Ophthalmology – Retinal Vascular Tumors

Basics

Description

“Retinal vascular tumors” is a traditional umbrella term for several uncommon vascular lesions of the retina.

The major entities include:

• Retinal hemangioblastoma (RHB)
• Retinal cavernous hemangioma/cavernous malformation (RCH)
• Retinal arteriovenous malformation (AVM), historically called racemose hemangioma
• Retinal vasoproliferative tumor (VPT)

A useful modern distinction is that these are not all true neoplasms:

• RHB is a vascular tumor and may be associated with von Hippel-Lindau disease
• RCH is primarily a congenital vascular malformation
• Retinal AVM is a congenital arteriovenous malformation
• VPT is better regarded as a reactive gliovascular proliferation, not a true vascular neoplasm

The major clinical concern is that some lesions may indicate:

Serious hereditary or CNS/systemic disease.

Key Clinical Principle

When a retinal vascular lesion is discovered, determine:

1. What type of lesion is present?
2. Is it visually threatening?
3. Is it associated with systemic or hereditary disease?
4. Does the patient require genetic counseling or systemic imaging?

Retinal Hemangioblastoma

Description

Retinal hemangioblastoma (RHB) is a benign retinal vascular tumor composed of:

• Capillary-sized vessels
• Vacuolated stromal cells

Older names include:

• Retinal capillary hemangioma
• Retinal angioma
• Angiomatosis retinae

The preferred modern term is:

Retinal hemangioblastoma.

Association With von Hippel-Lindau Disease

RHB is one of the major manifestations of:

von Hippel-Lindau (VHL) disease

VHL is an:

Autosomal dominant tumor-predisposition syndrome

caused by pathogenic variants in the:

VHL tumor suppressor gene on chromosome 3p25.3

VHL Pathophysiology

Loss of VHL protein leads to failure of degradation of:

Hypoxia-inducible factors (HIFs)

resulting in increased expression of:

• VEGF
• Erythropoietin
• PDGF
• Other hypoxia-related growth signals

This promotes highly vascular tumors.

Systemic Manifestations of VHL

Important associated lesions include:

• CNS hemangioblastomas
• Clear-cell renal cell carcinoma
• Pheochromocytoma/paraganglioma
• Pancreatic cysts
• Pancreatic neuroendocrine tumors
• Endolymphatic sac tumors
• Epididymal cystadenomas
• Broad-ligament cystadenomas

Because some are life-threatening:

Recognition of a retinal hemangioblastoma may lead to diagnosis of VHL before systemic disease becomes symptomatic.

When to Suspect VHL

The likelihood of germline VHL disease is higher with:

• Young age at diagnosis
• Multiple RHBs
• Bilateral RHBs
• Family history of VHL
• Other VHL-associated tumors

A solitary lesion in an older adult is more likely sporadic, but:

Age alone does not completely exclude VHL.

Genetic Evaluation

Patients with RHB, particularly:

• Children
• Young adults
• Bilateral disease
• Multifocal disease
• Positive family history

should be considered for:

• VHL genetic counseling
• Germline VHL testing

When VHL is confirmed, relatives may also require evaluation.

RHB Clinical Appearance

Classic RHB appears as:

A round or oval orange-red retinal vascular mass

with:

• Dilated feeding arteriole
• Dilated draining vein

The lesion may occur:

• In the peripheral retina
• Juxtapapillary to the optic disc

Peripheral RHB

Peripheral lesions are more common.

Typical features include:

• Red-orange nodular lesion
• Prominent feeder arteriole
• Dilated draining vein
• Lipid exudation
• Retinal edema

Juxtapapillary RHB

Juxtapapillary lesions arise:

• On or immediately adjacent to the optic disc

They are particularly difficult to treat because therapy may damage:

• Optic nerve fibers
• Papillomacular bundle

Therefore observation may be preferred when:

• Vision is good
• Exudation is minimal
• Lesion is stable

RHB Complications

Progressive lesions may cause:

• Macular edema
• Hard exudates
• Subretinal fluid
• Exudative retinal detachment
• Epiretinal membrane
• Retinal traction
• Tractional retinal detachment
• Vitreous hemorrhage
• Neovascular glaucoma in very advanced disease

Remote Macular Exudation

A peripheral RHB can cause:

Macular edema and lipid exudation far from the tumor

because of chronic leakage from the abnormal vascular bed.

Thus visual loss can occur despite a peripheral lesion.

