Diffuse Choroidal Hemangioma

Key points of this disease

• Diffuse choroidal hemangioma almost always occurs with Sturge-Weber syndrome (encephalofacial angiomatosis) and is a distinct condition from sporadic circumscribed choroidal hemangioma.
• Sturge-Weber syndrome occurs in 1 in 20,000 to 50,000 people and is not hereditary. It is known to be caused by a somatic mosaic mutation in the GNAQ gene.
• The characteristic “tomato ketchup fundus” shows a diffuse orange-red appearance of the entire fundus with ill-defined choroidal thickening.
• Serous retinal detachment frequently occurs and is a major cause of vision loss. Hyperopia is also observed.
• Glaucoma is present in more than half of cases. About half develop in infancy and half in childhood, requiring long-term intraocular pressure management.
• For serous retinal detachment, PDT (photodynamic therapy) or low-dose radiation (approximately 20 Gy) is used.
• Multidisciplinary collaboration with pediatric neurologists is important, and management of epilepsy and developmental delay should be performed concurrently.

1. What is diffuse choroidal hemangioma?

Definition and Concept

There are two types of choroidal hemangioma: circumscribed (solitary) and diffuse. Circumscribed type is well-defined and occurs sporadically, while diffuse type often has extensive tumor involvement and unclear borders. Diffuse choroidal hemangioma almost always occurs in association with Sturge-Weber syndrome (encephalofacial angiomatosis).

Sturge-Weber syndrome is one of the phakomatoses (neurocutaneous syndromes) and is caused by ectopic proliferation of neural crest cells during embryonic development. It is characterized by the formation of hemangiomas on the face, eye, and leptomeninges.

Epidemiology

The incidence of Sturge-Weber syndrome is estimated at 1 in 20,000 to 50,000. It is not hereditary; the main cause is a sporadic somatic mosaic mutation in the GNAQ gene. It is a congenital condition present at birth and is detected in infancy or early childhood. It occurs in the ipsilateral fundus of patients with cutaneous hemangioma (port-wine stain) in the distribution of the first and second branches of the trigeminal nerve. Clear data on gender or racial differences are lacking, but as a sporadic disease, it can occur in all races.

Comparison with Circumscribed Choroidal Hemangioma

Feature	Diffuse Choroidal Hemangioma	Circumscribed (Solitary) Choroidal Hemangioma
Associated Syndrome	Always associated with Sturge-Weber syndrome	No systemic disease (sporadic)
Fundus Distribution	Extensive, ill-defined borders	Localized, relatively well-defined borders
Color tone	Tomato ketchup fundus	Orange elevated lesion
Glaucoma association	More than half	Rare
Onset timing	Congenital / infancy	Often in adulthood

Q What is the relationship between diffuse choroidal hemangioma and Sturge-Weber syndrome?

A

Diffuse choroidal hemangioma almost always occurs in association with Sturge-Weber syndrome (encephalofacial angiomatosis). Sturge-Weber syndrome is characterized by the triad of facial port-wine stain, leptomeningeal angioma, and ocular findings (diffuse choroidal hemangioma, glaucoma). The incidence is 1 in 20,000 to 50,000, and it is not hereditary. The hemangioma occurs in the fundus on the same side as the facial port-wine stain.

2. Main symptoms and clinical findings

Diffuse choroidal hemangioma in Sturge-Weber syndrome: bilateral diffuse choroidal thickening on EDI-OCT

Sacconi R, Corbelli E, Carnevali A, et al. Multimodal imaging of diffuse choroidal hemangioma in Sturge-Weber syndrome. Vision (Basel). 2023;7(4):64. Figure 3. PMCID: PMC10594527. License: CC BY.

Enhanced depth imaging (EDI) spectral-domain OCT images of a patient with Sturge-Weber syndrome: Comparison of the right eye (RE) and left eye (LE) shows bilateral diffuse choroidal thickening and a dome-shaped macular profile, more pronounced in the left eye. No structural changes are seen in the retinal layers. This corresponds to the OCT diagnostic findings of diffuse choroidal hemangioma (choroidal thickening, dome-shaped elevation) discussed in the section “Main symptoms and clinical findings.”

Fundus findings

The most characteristic fundus finding of diffuse choroidal hemangioma is the “tomato ketchup fundus,” where the entire fundus takes on a widespread orange-red hue. The tumor occupies a large area of the choroid, and its borders are indistinct. In ordinary fundus photographs, it can be recognized as a marked difference in redness compared to a normal fundus.

The main fundus and ocular findings are shown below.

• Diffuse choroidal thickening: The choroid is thickened extensively from the posterior pole to the periphery.
• Indistinct borders: Unlike circumscribed hemangioma, the tumor margins are unclear.
• Serous retinal detachment: The main cause of vision loss. Presents with visual field defects and metamorphopsia.
• Hyperopia: Refractive changes occur along the ocular axis due to choroidal elevation.
• Orange elevated lesion: Recognized as an orange elevation in the posterior pole.

