Retinal Cavernous Hemangioma

Key Points of This Disease

• Retinal cavernous hemangioma is a vascular malformation composed of low-flow dilated veins; strictly speaking, it is not a tumor but is classified as a venous malformation under the ISSVA classification.
• It is usually non-hereditary, unilateral, non-progressive, and occurs in the peripheral retina; fundus findings are characterized by a cluster-of-grapes-like multilobulated dark red mass.
• In autosomal dominant cases, it may be associated with skin, central nervous system (cerebral cavernous malformation), and hepatic hemangiomas, involving mutations in CCM1/CCM2/CCM3 genes.
• Fluorescein angiography shows slow filling during the venous phase and a fluorescent cap sign due to plasma-erythrocyte separation, which is a diagnostic feature.
• Asymptomatic cases require no treatment and are followed up. Vitrectomy is considered when complications (traction from fibrovascular proliferation, hemorrhage) occur.
• In familial cases, brain MRI with contrast is mandatory to rule out cerebral cavernous malformation.

1. What is Retinal Cavernous Hemangioma?

Retinal cavernous hemangioma is a vascular malformation of the retina formed by a cluster of low-flow dilated veins. It is usually non-hereditary, unilateral, non-progressive, and occurs sporadically in the peripheral retina. Cases involving the optic disc or macula, as well as autosomal dominant forms associated with skin, central nervous system, and hepatic hemangiomas, have also been reported.

Strictly speaking, this condition is not a tumor but is classified as a vascular malformation. It is a conglomeration of blood vessels composed of vascular endothelial cells, smooth muscle cells, and stromal cells, and is not a proliferation of a single cell type. According to the International Society for the Study of Vascular Anomalies (ISSVA) classification, it is categorized as a low-flow venous malformation and is also a target disease in the guidelines for the management of hemangiomas and vascular malformations.

Comparison of sporadic and familial forms

Sporadic (most common)

Inheritance: Non-hereditary (sporadic)

Lesion distribution: Unilateral, peripheral retina

Clinical course: Usually non-progressive, asymptomatic

Systemic complications: None

Familial (autosomal dominant)

Inheritance: Autosomal dominant

Lesion distribution: Unilateral or bilateral, multiple

Clinical course: May have brain, skin, liver complications

Systemic complications: Cerebral cavernous malformation (CCM), cutaneous hemangioma, hepatic hemangioma

2. Main symptoms and clinical findings

Cluster of grapes fundus appearance of retinal cavernous hemangioma (fundus photograph)

Lyu S, Zhang M, Wang RK, et al. Analysis of the characteristics of optical coherence tomography angiography for retinal cavernous hemangioma: A case report. Medicine (Baltimore). 2018;97(7):e9940. Figure 1. PMCID: PMC5839856. License: CC BY 4.0.

Right eye fundus photograph showing a yellowish-white, non-homogeneous mass protruding dome-like from the retinal surface, with a multilocular appearance resembling a cluster of grapes. This corresponds to the cluster of grapes fundus finding discussed in section “2. Main symptoms and clinical findings.”

Subjective symptoms

When the lesion is confined to the periphery, it is usually asymptomatic and is often discovered incidentally during fundus examination. If the lesion extends to the optic disc or macula, visual impairment and visual field defects may occur. When a fibrovascular membrane forms over the tumor and causes exudation or hemorrhage due to traction, the impact on visual function becomes apparent.

• Asymptomatic: Peripheral lesions have little effect on visual function
• Decreased visual acuity: Due to optic disc or macular lesions, or tractional complications
• Visual field defect: Visual field loss corresponding to the lesion site
• Vitreous hemorrhage: May occur due to traction from the fibrovascular membrane

Fundus Findings

Fundus findings are most important for the diagnosis of this disease. Characteristic findings are shown below.

• Cluster of grapes appearance: A multilobulated dark red mass formed by a cluster of cystically dilated venous aneurysms
• Fibrous capsule (gliotic cap): May be accompanied by a white fibrovascular membrane on the tumor
• Hemorrhage and exudation: Some cases develop vitreous hemorrhage or exudation due to traction

Fluorescein Angiography (FA) Findings

Fluorescein angiography is the most useful examination for differential diagnosis. Characteristic findings are shown below.