RHB Diagnosis

Diagnosis is usually based on:

• Fundus examination
• Wide-field photography
• Fluorescein angiography
• OCT

Fluorescein Angiography in RHB

FA typically shows:

• Early filling of feeder arteriole
• Rapid filling of tumor capillary network
• Prominent draining vein
• Late intense leakage

FA is very useful for:

• Tumor definition
• Identifying small occult lesions
• Treatment planning

OCT in RHB

OCT is most useful when:

• Lesion is juxtapapillary
• Macula is affected

It may demonstrate:

• Intraretinal edema
• Subretinal fluid
• Hard exudates
• Epiretinal membrane
• Traction

RHB Treatment Principles

The goals are to:

• Destroy or involute the tumor
• Stop exudation
• Preserve the macula
• Prevent retinal detachment

Treatment depends on:

• Tumor size
• Location
• Exudation
• Retinal detachment
• Visual potential

Observation of RHB

Observation may be appropriate for:

• Very small lesions
• Stable lesions
• Selected juxtapapillary tumors
• Lesions without threatening exudation

However, documented growth or increasing leakage favors treatment.

Laser Photocoagulation

Laser photocoagulation is first-line for many small peripheral RHBs.

Laser may be applied to:

• Tumor
• Feeding vessels

Multiple sessions may be required.

Small tumors are considerably easier to control than large ones.

Cryotherapy

Cryotherapy is useful for:

• Larger peripheral lesions
• Very anterior tumors
• Lesions with subretinal fluid that prevents adequate laser uptake

It can induce substantial inflammation and exudation, so treatment is usually staged when necessary.

Photodynamic Therapy

Photodynamic therapy (PDT) may be considered particularly for:

• Juxtapapillary RHB
• Posterior lesions difficult to treat with conventional laser

The goal is selective vascular closure while limiting damage to surrounding retina.

Anti-VEGF Therapy in RHB

Intravitreal anti-VEGF may reduce:

• Macular edema
• Exudation
• Subretinal fluid

However:

Anti-VEGF does not reliably eradicate the hemangioblastoma itself.

It is therefore:

Adjunctive rather than definitive treatment.

Systemic HIF-2α Inhibition

In patients with VHL disease, systemic HIF-2α inhibition with belzutifan may cause regression or reduced activity of some retinal hemangioblastomas.

Its role is primarily within multidisciplinary VHL care and:

Does not replace standard local ocular therapy for every isolated retinal lesion.

Advanced RHB

Severe disease may occasionally require:

• Vitrectomy
• Membrane peeling
• Retinal detachment repair
• Plaque radiotherapy
• Other focal radiotherapy in selected refractory cases

Enucleation is now rarely necessary and is reserved for:

• Blind painful end-stage eyes
• Severe untreatable complications

Retinal Cavernous Hemangioma

Description

Retinal cavernous hemangioma, also termed a retinal cavernous malformation, is a congenital vascular lesion consisting of:

Clusters of thin-walled saccular vascular spaces

It usually behaves benignly.

Clinical Appearance

The classic appearance is:

A cluster of dark-red, grape-like vascular saccules

The lesion may occur in:

• Retina
• Optic disc

Flow Characteristics

Blood flow is:

Very slow

within the vascular spaces.

This produces a characteristic:

Plasma–erythrocyte layering

with red cells settling dependently.

Fluorescein Angiography in RCH

FA shows:

• Slow delayed filling
• Progressive filling of saccules
• Superior plasma fluorescence
• Inferior hypofluorescent erythrocyte layering

Most importantly:

There is little or no fluorescein leakage.

This helps distinguish RCH from:

• Retinal hemangioblastoma
• Coats disease
• Other leaking vascular lesions

Exudation in RCH

Unlike RHB:

Exudation is typically absent.

Therefore:

• Hard exudates are uncommon
• Macular edema is uncommon

RCH Complications

Most lesions remain stable.

Occasional complications include:

• Vitreous hemorrhage
• Epiretinal membrane
• Vitreoretinal traction
• Rare retinal vascular occlusion

Systemic Associations of RCH

Most retinal cavernous hemangiomas are:

Sporadic and isolated

Rare familial cases may occur with:

Cerebral cavernous malformation syndromes

associated with genes including:

• KRIT1 / CCM1
• CCM2
• PDCD10 / CCM3

Systemic imaging or genetic evaluation is most appropriate when there is:

• Family history
• Neurologic symptoms
• Multiple vascular malformations
• Other suggestive lesions

Routine brain imaging is not necessarily required for every isolated typical RCH.

Treatment of RCH

Most retinal cavernous hemangiomas require:

Observation only

because they are usually:

• Stable
• Nonleaking
• Asymptomatic

Treatment is directed at complications rather than the vascular lesion itself.

