Von Hippel Lindau Disease

By Paul T. Finger, MD

Description

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited multisystem cancer syndrome with a predilection for the central nervous system (CNS) and the retina. Retinal capillary “Vvon Hippel” hemangioma is one of the most common and often the earliest manifestations of VHL disease and, therefore, ophthalmologists are frequently involved in the care of patients with this disease. The incidence of VHL disease is approximately one in 40,000 live births and it is estimated that there are approximately 7,000 patients with VHL disease in the United States.

Symptoms

Ophthalmic Findings:

The main ophthalmic finding in VHL is retinal capillary hemangioma, which is a benign hamartoma. The anterior segment can be secondarily involved due to complications such as neovascular glaucoma and cataract formation. A large cohort study found only 2% of eyes had neovascularization of the iris. If a patient has a solitary retinal capillary hemangioma, they do not necessarily have VHL disease. However, they should undergo genetic testing.

Diagnosis

Retinal capillary hemangiomas are usually orange red, circumscribed, round, vascular tumors supplied by a pair of dilated and tortuous feeder vessels. They are most commonly located in the temporal peripheral retina. Juxtapapillary retinal capillary hemangiomas are less common, representing about 11% to 15% of cases, and their appearance can vary depending on whether the lesion is endophytic (grow from the retina into the vitreous gel of the eye), exophytic (grow beneath the retina), or sessile (flat).

Retinal capillary hemangioma usually manifests as a solitary tumor, but approximately one-third of patients have multiple retinal hemangiomas, and up to half of patients have bilateral involvement.

Secondary effects (from the retinal angioma) leading to visual loss, such as intraretinal and subretinal exudation, are often limited to the vicinity of the hemangioma but can be remote, often producing a macular star of exudates. Glial proliferation can lead to tractional retinal detachment and macular pucker. Retinal or vitreal hemorrhages are rarely observed, occurring in fewer than 3% of cases.

Frequency and Patient Related Findings: 

The frequency of occurrence of retinal capillary hemangiomas in VHL disease has been
reported to vary from 49% to 85%. The mean age at diagnosis of retinal capillary hemangioma in VHL disease is approximately 25 years, and most patients present between the ages of 10 and 40 years. The probability of developing a retinal capillary hemangiomas increases progressively with age. Recent publications indicate that the hemangioma is usually manifested by age 30, and the prevalence rate is stable thereafter. Therefore adults with a normal retina at age 30 years may have a low risk of developing a retinal capillary hemangioma during the reminder of their lives. The natural course of retinal capillary hemangiomas is variable (progression, stability or spontaneous regression). Small lesions may remain stable for years or may show evidence of gliosis without leakage, but some have been documented to enlarge. Most hemangiomas, however, tend to enlarge progressively and lead to retinal changes. In late stages they may cause massive exudation and retinal detachment, uveitis (inflammation), glaucoma and phthisis (shrinking of the eye). Classification systems to aid in staging the clinical progression have been developed.

Other Tumors That May Look Like Von Hippel Angiomas: 

The fundus findings of retinal capillary hemangioma are usually typical, and diagnosis can be made based on ophthalmoscopic examination. The diagnosis might be confused with retinal macroaneurysm or adult Coats disease when severe exudation exists.

Treatments

For treatment of Von Hippel retinal angiomas, see Conditions (Von Hippel Angioma) However, in ths section we will discuss the diagnosis of systemic disease and genetics:

The systemic manifestations of VHL are multiple and include CNS hemangiomas of the brain and spinal cord, renal cell carcinomas, renal cysts, pheochromocytomas, pancreatic cysts, islet cell tumors, epididymal cystadenomas, endolymphatic sac tumors of the inner ear, and adnexal papillary cystadenomas of the broad ligament. After retinal capillary hemangioma, the most frequently affected organ systems are the CNS, kidneys and adrenal glands, many of them occurring years after the initial presentation with retinal capillary hemangiomas.

The diagnosis of VHL disease is based on three elements which include: 

  1. retinal capillary hemangioma or CNS hemangioma
  2. visceral lesions
  3. family history of similar lesions

Surveillance: 

After diagnosis is made, screening protocols should be followed, including urinary catecholamines and ophthalmoscopy on an annual basis with MRI of the brain and spinal cord every 2 to 3 years, and yearly abdominal US with an additional abdominal CT scan every 2 to 3 years.