Fluorescein Angiography and Imaging Findings

Characteristic findings on various imaging tests are shown below.

• FA (Fluorescein Angiography): Reticular hyperfluorescence within the tumor is seen from the early phase, and dye pooling increases in the late phase (diffuse pattern).
• ICGA (Indocyanine Green Angiography): Better visualization of choroidal vessels than FA, allowing clear identification of tumor vascular structures.
• OCT: Observed as a broad, localized elevation of the posterior choroid. Also useful for evaluating serous retinal detachment.
• Ultrasound: Depicted as a solid elevated lesion. B-scan shows extensive choroidal thickening.
• CT: Similar to ultrasound, depicted as a solid lesion.

Glaucoma Complication

In Sturge-Weber syndrome, glaucoma occurs in more than half of cases. Depending on the age of onset, infantile-onset (congenital glaucoma type) and childhood-onset (acquired type) are each observed in about half of the cases.

• Infantile-onset type: Presents with features of congenital glaucoma such as corneal enlargement, buphthalmos (corneal enlargement), and Haab’s striae. Surgery is often required.
• Childhood-onset type: Intraocular pressure may initially stabilize within the normal range, but an increase in intraocular pressure may occur during follow-up.
• Episcleral hemangioma: Some cases also have hemangioma in the episclera on the affected side.

Q Why is attention to glaucoma necessary?

A

Glaucoma occurs in more than half of patients with Sturge-Weber syndrome. Infantile-onset and childhood-onset each account for half, and an increase in intraocular pressure may occur later during follow-up. If not properly managed, glaucoma can lead to visual field defects and vision loss, so long-term regular intraocular pressure measurement and fundus examination are essential. Particularly in infancy, buphthalmos and corneal opacity require urgent intervention.

3. Causes and Risk Factors

Pathogenesis

The development of Sturge-Weber syndrome and diffuse choroidal hemangioma is caused by ectopic proliferation of neural crest cells during the embryonic period. A choroidal hamartoma is formed, and the normal choroidal structure is extensively replaced by vascular tissue.

At the genetic level, mutations in the GNAQ gene (guanine nucleotide-binding protein Gq alpha) (c.548G>A, p.Arg183Gln) are detected in many cases. This mutation occurs as a somatic mosaic mutation, so it is not hereditary and is not transmitted from parent to child in principle. The GNAQ mutation is thought to reduce GTPase activity and constitutively activate angiogenic signaling.

Main Risk Factors and Characteristics

• GNAQ somatic mosaic mutation: Most important as a causative mutation. It is not a germline mutation and is not hereditary.
• Congenital condition: Present from birth, mainly due to accidental mutations during the embryonic period rather than genetic background.
• Environmental factors: No established environmental risk factors.
• Family history: In principle, it is not inherited, so familial clustering is usually not observed.

Collaboration with other departments

If Sturge-Weber syndrome is suspected, consultation with a pediatric neurologist is recommended. Systemic management of epilepsy and mental development may be necessary. It is important to evaluate leptomeningeal angioma and calcification with head MRI and manage the patient long-term through multidisciplinary collaboration.

Pathogenesis of glaucoma

Two main mechanisms are involved in the development of glaucoma in Sturge-Weber syndrome.

• Elevated episcleral venous pressure: Angioma of the episclera increases venous pressure, leading to increased resistance to aqueous outflow. This mechanism is common in glaucoma after childhood.
• Angle abnormality: Developmental abnormality of the anterior chamber angle impairs aqueous outflow. This is often involved in glaucoma that develops in infancy.

4. Diagnosis and examination methods

Diagnostic approach

The combination of facial port-wine stain (cutaneous angioma in the distribution of the trigeminal nerve) and ipsilateral fundus changes strongly supports the diagnosis of diffuse choroidal hemangioma. The following examinations are used for ophthalmic diagnosis.

Fundus examination and imaging:

• Fundus photography (including wide-angle fundus imaging): documentation and follow-up of tomato ketchup fundus
• FA/ICGA: confirmation of early reticular hyperfluorescence (diffuse pattern)
• OCT: evaluation of extensive choroidal thickening and serous retinal detachment
• Ultrasound (A-scan and B-scan): confirmation of solid lesion and measurement of thickness

Systemic evaluation:

• Head MRI: Leptomeningeal angioma and calcification (evaluated by a pediatric neurologist in conjunction with ophthalmic findings)
• Intraocular pressure measurement: Glaucoma screening (under general anesthesia if necessary)
• Gonioscopy: Evaluation of angle abnormalities

Differential Diagnosis

Diseases that require differentiation from diffuse choroidal hemangioma are listed below.

