Intraocular vascular tumors are a general term for benign tumorous or malformative lesions of vascular origin that occur within the eyeball.
They are broadly divided into hemangiomas (neoplastic proliferation) and vascular malformations (congenital abnormalities). Neoplastic lesions include retinal capillary hemangioma, choroidal hemangioma, and retinal vascular proliferative tumor (VPT), while congenital vascular malformations include retinal cavernous hemangioma and retinal arteriovenous malformation (Wyburn-Mason syndrome).
Retinal Capillary Hemangioma
Also known as: Retinal hemangioblastoma
Features: Red spherical lesion. Accompanied by dilated and tortuous feeding vessels.
Associated systemic disease: VHL disease (autosomal dominant). Occurs in about 60% of VHL patients. 1)
Choroidal hemangioma
Circumscribed type: Sporadic. Red-orange hemispherical mass. Commonly occurs in the 20s to 40s.
Diffuse type: Associated with Sturge-Weber syndrome. “Tomato ketchup-like” fundus appearance.
Associated systemic disease: Diffuse type is associated with Sturge-Weber syndrome (facial port-wine stain + glaucoma).
Retinal vasoproliferative tumor
Alternative name: VPT (vasoproliferative tumor of the retina)
Features: Yellow-pink vascular mass in the peripheral retina. Lacks feeding vessels.
Classification: Divided into primary (74%) and secondary (26%). Commonly occurs in the 30s to 40s.
Intraocular vascular tumors are classified into the following 5 types.
VHL disease (von Hippel-Lindau disease) is an autosomal dominant genetic disorder caused by mutations in the VHL tumor suppressor gene on the short arm of chromosome 3 (3p25-26). The prevalence is approximately 1 in 36,000 people, and the number of patients in Japan is estimated to be 600–1,000 cases. 1)
In addition to retinal capillary hemangioma, it is associated with systemic tumors such as cerebellar and spinal hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, and pancreatic cysts. Retinal lesions usually appear by age 30, and in half of cases, they are bilateral and multiple. 1)
None of the intraocular vascular tumors are malignant themselves, and malignant transformation does not occur. However, in cases of retinal capillary hemangioma associated with VHL disease, there is a risk of systemic malignant tumors (such as renal cell carcinoma and pheochromocytoma). Systemic management is necessary, not just based on ocular findings.
The subjective symptoms of each tumor type are shown below. Small tumors are often asymptomatic.
The characteristic fundus findings for each tumor type are summarized below.
| Tumor Type | Typical Age of Onset | Characteristic Findings |
|---|---|---|
| Retinal Capillary Hemangioma | 10s–30s | Red spherical lesion + dilated feeding vessels |
| Retinal cavernous hemangioma | 20s–40s | Grape-like cystic lesions |
| Choroidal hemangioma (circumscribed) | 20s–40s | Red-orange hemispherical mass |
| Choroidal hemangioma (diffuse) | Children to adults | Tomato ketchup fundus |
| Retinal arteriovenous malformation | Congenital | Direct arteriovenous anastomosis |
| VPT | 30s to 40s | Yellow-pink peripheral vascular mass |
It appears as a red spherical lesion in the peripheral retina of the upper and lower temporal quadrants. Characteristic features include a pair of dilated and tortuous feeding artery and draining vein entering the tumor. In juxtapapillary type (endophytic and exophytic), the feeding vessels are indistinct, leading to delayed diagnosis.
Changes associated with disease progression are as follows:
In advanced VHL disease, intraocular pressure may rise above 45 mmHg, with marked conjunctival vascular dilation and possible loss of light perception. 2)
A reddish-orange hemispherical tumor, typically 3–7 mm in diameter and 1–3 mm in thickness. It commonly occurs in the posterior pole within 2 disc diameters of the optic nerve or fovea.
Associated with Sturge-Weber syndrome. The entire fundus appears reddish-orange, described as “tomato ketchup-like.” A flame nevus (port-wine stain) is present on the ipsilateral face. Secondary glaucoma is a concern.
Classified into three groups according to the Archer classification.
Unilateral and non-hereditary; Wyburn-Mason syndrome is associated with CNS (midbrain, thalamus, etc.) arteriovenous malformations.
A yellowish-pink vascular mass commonly located in the inferotemporal peripheral retina. Unlike retinal capillary hemangioma, it lacks dilated feeding vessels. Frequently associated with surrounding retinal exudation and exudative retinal detachment. Secondary VPT occurs secondary to retinitis pigmentosa, uveitis, ocular trauma, etc.
Both are observed as vascular masses in the peripheral retina, but there are distinguishing features. Retinal capillary hemangioma has a clearly defined pair of dilated and tortuous feeding artery and draining vein, whereas VPT lacks prominent feeding vessels. Fluorescein angiography (FA) also shows different filling patterns, which is useful for differentiation.