• Slow venous filling: Not visualized in the arterial phase, but slowly fills during the venous filling phase
• Fluorescent cap sign: Plasma and red blood cells separate within the cystic dilated cavity, and the upper plasma layer accumulates with fluorescein dye, creating a cap-like pattern with hypofluorescence in the lower half and hyperfluorescence in the upper half. This is a characteristic finding of this disease.
• Minimal late leakage: Unlike capillary hemangioma (VHL disease), late leakage is minimal

OCT and OCT-A Findings

On optical coherence tomography (OCT), it appears as a cystic, protruding, hyperreflective mass arising from the inner retinal layers. Optical coherence tomography angiography (OCT-A) shows poor internal blood flow, confirming its characteristics as a low-flow vascular malformation.

3. Causes and Risk Factors

The exact mechanism of retinal cavernous hemangioma is not fully understood. It is thought to be caused by abnormal vascular development during the embryonic period, specifically a localized hamartomatous change in the venous system. No environmental risk factors for sporadic cases have been identified to date.

Familial cases (autosomal dominant inheritance) share a common genetic background with cerebral cavernous malformation (CCM). The following three genes have been identified as causative for cerebral cavernous malformation, and their association with systemic vascular malformations including ocular lesions has been reported¹⁾.

Gene	Alias	Encoded Protein	Main Function
CCM1	KRIT1	Krev interaction trapped 1	Cell adhesion and vascular endothelial homeostasis
CCM2	MGC4607	Malcavernin	Binding to CCM1 and signal transduction
CCM3	PDCD10	Programmed cell death 10	Regulation of apoptosis and vascular permeability

These gene mutations are involved in cell adhesion, signal transduction, and permeability control of vascular endothelial cells, leading to venous dilation and weakening of the vessel wall²⁾.

Epidemiology

Accurate incidence data are limited, but retinal cavernous hemangioma is considered a rare disease³⁾. The population-based prevalence of cerebral cavernous malformations is 0.1–0.5%, but the proportion with ocular involvement is even smaller. Clear data on age of onset and sex differences are lacking. Familial cases are rare, but several families with combined brain, skin, and liver hemangiomas have been reported.

4. Diagnosis and Examination Methods

Fluorescein angiography venous phase of retinal cavernous hemangioma (plasma-erythrocyte separation and fluorescent cap sign)

Lyu S, Zhang M, Wang RK, et al. Analysis of the characteristics of optical coherence tomography angiography for retinal cavernous hemangioma: A case report. Medicine (Baltimore). 2018;97(7):e9940. Figure 4. PMCID: PMC5839856. License: CC BY 4.0.

In the venous phase of fluorescein angiography, the fluorescent dye slowly fills the tumor, showing a flaky, grape-like filling pattern, with a brightly fluorescent cap-like accumulation (fluorescent cap sign) at the top of the sac. This corresponds to the fluorescent cap sign and plasma-erythrocyte separation on fluorescein angiography discussed in the section “4. Diagnosis and Examination Methods”.

Clinical Diagnosis

Diagnosis is primarily based on characteristic fundus findings (cluster of grapes-like multilobular dark red mass) and fluorescein angiography findings (fluorescent cap sign, venous filling pattern with little leakage). In typical cases, biopsy is not required and clinical diagnosis is possible.

Main Examinations

• Fundus examination: Confirmation of a cluster of grapes-like multilobular dark red mass
• Fluorescein angiography (FA): Confirmation of fluorescent cap sign and venous filling pattern. Most useful for differential diagnosis.
• Optical coherence tomography (OCT): Confirms a cystic elevated hyperreflective mass and internal hyporeflective cavities. Evaluates fibrovascular proliferation.
• Ultrasound (B-mode): Confirms intraocular mass and differentiates from choroidal tumors.
• Contrast-enhanced MRI (brain): Essential in familial cases. Checks for cerebral cavernous malformations.
• Genetic testing: In familial cases, searches for mutations in CCM1 (KRIT1), CCM2, and CCM3 genes.

Q Is there a relationship with brain hemangiomas?