Genetic Testing:

VHL disease is an autosomal dominant disease whose gene is located on chromosome 3p 25-26. The gene functions as a tumor suppressor gene that promotes tumor formation when its function is lost. The normal protein product of the VHL gene forms a complex with other proteins that targets hypoxia inducible factors (HIFs) for degradation. Mutations in the VHL gene result in stabilization of the HIFs, which bind to specific enhancer elements in the VEGF gene and stimulate angiogenesis. With a near-complete penetrance of the disease and only rare instances of mosaicism, genetic testing has been proved helpful in early diagnosis and clinical screening for disease manifestations.

SUMMARY 

VHL disease is an autosomal dominantly inherited multisystem cancer syndrome with a predilection for the central nervous system and the retina. Retinal capillary hemangioma is one of the most common and earliest manifestations of VHL disease. Fundus findings are usually typical, and diagnosis can be made based on ophthalmoscopic examination, but fluorescein angiography is an additional informative diagnostic tool. Various treatment modalities exist, although the mainstays of therapy are laser photocoagulation and cryotherapy. VHL disease, however, is associated with significant mortality secondary to either CNS hemangioma or renal cell carcinoma. Life expectancy of affected individuals can be improved by early detection, genetic testing and systemic treatment. Treatment of this syndrome requires cooperation of physicians from multiple specialists, including those to treat the central nervous system and kidney tumors.

References

  1. Annesly WJ, Leonard BC, Shields JA, Tasman WS. Fifteen year review of treated cases of retinal angiomatosis. Trans Am Acad Ophthalmol Otolaryngol. 1977;83:446-453.
  2. Choyke PL, Glenn GM, Walther et al. The natural history of renal lesions in von Hippel- Lindau disease: a serial CT study in 28 patients. Am J Roentgenol. 1992;159:1229-1234.
  3. Dahr SS, Cusick M, Roudriguez-Coleman H, et al. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina. 2007;27:150-158.
  4. Harris AL. von Hippel-Lindau syndrome. Target for anti-vascular endothelial growth factor (VEGF) receptor therapy. The Oncologist. 2000;5(suppl):32-36.
  5. Madhusudan S, Deplanque G, Braybrooke JP, et al. Antiangiogenic therapy for von Hippel-Lindau disease. JAMA. 2004;291:943-944.
  6. Magee MA, Kroll AJ, Lou PL, Ryan EA. Retinal capillary hemangiomas and von Hippel-Lindau disease. Semin Opthalmol. 2006;21:143-150.
  7. Maher ER, Yates JR, Harries, et al. Clinical features and natural history of von Hippel-Lindau disease. QJM. 1990;77:1151-1163.
  8. Maher ER, Lselius L, Yates JR, Et al. von Hippel-Lindau disease: a genetic study. J Med Genet. 1991;28:443-447.
  9. Shields CL, Shields JA, Barret J, et al. Vasoproliferative tumors of the ocular fundus. Classification and clinical manifestations in 103 patients. Arch Ophthalmol. 1995;113:615-623.
  10. Sigelman J. Retinal diseases. Pathogenesis, laser therapy and surgery. Boston:Little Brown and Company. 1984:316.
  11. Singh AD, Shields CL, Shields JA. von Hippel-Lindau disease. Surv Ophthalmol. 2001;46:117-142.
  12. Vail D. Angiomatosis retinae, eleven years after diathermy coagulation. Am J Ophthalmol. 1958;46:525-534.
  13. Webster AR, Maher ER, Moore AT. Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. Arch Ophthalmol. 1999;117:371-378.
  14. Wong WT, Chew EY. Ocular von Hippel-Lindau disease: clinical update and emerging treatments. Curr Opin Ophthalmol. 2008;19:213-217.
  15. Wong WT, Liang KJ, Hammel K, Coleman HR, Chew EY. Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology. 2008;115:1957-1964.

Von Hippel Angioma

By Paul T. Finger, MD

Description

von_h
von Hippel angioma

Von Hippel angioma can grow within the retina or optic nerve. They characteristically have a “feeding” retinal arteriole and a “draining” retinal vein. Bilateral involvement can be seen in up to 50% of individuals.

Von Hippel angioma are vascular tumors, not cancers and do not metastasize. Twenty percent of patients will be found to have the von Hippel Lindau Syndrome–associated with cerebellar hemangioma, pheochromocytomas, visceral cysts and renal cell carcinomas.

Symptoms

Von Hippel angioma patients either have no symptoms, or become symptomatic due to secondary retinal detachment or rarely neovascular glaucoma. The symptoms of retinal detachment are flashes of light, spots in the vision (floaters), and loss of vision. The symptoms of neovascular glaucoma are eye pain, light sensitivity, vision loss, and headache.