VHL disease is an autosomal dominant disorder caused by mutations in the VHL tumor suppressor gene at 3p25-26. 1) According to the “two-hit” hypothesis, tumor formation occurs when a germline mutation (first hit) is followed by a somatic mutation in the other allele (second hit). 1)
Sporadic retinal capillary hemangioma (von Hippel disease) also exists, but it is known that 45% of sporadic cases under 10 years of age are later diagnosed with VHL disease, making systemic evaluation particularly important in young patients.
It is considered a type of hamartoma, and no clear genetic background has been identified. In the diffuse type, an association with Sturge-Weber syndrome (trigeminal angiomatosis) is established.
These are congenital vascular malformations thought to result from abnormal vascular development during embryogenesis. In familial cavernous hemangioma, association with cerebral cavernous hemangioma may be observed.
This is an acquired lesion, broadly divided into secondary VPT (associated with retinitis pigmentosa, intermediate uveitis, intraocular surgery, etc.) and primary VPT of unknown cause. It is thought to be a reactive proliferation of glial cells and capillaries.
Yes, it is necessary. Even if it appears to be a sporadic case, especially in children under 10 years old, 45% are later diagnosed with VHL disease. Since VHL disease involves life-threatening lesions such as renal cell carcinoma, pheochromocytoma, and cerebellar hemangioblastoma, systemic evaluation including genetic testing, abdominal MRI/CT, and brain/spinal MRI is recommended. 1)
Diagnosis of intraocular vascular tumors involves a combination of slit-lamp microscopy, dilated fundus examination, and various imaging tests.
Each tumor type exhibits a characteristic filling pattern.
FA of Capillary Hemangioma
Arterial phase: Rapid filling from the afferent artery. The tumor itself becomes hyperfluorescent early.
Late phase: Fluorescein leakage from the tumor into the vitreous. Caution is needed in interpreting juxtapapillary type.
FA of Cavernous Hemangioma
Characteristic: Extremely slow filling of the saccular vessels. Fluid level formation (F/RBC level) due to plasma–red blood cell layering.
Leakage: No fluorescein leakage is observed. This is an important distinguishing point from capillary hemangioma.
FA of Choroidal Hemangioma
Early phase: Very early hyperfluorescence in the arterial phase (characteristic of choroidal hemangioma).
Late phase: Homogeneous staining of the entire tumor. The tumor margin shows particularly intense fluorescence.
ICGA is useful for delineating the entire extent of choroidal hemangioma. It allows detailed evaluation of tumor spread and choroidal vascular structure. In diffuse choroidal hemangioma, the lesion extent is clearer than with FA.
It is useful for monitoring exudative retinal detachment and intraretinal fluid. It is also used to follow up treatment effects. In retinal capillary hemangioma, it evaluates the layered structure of the tumor itself and surrounding exudative changes.
Choroidal hemangioma presents a spindle-shaped (flat hemispherical) morphology, with characteristic high internal reflectivity echoes. This is an important finding for differentiation from choroidal melanoma (low internal reflectivity). Evaluation is performed using a combination of A-mode and B-mode ultrasound.
If VHL disease is suspected, abdominal CT/MRI and brain/spinal MRI are performed as screening for systemic lesions. The purpose is to search for renal cell carcinoma, pheochromocytoma, and cerebellar hemangioblastoma. In Wyburn-Mason syndrome, head MRI/MRA is performed to evaluate cerebral arteriovenous malformations.
Both present with serous retinal detachment, but choroidal hemangioma shows a reddish-orange mass lesion at the posterior pole. In FA, early hyperfluorescence in the arterial phase is useful for differentiation from CSC. ICGA delineates the tumor more clearly. Ultrasound reveals a spindle-shaped mass with high internal reflectivity.
Treatment is selected according to the characteristics of each tumor type. Since all are benign lesions, the goal of treatment is to preserve vision and prevent/manage complications (exudative retinal detachment, glaucoma).
The main treatments for each tumor type are shown below.
| Tumor type | First-line | Other options |
|---|---|---|
| Retinal capillary hemangioma | Photocoagulation | Cryotherapy, TTT, photodynamic therapy, anti-VEGF, PPV, plaque |
| Retinal cavernous hemangioma | Observation | Vitrectomy (if bleeding) |
| Choroidal hemangioma | Photodynamic therapy | Photocoagulation, TTT, radiotherapy |
| Retinal arteriovenous malformation | Observation | (Difficult to treat) |
| VPT | Cryotherapy | Plaque, laser, photodynamic therapy |
Particularly effective for tumors ≤2 mm in diameter. Directly coagulate the tumor using a continuous-wave laser or yellow 577 nm laser. 1) Repeat irradiation at 4-6 week intervals until the tumor becomes scarred. In cases with significant exudation, reduce the surrounding exudate before coagulating the tumor.
