Carol L. Shields

BASICS

DESCRIPTION

• Retinal vascular tumors are uncommon and diverse hamartomas or malformations of the neurosensory retina.

• They may have systemic associations involving the central nervous system (CNS) and other organs that may be life-threatening.

• They may be familial or sporadic.

• Types (and synonyms):

– Retinal hemangioblastoma (RHB, capillary hemangioma, angiomatosis retinae)

– Retinal cavernous hemangioma (RCH)

– Retinal racemose hemangioma (RRH, congenital arteriovenous anastomoses, cirsoid aneurysm, arteriovenous aneurysms)

– Retinal vasoproliferative tumor (VPT; see the chapter on this topic)

Pediatric Considerations

Genetic testing and systemic work-up is advised for affected patients.

Pregnancy Considerations

Genetic counseling is recommended for affected pregnant women

EPIDEMIOLOGY

Incidence

• RHB: Incidence is unknown; however, its associated syndrome, von Hippel–Lindau’s disease (VHL), occurs in 1 in 40,000 live births.

• In a report by Singh, Shields, and Shields, a solitary RHB in a young patient (≤10 years) is associated with 45% risk for VHL compared to 0.5% when diagnosed in older patients (61–70 years) (see “Additional reading” below).

• RCH: Incidence of RCH is unknown.

• RRH: Incidence of RRH is unknown.

Prevalence

• RHB: Prevalence unknown

• RCH: Prevalence unknown

• RRH: Prevalence unknown

• No definite racial or gender predilections for any retinal vascular tumor

RISK FACTORS

None

Genetics

• RHB: Currently accepted mechanism follows Knudson’s two-hit hypothesis affecting the VHL gene (chromosome 3p25–26)

• RCH: Two-hit mechanism in the cerebral cavernous malformation (CCM) gene on chromosome 7q11.2–q21

• RRH: No genetic mutation

GENERAL PREVENTION

None

PATHOPHYSIOLOGY

• RHB: VHL gene is a tumor suppressor gene that controls proliferation of blood vessels and mutation causes elevation of hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) with formation of hemangioblastomas in the brain and retina.

• RCH: Mutation in the CCM gene leads to loss or decreased expression of CCM protein and malformation of endothelial cells in utero.

• RRH: Characterized by congenital arteriovenous malformations (AVMs) without capillary interposition producing turbulent blood flow and dilation of blood vessels.

ETIOLOGY

• RHB: Sporadic or germline mutation in the VHL gene leads to formation of hemangioblastomas.

• RCH: Sporadic or germline mutation in the CCM gene leads to cavernous malformations.

• RRH: It is presumably caused by a local defect in maturation of retinal mesenchyme that gives rise to vascular tissue at the 7th week of gestation.

COMMONLY ASSOCIATED CONDITIONS

• RHB: VHL disease

– Autosomal dominant inheritance

– Associated with RHB (57%), cerebellar hemangioma (55%), spinal cord hemangioma (14%), renal cell carcinoma (24%), and pheochromocytoma (19%)

• RCH: Familial cavernous malformation (FCM)

– Autosomal dominant inheritance

– Cavernous malformations in the brain, skin, and retina (RCH)

• RRH: Congenital retinocephalic (CRC) vascular malformation syndrome (Wyburn–Mason or Bonnet–Dechaume–Blanc syndrome)

– Unilateral, progressive, and nonhereditary

– AVMs involving the skin, brain, and retina (RRH)

DIAGNOSIS

HISTORY

• RHB: Asymptomatic early but may cause severe pain and blindness from neovascular glaucoma when advanced

• RCH: Mostly asymptomatic and are detected only during routine examination

• RRH: Presents as a unilateral blind eye in 48% when associated with CRC but are mostly asymptomatic when isolated

• Family history is extremely important, especially in cases of RHB and RCH, to rule out familial disease or germline mutation.

PHYSICAL EXAM

• Retinal hemangioblastoma (RHB):

– Orange-red circumscribed retinal lesion typically with dilated feeder vessels

– Peripheral (85%) or juxtapapillary (15%)

– May be associated with localized or remote retinal exudation, retinal detachment, glial proliferation with traction detachment, macular pucker, twin vessels, or neovascular glaucoma

• Retinal cavernous hemangioma (RCH)

– Dark-red, grapelike, saccular aneurysms

– May occur in the retina or optic disc

– May be associated with overlying fibrosis with macular traction, vitreous hemorrhage, and vascular occlusion

– Not associated with leakage and exudation

• Retinal racemose hemangioma (RRH)

– Dilated arteriovenous communications without capillary interposition

– Extensive retinal involvement in cases with systemic associations and localized or sectorial involvement when isolated

– Rarely located in the macula

– May be associated with neovascular glaucoma, vitreous hemorrhage, vascular occlusion, and conjunctival injection

– Not associated with leakage and exudation

– Pulsating exophthalmos or visual field defects when AVMs are present in the orbit or visual pathway, respectively

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

Genetic testing to rule out systemic disease

Follow-up & special considerations

• Genetic counseling is recommended when germline mutations are found.

