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 hemangioma is one of the most common and often the earliest manifestations of VHL disease1 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,2 and it is estimated that there are approximately 7,000 patients with VHL disease in the United States.3
OPHTHALMIC MANIFESTATIONS
AND NATURAL HISTORY
The main ophthalmic finding in VHL is
retinal capillary hemangioma, which is a
benign hamartoma. The anterior segment is
only rarely secondarily involved due to complications
such as neovascular glaucoma and
cataract formation.4 A large cohort study
found only 2% of eyes had neovascularization of the iris.5
RETINAL FINDINGS
Retinal capillary hemangiomas are usually orangered,
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, exophytic, or sessile. The
endophytic form protrudes from the optic disc and
adjacent retina into the vitreous, while the exophytic
form presents as a nodular orange lesion that grows in
the outer layers of the retina and might stimulate
chronic optic disc edema. The sessile variant is subtle
and might be difficult to diagnose.4,6 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 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 exudate. 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.5
EPIDEMIOLOGY AND
NATURAL COURSE
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 hemangiomas
in VHL disease is
approximately 25 years, and
most patients present between
the ages of 10 and 40 years.6
The probability of developing a
retinal capillary hemangioma
increases progressively with
age. Recent publications indicate
that the hemangioma is
usually manifest 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
remainder of their lives.4
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, glaucoma and phthisis.6 Classification systems to aid in staging the clinical progression have been developed.7,8
DIFFERENTIAL DIAGNOSIS
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, as peripheral
capillary hemangiomas might be overlooked.6 The
vascular abnormality, however, in Coats disease is diffuse
rather then localized. Wyburn-Mason disease
(congenital retinal arteriovenous malformation, racemose
hemangioma) is characterized by dilation and
tortuosity of retinal arteries and veins; however, these
vessels do not have an intervening hemangioma, and
they do not leak or cause exudation. In retinal cavernous
hemangioma there is a cluster of small vascular
dilations around a central vein, but there are no prominent
feeder vessels or exudation.4
Vasoproliferative tumors of the retina are benign, vascular, pink-to-yellow lesions, occurring in healthy patients between ages 40 and 60 years.9 They are often associated with exudation and intraretinal hemorrhages as retinal capillary hemangiomas but lack feeder vessels or stellate macular exudates. They are found in the extreme inferior retinal quadrants, while retinal capillary hemangiomas are mostly evident in the midperipheral temporal retina. Approximately one-quarter of these lesions are secondary to retinitis pigmentosa, uveitis, or long-standing retinal detachment.10
Juxtapapillary retinal capillary hemangioma can stimulate unilateral disc edema, juxtapapillary choroiditis, choroidal neovascularization, choroidal hemangioma, and amelanotic choroidal melanoma.6
DIAGNOSTIC METHODS
Indirect ophthalmoscopy, fundus photography, and
fluorescein angiography are the most informative diagnostic
tools. Fluorescein hyperfluorescence is evident in
the arterial phase in the dilated feeder arteriole; the
tumor displays fine capillary homogeneous filling, and
the draining vein becomes prominent in the venous phase. The tumor demonstrates progressive hyperfluorescence
with late leakage of dye into the surrounding
structures and vitreous. Fluorescein angiography is
helpful in establishing the diagnosis for juxtapapillary
retinal capillary hemangioma and may detect occult
lesions. Photography with angiography is used as an
adjunct to treatment planning; differentiating the
feeder arteriole from the draining vein and can help
assess the therapeutic response.6 Indocyanine green
can help differentiate choroidal lesions,10 while ultrasonography
(US) can help measure the tumor thickness.
The A-scan demonstrates high internal reflectivity,
and B-scan shows a well-demarcated retinal lesion
without choroidal invasion. Magnetic resonance imaging
or computed axial tomography should be employed
to detect synchronous central nervous system and
visceral tumors.4
TREATMENT
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 loss of visual acuity to
less than 20/40 in one or both eyes. Various treatment
modalities, including observation, cryotherapy, plaque
radiotherapy, and vitreoretinal surgery, have been utilized.
