treated by scleral encircling procedures. Macular preretinal fibrosis, vitreous hemorrhage or retinal detachment threatening the macula may necessitate vitreoretinal surgery which has improved the prognosis of vision in eyes with large HBs. Neovascular glaucoma following total retinal detachment is a late complications of the disease. Enucleation may become mandatory in the case of a blind and painful eye.

Renal cell carcinoma

VHL patients tend to develop multiple bilateral RCCs threatening renal function and life. The decision to proceed with nephron-sparing surgery or radical nephrectomy depends on the extent of the disease. Nephron-sparing surgery may be effective for patients with localized RCC, but most will have local recurrences. There are also patients in whom nephron-sparing surgery is not feasible and bilateral nephrectomy has to be performed, and at this stage, management options include dialysis or renal transplantation.

Upper abdominal CT in a 64-year-old VHL patient, the right kidney has been removed because of RCC 10 years earlier.

a. RCC.

b. Cysts in the left kidney.

Novel treatment methods

Stereotactic radiotherapy

Stereotactic radiotherapy (SR) is a non-invasive and well-tolerated means to shrink or control well-delineated intracranial neoplasms and to occlude AVMs. For single session treatment (‘radiosurgery’) the targets should be small (< 30 mm) because of a dose-volume-dependent risk of delayed radiation injury, but fractionation using a relocatable head frame allows larger volumes.

HBs should be ideal targets for RS because they are usually small, rounded, well-delineated and highly vascular, and in VHL patients they are often multiple. They receive an intense arterial supply from the adjacent brain tissue, and one might expect obliteration of these feeding vessels. It has been shown that a solitary small or medium-sized HB usually shrinks or stops growing after radiosurgery, and a margin dose of 10 to 15 Gy is sufficient. The adjoining cyst often does not respond to the radiosurgery of the solid part, but requires later evacuation, even repeatedly. Therefore, it is mandatory to follow-up radiosurgically treated HBs regularly by CT or preferably MRI.

Angiogenesis and antiangiogenic treatment

Angiogenesis is fundamental to reproduction, development and repair. Pathological angiogenesis with unabated blood vessel growth sustains progression of many neoplastic and non-neoplastic diseases. Antiangiogenic tumor therapy is targeted at small foci of migrating and proliferating endothelial cells in capillaries at sites of angiogenesis, an attempt to inhibit tumor growth.

Future Trends

More potent antiangiogenic drugs such as angiostatin and endostatin derivatives may offer means to prevent the appearance of new lesions or to shrink or stabilize established ones. These drugs may be successfully combined with radiotherapy, chemotherapy or immunotherapy.

In VHL, HBs of the CNS and retina could be ideal targets for systemic antiangiogenic therapy because they are highly vascular, often multiple, and located in eloquent brain areas with increased microsurgical and radiosurgical risks, and VEGF may have a role in their pathogenesis.

Early in 2002 a phase II clinical trial will begin on a novel anti-angiogenic small molecule with DFCI and Novartis.