Diagnosis

Some patients with von Hippel angioma will have a family history of this disease. Von Hippel angioma are usually visible by dilated eye examination (ophthalmoscopy). Ultrasound can be used to measure the tumor’s size, and to evaluate for high internal reflectivity. Ophthalmoscopy typically reveals a dilated feeder artery and draining vein. An associated retinal detachment may be seen around the tumor or may be so large as to cover (obscure) an underlying von Hippel angioma.

von_h_2
Fluorescein Angiography – Note the feeder and draining vessels, as well as the bright “light-bulb” appearance.

Fluorescein Angiography: Eye-care specialists perform studies of the blood vessels in the eye with a synthetic organic dye called fluorescein. The dye is injected into the arm and travels to the blood vessels inside the eye. If a tumor is in the eye, we can see specific characteristics of its circulation which can help us differentiate between it and other types of tumors. Von Hippel angiomas have a unique pattern of circulation with a feeder arteriole and a draining vein. Since the tumor extends  from the retina into the eye (vitreous humor), von Hippel angiomas exhibit intense hyperfluorescence, often compared to a “light-bulb.”

Treatments

Von Hippel angiomas can appear in both an autosomal dominant hereditary or sporadic forms. All patients should be given periodic systemic examinations including imaging studies for cerebellar hemangiomas and renal cell carcinoma. Family members should be examined with indirect ophthalmoscopy. Genetic testing is available (see related links below).

The treatment of retinal capillary hemangiomas can be a challenge to the ophthalmologist due to the presence of bilateral multiple tumors and the likelihood of new tumor formation. Despite treatment, up to 25% of cases can have permanent visual loss of acuity less to than 20/40 in one or both eyes. Various treatment modalities including observation, cryotherapy, plaque radiotherapy, and vitreoretinal surgery have been utilized.

Recent advances in the understanding of VHL protein function and tumorigenesis have led to new treatments targeting the biology of the disease, as opposed to ablative or surgical approaches. Molecules upregulated or increased in the context of a VHL mutation, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), have been targeted in investigational anti-angiogenic therapies, both in systemic manifestations of the disease and in ocular disease.

OBSERVATION AS TREATMENT


Observation is rarely employed due to the tendency of retinal capillary hemangiomas to progress. However, observation only might be chosen in small (Juxtapapillary hemangiomas (those next to the optic nerve disc) are particularly difficult to treat and are initially managed with observation because they can remain stable for years. As a general rule; since these tumors are not cancer and cannot metastasize; treatment should only be undertaken in case of tumor progression or a threat to visual acuity due to the adverse effect of treatment on the optic nerve and major blood vessels.

LASER PHOTOCOAGULATION

Laser photocoagulation is currently used to treat small retinal capillary hemangiomas located in the retina in eyes with clear media. When possible, we first occlude the feeder artery, then (if necessary) to surround/demarcate the posterior 180 degrees of the tumor, lastly and again if needed directly treat the tumor’s surface. Patients should be informed that multiple laser treatment sessions are typically required. Potential complications include retinal detachment, retinal and vitreous hemorrhages.

CRYOTHERAPY


Typical indications for cryotherapy are anterior retinal location of the hemangioma and massive subretinal fluid, which can reduce the laser energy uptake. Double freeze-thaw technique is employed under indirect ophthalmoscopic observation. A 15-year review found that most all hemangiomas under 3.75 mm in diameter successfully responded to cryotherapy.

ANTI-VEGF STRATEGIES


Recent studies have indicated that anti-VEGF strategies may be effective. However, no large clinical trials have been reported.

Additional Info

  1. Wong WT, Liang KJ, Hammel K, Coleman HR, Chew EY. Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology. 2008;115:1957-1964.
  2. Annesly WJ, Leonard BC, Shields JA, Tasman WS. Fifteen year review of treated cases of retinal angiomatosis. Trans Am Acad Ophthalmol Otolaryngol. 1977;83:446-453.
  3. Madhusudan S, Deplanque G, Braybrooke JP, et al. Antiangiogenic therapy for von Hippel-Lindau disease. JAMA. 2004;291:943-944.

Patient Stories

"Very well treated by Dr. Finger. He explained everything I needed to know about my issue with detail and attention, putting me at ease and giving me confidence to handle this problem for the rest of my life.”
N.N.

Read More

REQUEST AN APPOINTMENT

  • This field is for validation purposes and should be left unchanged.

CONNECT AND SHARE