4 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 in the context of 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.11
OBSERVATION AS TREATMENT
Observation is rarely employed due to the tendency
of retinal capillary hemangiomas to progress. Observation
only might be chosen in small (<500 µm) nasal
hemangiomas lacking exudation that do not threaten
vision, and in hemangiomas that have undergone spontaneous
regression with gliosis, sheathing and lack of
feeder vessels.
Juxtapapillary hemangiomas are initially managed with observation, because they can remain stable for years. 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 vessels.4,6
LASER PHOTOCOAGULATION
Laser photocoagulation is currently used to treat
small retinal capillary hemangiomas located in the posterior
retina in eyes with clear media. When possible, we
first occlude the feeder artery, then (if necessary) treat
the tumor's surface. A response rate of 91% to 100% has
been shown with direct tumor treatment. Multiple
treatment sessions might be required. Complications,
such as transient retinal detachment or retinal and vitreal
hemorrhages, are uncommon.
CRYOTHERAPY
Indications for cryotherapy are anterior location of
the hemangioma and subretinal fluid, which can reduce
the laser energy uptake and diameter greater than
3 mm (up to 4.5 mm). Double freeze-thaw technique is
employed under indirect ophthalmoscopy.4,6 A 15-year
review found that all hemangiomas under 3.75 mm in
diameter successfully responded to cryotherapy.12
ANTI-VEGF STRATEGIES
Recent studies have indicated that anti-VEGF strategies
can be effective in the treatment of tumors associated
with loss of VHL function, especially renal cell carcinoma.
For retinal capillary hemangiomas, recent case
reports involving anti-VEGF agents, delivered systemically
or via intravitreal injection, show conflicting
results.13 SU5416, a systemic intravenously administered
inhibitor of VEGF-receptor-2, was studied in a case
series of six patients. Of these, only two were reported
to achieve stability or improvement in retinal lesions.14
A prospective study of intravitreal pegaptanib, an
aptamer that inhibits VEGF isoform 165, found that
pegaptanib did not have an effect on lesion regression
but can minimally decrease exudation in some cases.15
Recently, a prospective study regarding five patients
with retinal capillary hemangiomas related to von
Hippel-Lindau disease using monthly injections of
ranibizumab also did not show broadly positive
anatomical or functional results.13
Other therapy modalities described for retinal capillary hemangiomas include transpupillary thermotherapy (TTT), photodynamic therapy, proton beam radiation, plaque radiotherapy, and, finally, pars plana vitrectomy and enucleation for complex complications.4
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.4
The diagnosis of VHL disease is based on three elements, which include retinal capillary hemangioma or CNS hemangioma, visceral lesions, and a family history of similar lesions.4,6 After diagnosis is made, screening protocols should be followed, including urinary catecholamines and ophthalmoscopy on a periodic basis with MRI of the brain and spinal cord at least every 2 years, and yearly abdominal US with an additional abdominal CT scan every 2 to 3 years.4
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 tumorigenesis
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.6
Mutations in the VHL gene result in stabilization of the
HIFs, which bind to specific enhancer elements in the VEGF
gene and stimulate angiogenesis.16 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.11
SUMMARY
VHL disease is an autosomal dominantly inherited multisystem
cancer syndrome with a predilection for the CNS
and the retina. Retinal capillary hemangioma is one of the
most common and earliest manifestations of VHL disease.
Fundus findings are usually typical, and the diagnosis can
be made based on ophthalmoscopic examination; however,
fluorescein angiography is an additional and 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.
Hadas Newman, MD, is with the Department of Ophthalmology, Tel-Aviv Sourasky Medical Center in Israel and is on the Sackler Faculty of Medicine at Tel-Aviv University. She is currently a fellow with Dr. Finger sponsored by The Eye Cancer Foundation (http://eyecancerfoundation.net).
Paul T. Finger, MD, is Director of The New York Eye Cancer Center, Clinical Professor of Ophthalmology at New York University School of Medicine, and Director of Ocular Oncology at The New York Eye and Ear Infirmary. He may be reached via e-mail at pfinger@eyecancer.com.
The authors report that they have no financial relationships to disclose.
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