• Patients with systemic associations should be promptly referred to a pediatric oncologist, oncologist, neurologist, or neurosurgeon.

Imaging

Initial approach

• Fluorescein angiography (FA) is most helpful:

– RHB (peripheral): Rapid filling of dilated feeder arteriole in arterial phase, intrinsic fine capillaries, with prominent draining vein and leakage on later films

– RHB (juxtapapillary): Diagnosis is established by the fine vascular pattern visualized on the angiogram

– RCH: Slow filling of the aneurysms with hyperfluorescent caps superiorly and hypofluorescence inferiorly due to settling of red blood cells under the supernatant plasma, typically without leakage of dye

– RRH: Rapid filling of high-flow retinal AVMs with adjacent capillary dropout

Follow-up & special considerations

• Asymptomatic patients with exudates or retinal detachment threatening vision should be followed closely and offered treatment.

• Early treatment is needed for symptomatic patients.

• Frequency of follow-up is determined by severity of the condition and degree of visual impairment.

Diagnostic Procedures/Other

• MRI, MRA, CTA, or angiography may be required to rule out associated systemic disease.

Pathological Findings

• RHB: Composed of capillary-sized blood vessels with normal endothelium, vacuolated stromal cells, and gliosis (1)

• RCH: Dilated, thin-walled blood vessels, with interconnections and an intact endothelium (1)

• RRH: Dilated retinal vessels sometimes occupying the entire retinal thickness causing cystic degeneration and attenuation of the adjacent retinal tissue (1)

DIFFERENTIAL DIAGNOSIS

• Choroidal melanoma

• Choroidal granuloma

• Circumscribed choroidal hemangioma

• Retinal macroaneurysm

• Retinoblastoma

• Coats’ disease

TREATMENT

MEDICATION

See “General measures” below.

ADDITIONAL TREATMENT

General Measures

• Retinal hemangioblastoma (RHB):

– May be observed if small or juxtapapillary, if it is not visually threatening, or if the patient is asymptomatic (2)

– Laser photocoagulation or photodynamic therapy preferred for posterior RHB and cryotherapy when more anterior (2)

– Plaque radiotherapy reserved for more advanced RHB (2)

• Retinal cavernous hemangioma (RCH):

– Mostly nonprogressive and do not require treatment (1,4,5)

• Retinal racemose hemangioma (RRH):

– Mostly nonprogressive and do not require treatment (1,6)

Issues for Referral

• Treatment should usually be performed by a retina specialist or an ocular oncologist.

• Patients with positive genetic analyses or imaging tests should be promptly referred to a neurologist, neurosurgeon, or pediatric oncologist.

Additional Therapies

• Retinal surgery is required for persistent vitreous hemorrhage or retinal detachment (1)[C].

• Enucleation may be needed for blind and painful eyes with no potential for vision (1)[C].

• Associated hemorrhage, vascular occlusion, or neovascularization requires appropriate treatment with laser, cryopexy, or retinal surgery (1,4–6)[C].

COMPLEMENTARY & ALTERNATIVE THERAPIES

• RHB: Transpupillary thermotherapy, external or proton beam radiotherapy, and local or systemic anti-VEGF therapy have been used for RHB, but efficacy is inconclusive and role is still uncertain (1–3)[C].

• RCH: There is no proven treatment (1)[C].

• RRH: There is no proven treatment (1)[C].

SURGERY/OTHER PROCEDURES

• RHB: Resection and ligature of feeder vessels has been reported but is technically difficult (2)

• RCH: No surgical reports

• RRH: No surgical reports

IN-PATIENT CONSIDERATIONS

Outpatient management

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Outpatient care for photocoagulation, photodynamic therapy, or cryotherapy

• In-patient or outpatient for plaque radiotherapy, vitrectomy, or enucleation

Patient Monitoring

• 6-month follow-ups are recommended for most patients.

• Follow more closely when vision is threatened.

DIET

No restrictions

PATIENT EDUCATION

• Advice regarding implications of genetic analysis and systemic associations

• Genetic counseling is essential

• Use of the Amsler grid for self-monitoring of visual changes for early diagnosis and treatment

PROGNOSIS

• Retinal hemangioblastoma (RHB):

– 40% of affected eyes have vision <20/200.

– Worse when tumors are larger (> 4 mm), juxtapapillary, or multiple.

– Enucleation may be required in 6% of eyes.

• Retinal cavernous hemangioma (RCH):

– Most patients maintain good vision.

– Progressive growth is rare.

• Retinal racemose hemangioma (RRH):

– NLP in 48% if cerebral AVMs are present

– Vision ≥20/50 in 56% in isolated cases

COMPLICATIONS

Loss of vision or globe, and even death when systemic associations are not detected.

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