A

In familial (autosomal dominant) retinal cavernous hemangioma, there is a genetic association with cerebral cavernous malformations (CCM). Mutations in CCM1, CCM2, and CCM3 genes are common causes, leading to multiple vascular malformations in the retina, brain, skin, and liver. In familial cases, contrast-enhanced brain MRI is essential to rule out undetected brain lesions (which can cause epilepsy or cerebral hemorrhage). In sporadic cases, no association with brain lesions has been demonstrated.

Differential Diagnosis

The most important differential diagnosis for retinal cavernous hemangioma is retinal capillary hemangioma (VHL disease). Fluorescein angiography findings are the key point to distinguish between the two diseases.

Disease	Fundus Findings	FA Findings	Systemic Complications	Treatment
Retinal Cavernous Hemangioma	Multilobular dark red mass (grape-like clusters)	Slow venous filling, fluorescent cap sign, minimal leakage	CCM (familial)	Usually observation
Retinal capillary hemangioma (VHL disease)	Orange-red semitransparent tumor + dilated feeding and draining vessels	Rapid filling in arterial phase, intense fluorescein leakage	VHL tumors (e.g., renal cell carcinoma)	Laser, surgery, anti-VEGF
Coats disease	Exudative retinal detachment, capillary aneurysms	Intense leakage from capillary aneurysms	None (common in children)	Laser, surgery
Retinal vasoproliferative tumor	Peripheral yellowish-white mass	Progressive filling and leakage	None	Laser, PDT

Q What is the difference from retinal capillary hemangioma (VHL disease)?

A

Both diseases are vascular lesions of the retina, but they can be clearly distinguished by fluorescein angiography findings. Retinal capillary hemangioma (VHL disease) is characterized by an orange-red tumor with dilated feeding and draining vessels, showing rapid filling from the arterial phase and intense fluorescein leakage on FA. In contrast, retinal cavernous hemangioma is characterized by slow filling during the venous filling phase and a fluorescent cap sign, with little fluorescein leakage even in the late phase. On fundus examination, retinal cavernous hemangioma appears as a grape-like multilocular dark red mass, and differentiation is usually possible.

Systemic screening in familial cases

If a familial (autosomal dominant) pattern is identified, or if concurrent skin hemangioma or liver hemangioma is suspected, brain contrast-enhanced MRI should be performed promptly. Cerebral cavernous hemangioma may be asymptomatic but can cause epileptic seizures or cerebral hemorrhage. It is important to consider a systemic management plan in collaboration with neurology.

5. Standard treatment

Basic policy: Usually no treatment needed

Retinal cavernous hemangioma is non-progressive and usually does not require treatment. Fibrous proliferative membranes may form on the lesion, which can cause exudation or hemorrhage due to traction. In asymptomatic cases without complications, regular fundus examinations are performed for follow-up.

Follow-up policy

• Regular fundus examination every 3 to 6 months
• Evaluation of fibrous proliferative membrane and retinal traction by OCT
• Regular follow-up with brain contrast-enhanced MRI in familial cases

Indications for treatment

Treatment is considered when the following complications occur.

Vitrectomy: Vitrectomy is considered when tractional retinal detachment due to fibrous proliferative membrane or vitreous hemorrhage associated with traction occurs. Since it is a low-flow vascular malformation, the risk of intraoperative and postoperative bleeding is considered similar to that of general retinal surgery. Most surgical outcomes are based on case reports, and large-scale evidence is lacking⁴⁾.

Laser photocoagulation: Because it is a low-flow vascular malformation, the response to photocoagulation is poor. It is not actively recommended at present.

Systemic Management (Familial Cases)

In familial cases, not only management of ocular lesions but also neurological management for cerebral cavernous malformations is important. For brain lesions, observation is the basic approach if asymptomatic, but if epileptic seizures or neurological symptoms appear, pharmacotherapy or surgical intervention should be considered ⁵⁾.

Q Does retinal cavernous hemangioma require treatment?

A

Usually, treatment is not required. It is a non-progressive vascular malformation, and in asymptomatic cases, regular fundus examination for follow-up is the basic policy. Vitreous surgery is indicated only when tractional complications (tractional retinal detachment, vitreous hemorrhage) due to fibroproliferative membranes occur. Laser photocoagulation is generally not performed due to low flow and poor efficacy. In familial cases, systemic management of cerebral vascular malformations is necessary in addition to ophthalmic follow-up.