Applied to large tumors located at or anterior to the equator. Performed transsclerally with a double freeze-thaw cycle at -70 to -80°C. This is the main treatment for peripheral lesions where photocoagulation is difficult.
For tumors in areas where direct coagulation is difficult, the following approaches are combined.
Indicated for medium to large tumors located 3 mm or more from the optic nerve. Irradiation is performed by suturing a 106Ru or 125I plaque onto the sclera.
Performed for advanced cases with exudative retinal detachment or tractional retinal detachment. Photocoagulation or cryocoagulation of the tumor may be combined during surgery.
Most cases are asymptomatic and do not undergo malignant transformation, so regular follow-up is usually sufficient without treatment. If vitreous hemorrhage occurs, vitrectomy may be considered.
PDT is the first-line treatment for small to medium-sized circumscribed choroidal hemangioma. After intravenous administration of verteporfin, a 689 nm diode laser is applied to selectively occlude tumor vessels. Resolution of serous retinal detachment and improvement in visual acuity can be expected.
In diffuse choroidal hemangioma (Sturge-Weber syndrome), management of secondary glaucoma is important, and eye drops, surgery (trabeculotomy, filtering surgery), etc., may be necessary.
Since it is a vascular malformation, standard treatments are often ineffective. If vision is preserved, observation is the basic approach. If vitreous hemorrhage occurs, vitrectomy may be considered. CNS arteriovenous malformations associated with Wyburn-Mason syndrome require collaboration with neurosurgery.
Cryocoagulation is the most common first-line treatment. Because the tumor is located in the periphery, a transscleral approach is suitable. Other treatments include plaque radiotherapy, laser photocoagulation, and photodynamic therapy. For secondary VPT, management of the underlying disease is also performed concurrently.
In VHL disease, the emergence of new lesions throughout life is more problematic than recurrence of treated lesions. Lozano et al. (2022) reported that 31 new hemangiomas were identified in one VHL patient over 25 years. 1) Regular fundus examinations after treatment and early detection and treatment of new lesions are key to preserving vision.
The VHL gene is a tumor suppressor gene that encodes a protein that promotes the degradation of hypoxia-inducible factor (HIF). Loss of VHL protein function due to VHL gene mutation leads to accumulation of HIF-1α regardless of hypoxia. 1)
Accumulation of HIF-1α activates transcription of downstream genes, leading to overexpression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), erythropoietin, and others. 1) This promotes pathological angiogenesis and tumor formation.
Details of the “two-hit” hypothesis are as follows. 1)
The tumor consists of foamy stromal cells and abundant capillaries. Stromal cells lack VHL protein and are considered the main tumor cells. VEGF overexpression within the tumor leads to abnormal vascular proliferation and exudation.
In recent years, the association of VHL disease in patients with retinopathy of prematurity (ROP) has been reported, suggesting that the HIF-1α/VEGF pathway plays a central role in both ROP and VHL disease. 1) Angiogenesis due to HIF-1α activation is also common in the pathology of ROP, and VHL mutations may enhance ROP-like vascular responses. 1)
VPT is composed of glial cells (Müller cells) and a fine capillary network with dilated vessels. Unlike retinal capillary hemangioma, it does not contain foamy stromal cells. It is considered an acquired reactive proliferation, triggered by chronic inflammation and hypoxia from underlying diseases of secondary VPT (e.g., retinitis pigmentosa, uveitis).
Lozanoら（2022）は、未熟児網膜症の既往を持つ患者がVHL病と診断された初報告例を発表した。1) この患者では25年間に31個の新規網膜血管腫が確認され、VHL遺伝子変異が未熟児網膜症の血管増殖反応を増強した可能性が示唆された。HIF-1α/VEGF経路が未熟児網膜症とVHL病の双方で共通の病態基盤となることが示され、VEGF標的治療の両疾患への応用可能性を示す報告である。
Lin et al. (2022) reported marked conjunctival vasodilation associated with VHL syndrome. 2) This finding suggests that systemic activation of the HIF-1α/VEGF pathway may also affect ocular surface vessels, and may be useful as an auxiliary ocular sign for diagnosing VHL disease.
Case reports on combination therapy with photodynamic therapy and anti-VEGF agents for retinal capillary hemangioma and choroidal hemangioma are accumulating. While anti-VEGF agents alone have limited tumor shrinkage effects, attempts to use them as adjunctive therapy before and after photodynamic therapy by leveraging their exudation-suppressing effects have been reported. Large-scale prospective studies are still scarce.