Differential Diagnosis	Key Differences
Circumscribed choroidal hemangioma	Well-defined, localized, no systemic syndrome
Choroidal malignant melanoma (diffuse type)	Malignant features, pigment changes, risk of metastasis
Posterior uveitis	Inflammatory findings, vitreous opacity
Normal fundus color variation	No systemic findings of Sturge-Weber syndrome

Points to note at diagnosis

If the fundus appears “somewhat red,” especially in infants with port-wine stains, this disease should be actively suspected. In infants, general anesthesia may be required for examination, and collaboration with anesthesiology and pediatrics is important.

5. Standard treatment

Overview of treatment strategy

Treatment of diffuse choroidal hemangioma is performed stepwise depending on the presence of symptoms and the type of complications. Surgical removal of the choroidal hemangioma itself is not usually performed. The main targets of treatment are serous retinal detachment (the main cause of vision loss) and glaucoma.

Long-term management of glaucoma

Glaucoma may develop or progress during the course of the disease, requiring long-term regular intraocular pressure measurements. In infantile glaucoma (congenital glaucoma type), surgery may be necessary. If elevated intraocular pressure is detected after childhood, drug therapy with eye drops is initiated, and surgery is considered if the effect is insufficient.

1. Observation

If asymptomatic and there are no problems with vision or intraocular pressure, continue the following regular observations:

• Intraocular pressure measurement (early detection of glaucoma)
• Fundus photography and OCT to check for serous retinal detachment
• Visual acuity and refraction tests (assessment of hyperopia and amblyopia)
• Follow-up with FA/OCT as needed

2. Treatment for serous retinal detachment and visual dysfunction

If vision loss or serous retinal detachment is observed, active treatment is performed.

PDT (Photodynamic Therapy):

• Intravenous administration of verteporfin (photosensitizer) followed by irradiation with a 689 nm wavelength laser
• The efficacy of PDT for choroidal hemangioma has been reported
• Not covered by insurance (for diffuse choroidal hemangioma)
• Expected to resolve serous retinal detachment and improve visual acuity
• Efficacy for circumscribed choroidal hemangioma is established, but application to diffuse type has technical limitations due to the large irradiation area

Low-dose radiation therapy:

• Low-dose irradiation of approximately 20 Gy is performed
• May be effective. Expected to resolve retinal detachment and improve visual acuity
• External beam radiation (teletherapy) is often used

Q Can the choroidal hemangioma itself be surgically removed?

A

Surgical removal is not usually performed. Diffuse choroidal hemangioma extensively involves the entire choroid, making surgical removal technically and functionally difficult. For serous retinal detachment causing visual loss, PDT or low-dose radiation therapy (approximately 20 Gy) is performed and is often effective. For glaucoma, intraocular pressure is controlled with eye drops or surgery.

3. Glaucoma Treatment

Since glaucoma complicates more than half of cases, its management is an important treatment issue.

Pharmacotherapy (eye drops):

• Prostaglandin-related drugs (suppress aqueous humor production, enhance outflow)
• Beta-blockers (suppress aqueous humor production)
• Carbonic anhydrase inhibitors (topical or oral)
• However, in glaucoma due to elevated episcleral venous pressure, eye drops may have limited effectiveness

Surgical treatment:

• For infantile-onset (congenital glaucoma type), goniotomy or trabeculotomy may be attempted
• In adult type, filtering surgery (trabeculectomy or tube shunt surgery) is considered
• When episcleral venous pressure is high, careful postoperative management of trabeculectomy is required

4. Systemic management

• Epilepsy management: Seizure control with antiepileptic drugs (pediatric neurology)
• Management of intellectual disability: Early intervention and support systems
• Headache and hemiparesis: Monitoring of neurological symptoms and symptomatic treatment
• Multidisciplinary collaboration: Cooperation among ophthalmology, pediatric neurology, dermatology, epilepsy specialists, and habilitation team

6. Pathophysiology and detailed mechanisms

Nature as a vascular hamartoma

Diffuse choroidal hemangioma is embryologically classified as a vascular hamartoma. A hamartoma is a benign tumor-like lesion characterized by abnormal proliferation of tissue components normally present at that site, distinct from a true neoplasm. In this condition, mature vascular elements proliferate excessively within the choroid, replacing the normal choriocapillaris and medium-to-large vessel structures.

GNAQ Gene Mutation and Molecular Mechanisms

As the molecular basis of Sturge-Weber syndrome, somatic mosaic mutations in the GNAQ gene (c.548G>A, p.Arg183Gln) have been identified in many cases.