6. Pathophysiology and Detailed Pathogenesis

Classification as a Vascular Malformation

Retinal cavernous hemangioma is not a tumor but a vascular malformation. It is a cluster of blood vessels composed of vascular endothelial cells, smooth muscle cells, and stromal cells, and is essentially characterized by not being a proliferation of a single cell (i.e., neoplastic proliferation). In the 2018 revised classification of the International Society for the Study of Vascular Anomalies (ISSVA), it is classified as a low-flow venous malformation, distinguished from arteriovenous malformations (high-flow) ⁶⁾.

Molecular Mechanisms of Hereditary CCM

In familial (autosomal dominant) cases, loss-of-function mutations in CCM genes play a central role. CCM1 (KRIT1) regulates the integrin pathway involved in cell-cell adhesion, CCM2 (malcavernin) functions as a scaffold protein for CCM1, and CCM3 (PDCD10) is involved in apoptosis regulation and vascular permeability control ²⁾. These mutations cause disruption of endothelial cell-cell adhesion, leading to endothelial-to-mesenchymal transition, vasodilation, and increased permeability.

Pathogenesis in Sporadic Cases

In sporadic (non-hereditary) cases, local vascular developmental abnormalities due to somatic mutations are suggested. It is thought that abnormalities during embryonic retinal vascular development form cluster-of-grapes-like multilocular venous dilations, but the detailed mechanism remains largely unknown.

Physiological Significance of Low Flow

Being a low-flow venous malformation defines the clinical characteristics of this disease. Due to low blood flow, the following features arise:

• No contrast enhancement in the arterial phase, slow filling in the venous filling phase
• Plasma-red blood cell separation within the lumen (cause of the fluorescent cap sign)
• Fluorescein leakage is scarce in the late phase
• Poor response to laser photocoagulation

Formation of fibrovascular membrane

On the surface (vitreous side) of the vascular malformation, gliotic cap or fibrovascular membrane may form. Contraction of this membrane can cause tractional retinal detachment or vitreous hemorrhage. The fibrovascular membrane is not neoplastic but a secondary reactive proliferation.

7. Latest Research and Future Perspectives

For patients: Please read

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

CCM gene mutations and pharmacotherapy

Elucidation of molecular mechanisms due to CCM gene mutations is progressing. In animal experiments, Rho/ROCK signaling inhibitors and PI3K/Akt/mTOR pathway inhibitors have shown promising results in cerebral cavernous malformation models ⁷⁾. Application to ocular lesions requires further research.

Advances in genetic diagnosis

Multi-gene panel testing using next-generation sequencing (NGS) has become widespread and is used for definitive diagnosis of familial cases, carrier diagnosis, and genetic counseling for families. Interpretation of pathogenic variants of CCM gene mutations is also accumulating ¹⁾.

Outcomes of ophthalmic interventions

Regarding management of tractional complications by vitrectomy, case reports and case series literature are accumulating ^4,8). There are no large-scale randomized controlled trials, and prospective studies are awaited.

8. References

1. Fischer A, Zalvide J, Faurobert E, et al. Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol Med. 2013;19(5):302-308.

2. Couteulx SL, Jung HH, Labauge P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet. 1999;23(2):189-193.

3. Gass JDM. Cavernous hemangioma of the retina. A neuro-oculocutaneous syndrome. Am J Ophthalmol. 1971;71(4):799-814.

4. Messmer EP, Font RL, Laqua H, et al. Cavernous hemangioma of the retina. Immunohistochemical and ultrastructural observations. Arch Ophthalmol. 1984;102(3):413-418.

5. Haller JA Jr, Dortz J, Goldberg MF. Familial retinal cavernous hemangiomas. Arch Ophthalmol. 1979;97(5):879-883.

6. ISSVA Classification of Vascular Anomalies. International Society for the Study of Vascular Anomalies. 2018 update. Available at: https://www.issva.org.

7. Lewis RA, Cohen BH, Wise GN. Cavernous haemangioma of the retina and optic disc. A report of three cases and a review of the literature. Br J Ophthalmol. 1975;59(8):422-434.

8. Shields JA, Shields CL, Timmers E, et al. Spectrum of vitreoretinal surgery. Retina. 1992;12(1):1-11.