Vitreous Hemorrhage From RCH

If vitreous hemorrhage occurs:

• Observation may be appropriate if clearing
• Vitrectomy may be required if persistent or recurrent

Routine laser ablation is generally unnecessary.

Retinal Arteriovenous Malformation

Description

Retinal arteriovenous malformation (AVM) is the preferred term for what was historically called:

• Racemose hemangioma
• Arteriovenous aneurysm
• Cirsoid aneurysm

It consists of:

Direct congenital communication between retinal arteries and veins without an intervening normal capillary bed.

Pathophysiology

These lesions develop from abnormal embryologic vascular maturation.

They are:

• Congenital
• Usually unilateral
• Generally nonhereditary

Clinical Appearance

Retinal AVMs appear as:

• Markedly dilated arteries
• Markedly dilated veins
• Direct arteriovenous connections
• Tortuous vascular loops

The distinction between artery and vein may become difficult in extensive lesions.

Archer Classification

Retinal AVMs are sometimes classified into three groups.

Group 1

Small AV communication with:

• Relatively preserved artery/vein distinction

Group 2

More extensive direct AV connections with:

• Enlarged tortuous vessels

Group 3

Massive AV malformation with:

• Extensive retinal involvement
• Marked vascular dilatation
• Greater likelihood of intracranial involvement

Fluorescein Angiography in Retinal AVM

FA typically shows:

• Very rapid arterial-to-venous transit
• Filling of dilated abnormal vessels
• Little or no leakage

Areas of adjacent:

• Capillary nonperfusion

may be present.

Wyburn-Mason Syndrome

Retinal AVM may be associated with:

Wyburn-Mason syndrome

also called:

Bonnet-Dechaume-Blanc syndrome

This consists of AV malformations affecting combinations of:

• Retina
• Orbit
• Brain
• Facial structures

CNS Associations

Intracranial AVMs may involve:

• Midbrain
• Optic pathways
• Thalamus
• Other ipsilateral cerebral structures

Possible symptoms include:

• Headache
• Seizures
• Neurologic deficits
• Visual field defects
• Proptosis
• Orbital bruit

Imaging in Retinal AVM

Extensive retinal AVM should prompt:

MRI/MRA of the brain and orbits

to assess for:

• Intracranial AVM
• Orbital involvement
• Visual pathway disease

CTA or catheter angiography may be required in selected neurologic/neurosurgical cases.

Retinal AVM Complications

Possible ocular complications include:

• Retinal vein occlusion
• Retinal artery occlusion
• Vitreous hemorrhage
• Macular edema
• Retinal ischemia
• Neovascular glaucoma

However, many lesions remain stable for life.

Treatment of Retinal AVM

The retinal vascular malformation itself generally requires:

No direct treatment

unless complications arise.

Intervention is directed toward:

• Hemorrhage
• Macular edema
• Neovascularization
• Retinal ischemia

Associated intracranial AVMs require:

• Neurology
• Neurosurgery
• Neurointerventional assessment

Vasoproliferative Tumor

Important Modern Classification

A retinal vasoproliferative tumor (VPT) is traditionally grouped with retinal vascular tumors but is now better understood as:

A reactive gliovascular proliferation

rather than a true vascular neoplasm.

It usually appears as:

• Yellow-pink peripheral retinal mass
• Commonly inferotemporal
• With prominent exudation

It may be:

• Primary
• Secondary to chronic retinal disease

VPT Associations

Secondary VPT can occur with:

• Retinitis pigmentosa
• Uveitis
• Retinal detachment
• Retinal vascular disease
• Prior surgery
• Other chronic retinal pathology

Systemic Evaluation – General Approach

Systemic work-up should be tailored to lesion type.

RHB

Strong consideration for:

• VHL genetic testing
• VHL systemic surveillance

RCH

Systemic evaluation mainly if:

• Family history
• Neurologic symptoms
• Multiple lesions

Retinal AVM

Consider:

• MRI/MRA brain and orbits, especially if extensive

Differential Diagnosis

Important mimics include:

• Retinal arterial macroaneurysm
• Coats disease
• Retinal vasoproliferative tumor
• Retinoblastoma
• Retinal telangiectasia
• Choroidal hemangioma
• Choroidal melanoma
• Choroidal granuloma
• Retinal neovascularization

RHB vs RCH

Retinal Hemangioblastoma

• Orange-red solid lesion
• Feeder arteriole
• Draining vein
• Marked FA leakage
• Exudation common
• VHL association important

Retinal Cavernous Hemangioma

• Grape-like saccules
• Slow blood flow
• Plasma–RBC layering
• Little or no FA leakage
• Exudation usually absent

RHB vs Retinal AVM

RHB

• Discrete vascular mass
• Feeder and draining vessels
• Exudation common
• FA leakage prominent

Retinal AVM

• Direct artery-to-vein communication
• No discrete tumor mass
• Rapid AV transit
• Little leakage
• Consider Wyburn-Mason syndrome

Treatment Summary

Treatment is lesion specific.