• Function of GNAQ (Gqα): Gα subunit involved in downstream signaling of G protein-coupled receptors (GPCRs)
• Effect of mutation: The Arg183Gln mutation reduces GTPase activity, maintaining GNAQ in a constitutively active state
• Downstream signaling: Gq-mediated PLC-β activation → IP3/DAG production → PKC activation → constitutive activation of the MAPK cascade (MEK/ERK)
• Impact on angiogenesis: Overproduction of angiogenic factors such as VEGF is promoted, leading to abnormal blood vessel formation
• Significance of somatic mosaic mutation: Since mutations occur only in some cells during early embryogenesis, expression patterns vary among individuals, resulting in symptom diversity

Detailed Pathogenesis of Glaucoma

At least two mechanisms are proposed for the development of glaucoma in Sturge-Weber syndrome.

Mechanism 1: Elevated episcleral venous pressure Hemangiomas in the episclera (sub-Tenon’s capsule) increase episcleral venous pressure, impairing aqueous humor outflow through Schlemm’s canal and the trabecular meshwork. When episcleral venous pressure exceeds the normal value (approximately 10 mmHg), intraocular pressure increases additively. This mechanism is common in acquired glaucoma that develops after childhood.

Mechanism 2: Angle dysgenesis Developmental abnormalities of the anterior chamber angle (angle dysgenesis) result in incomplete development of the trabecular meshwork, causing anatomical dysfunction of the aqueous outflow pathway. This mechanism is often associated with infantile-onset (congenital) glaucoma.

Pathogenesis of Serous Retinal Detachment

Increased vascular permeability in diffuse choroidal hemangioma leads to extravasation of intravascular components and fluid accumulation in the subretinal space. This causes serous retinal detachment, which is the main cause of vision loss and visual field defects. PDT or radiation therapy reduces tumor vessels, decreasing exudation and allowing retinal reattachment.

Pathophysiology Outside the Eye

• Leptomeningeal angioma: Angioma of the cerebral cortex causes focal ischemia and calcification, leading to epilepsy, intellectual disability, and hemiparesis.
• Facial port-wine stain: Present from birth as telangiectasia of the skin.
• Calcification: “Tram-track” calcification in the cerebral cortex beneath the leptomeningeal angioma is a characteristic imaging finding of Sturge-Weber syndrome.

7. Latest Research and Future Perspectives

For patients: Please read this

The following content is still at the research stage and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Molecular targeted therapy targeting downstream of GNAQ

The MAPK cascade (MEK/ERK pathway) constitutively activated by GNAQ mutation is widely studied as a therapeutic target in uveal melanoma research. Since the same molecular abnormality exists in Sturge-Weber syndrome/diffuse choroidal hemangioma, the application of MEK inhibitors (trametinib, binimetinib, etc.) and GNAQ direct inhibitors (YM-254890, etc.) is being investigated at the basic research level.

In fact, as molecular targeted therapy for Sturge-Weber syndrome as a whole, mTOR inhibitors (sirolimus) and treatments targeting the PI3K-AKT-mTOR pathway have been trialed, with reports of symptom improvement in some patients. However, large-scale studies directly evaluating efficacy for diffuse choroidal hemangioma itself are currently limited.

Optimization of PDT treatment

PDT has been shown to be effective for serous retinal detachment in diffuse choroidal hemangioma in multiple case reports, but the protocol (irradiation field, energy, number of sessions) for diffuse extensive lesions has not been standardized. Compared to circumscribed choroidal hemangioma, diffuse lesions require a larger irradiation area, posing technical challenges. Establishment through future multicenter prospective studies is expected.

New developments in glaucoma management

Conventional filtration surgery for glaucoma caused by elevated episcleral venous pressure carries risks of choroidal effusion and malignant glaucoma under conditions of high episcleral venous pressure. Research on the efficacy of tube shunt surgery (Ahmed valve, Baerveldt tube) is progressing. Additionally, the potential application of selective laser trabeculoplasty (SLT) is being investigated.

Perspectives on GNAQ genetic diagnosis

Detection of GNAQ mutations in skin biopsy or blood samples is being applied for definitive diagnosis of Sturge-Weber syndrome. In the future, early diagnosis via liquid biopsy (ctDNA) and improved mutation detection rates are expected to enable more reliable diagnosis.

8. References

1. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971-1979.
2. Baselga E, Torrelo A, Mediero IG, et al. Sturge-Weber syndrome: report of 3 cases. Pediatr Dermatol. 2019;36(6):932-934.
3. Bhatt A, Bhatt N. Sturge-Weber syndrome: a rare neurocutaneous disorder. J Pediatr Neurosci. 2021;16(1):1-6.
4. Zreik O, Elabassy HM, Bakhurji E, Al-Johani SM. Sturge-Weber syndrome: an updated review. Clin Ophthalmol. 2023;17:2369-2381.
5. Nassiri N, Rootman DB, Rootman J, Goldberg RA. Orbital and adnexal lymphangiomas: a review of management. Surv Ophthalmol. 2015;60(3):245-257.