RHB

• Observation selected
• Laser for small peripheral lesions
• Cryotherapy for larger/anterior lesions
• PDT selected posterior/juxtapapillary lesions
• Anti-VEGF adjunct for exudation
• Surgery for traction/RD

RCH

• Usually observe
• Treat complications only

Retinal AVM

• Usually observe
• Treat complications
• Evaluate CNS/orbit when indicated

Follow-Up

Follow-up frequency depends on:

• Lesion type
• Exudation
• Growth
• Macular involvement
• Systemic disease

Stable lesions may be followed every:

6–12 months

Active or vision-threatening lesions require:

Closer surveillance.

Long-Term VHL Surveillance

Patients with confirmed VHL disease require lifelong multidisciplinary surveillance because the major threat is not only ocular disease but:

• Renal cell carcinoma
• CNS hemangioblastoma
• Pheochromocytoma
• Other VHL-associated tumors

Follow-up should be coordinated with:

• Genetics
• Oncology
• Neurology/neurosurgery
• Ophthalmology

Prognosis

Retinal Hemangioblastoma

Visual prognosis depends on:

• Tumor size
• Juxtapapillary location
• Macular exudation
• Retinal detachment
• Number of lesions

Early detection and treatment substantially improve outcomes.

Retinal Cavernous Hemangioma

Prognosis is usually:

Excellent

because most remain stable and nonexudative.

Visual loss is uncommon unless:

• Vitreous hemorrhage
• Traction

develops.

Retinal AVM

Isolated lesions often remain:

Stable

but visual prognosis may worsen with:

• Vascular occlusion
• Hemorrhage
• Macular involvement
• Extensive retinal disease

Systemic prognosis depends on whether associated:

Intracranial AVMs

are present.

Complications

Possible complications across this group include:

• Macular edema
• Lipid exudation
• Exudative retinal detachment
• Tractional retinal detachment
• Epiretinal membrane
• Vitreous hemorrhage
• Retinal vascular occlusion
• Neovascular glaucoma
• Permanent visual loss

Systemic complications may be life-threatening in:

• VHL disease
• Wyburn-Mason syndrome

Ophthalmology Pearls

• “Retinal vascular tumors” includes biologically different entities: RHB is a true vascular tumor, while cavernous hemangioma and retinal AVM are primarily congenital vascular malformations.
• A vasoproliferative tumor is better considered a reactive gliovascular proliferation, not a true vascular neoplasm.
• Retinal hemangioblastoma is classically an orange-red lesion with a dilated feeder arteriole and draining vein.
• RHB has a strong association with von Hippel-Lindau disease, especially when lesions are young-onset, bilateral, or multiple.
• VHL results from pathogenic variants in the VHL tumor suppressor gene on chromosome 3p25.3 and can predispose to CNS hemangioblastomas, renal cell carcinoma, pheochromocytoma, and other tumors.
• On FA, RHB shows rapid filling and marked late leakage.
• Laser is generally preferred for small peripheral RHBs, while cryotherapy is useful for larger or more anterior tumors.
• Juxtapapillary RHB requires caution because treatment can injure the optic nerve and papillomacular bundle.
• Anti-VEGF can reduce exudation from RHB but is generally adjunctive rather than curative.
• Retinal cavernous hemangioma has a characteristic grape-like appearance with plasma–erythrocyte layering and little or no fluorescein leakage.
• Most cavernous hemangiomas are stable and require observation only.
• Retinal cavernous lesions have only an occasional association with familial cerebral cavernous malformation syndromes, so systemic evaluation should be individualized.
• Retinal AVM consists of direct artery-to-vein communication without an intervening capillary bed and usually shows rapid AV transit with little leakage.
• Extensive retinal AVM should prompt consideration of Wyburn-Mason syndrome and generally warrants MRI/MRA of the brain and orbits.
• Most retinal AVMs themselves are not treated unless complications arise.
• The two major systemic associations to remember are: RHB → VHL disease; retinal AVM → Wyburn-Mason syndrome.
• Whenever a retinal vascular lesion is discovered, assess not only the eye but also whether it is a marker of a potentially life-threatening systemic condition.