From the Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Arun D. Singh, MD, Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.
Vasoproliferative tumor is an uncommon lesion composed of glial cells and a fine capillary network.1 Recognized as a distinct clinical entity only recently,2 this condition was originally termed “presumed acquired retinal hemangiomas.”3 The currently preferred term was coined by Shields et al. in 1995.4 Vasoproliferative tumor is most often idiopathic (74%), but can occur secondary to preexisting ocular disease (26%), including intermediate uveitis, retinitis pigmentosa, ocular toxoplasmosis, and Waardenburg’s syndrome.4–6 Vision loss can occur secondary to retinal fibrosis, subretinal exudation, and neovascular glaucoma.7 Successfully used treatment modalities have included transconjunctival cryotherapy,4 plaque brachytherapy,4,8,9 laser photocoagulation,4 photodynamic therapy,10,11 and transscleral local resection.1 This report describes a patient with neurofibromatosis type 1 and vasoproliferative tumor with neovascularization of the iris that was successfully treated with intravitreal bevacizumab and cryotherapy.
A 15-year-old girl with neurofibromatosis type 1 was referred for evaluation of painless floaters in the right eye of 1 month’s duration. The ocular history was significant for absence of light perception in the left eye and a temporal field defect in the right eye as a result of a glioma of the left optic nerve and optic chiasm that had been treated with chemotherapy.
In the right eye, visual acuity was 20/30 and intraocular pressure was 12 mm Hg. Anterior segment examination showed numerous Lisch nodules, florid neovascularization of the iris, and 360° neovascularization of the angle (Fig. 1A). Dilated fundus examination of the right eye showed 1+ to 2+ anterior vitreous cells and an inferiorly located elevated pink vascular mass with areas of surrounding subretinal fluid and lipid accumulation (Fig. 1B). Dilated tortuous feeder vessels, as seen with retinal capillary hemangioma, were not observed. Fluorescein angiogram showed diffuse lake leakage from the mass. B-scan ultrasound showed an irregular solid mass (8.5 × 8.5 × 2.5 mm) and high internal reflectivity, with a shallow exudative retinal detachment. The findings were consistent with vasoproliferative tumor with associated neovascularization of the iris. The patient also had a diffuse cutaneous hemangioma on the right shoulder (Fig. 2).
Figure 1. (A) Slit-Lamp Photograph of the Right Eye at Presentation Showing Multiple Lisch Nodules and Florid Neovascularization of the Iris. (B) On Gonioscopic Examination, 360° Neovascularization of the Angle Is Seen. In the Inferior Fundus, There Is an Elevated Pink Vascular Mass with Surrounding Lipid Exudate, Consistent with Vasoproliferative Tumor.
Figure 2. A Cutaneous Hemangioma Is Seen on the Right Shoulder.
The patient had just completed a tapering course of oral steroids (starting dose 60 mg daily, tapered by 20 mg/week) that had been prescribed by the referring physician. Various therapeutic options were discussed, and the patient was treated with double freeze–thaw transconjunctival cryotherapy and simultaneous intravitreal injection of bevacizumab (1.25 mg in 0.05 mL). Fully informed consent was obtained from the parents, with a clear explanation of the experimental nature of the treatment. One week later, neovascularization of the iris was nearly completely resolved and intraocular pressure was 13 mm Hg. One month after treatment, the retinal detachment overlying the vasoproliferative tumor had resolved and the tumor appeared less vascular, with fibrotic changes. However, neovascularization of the iris was increased and, because of concern about neovascular glaucoma, the decision was made to treat the patient with a second injection of intravitreal bevacizumab without additional cryotherapy.
Over the course of the next 6 months, the neovascularization of the iris resolved, with only a small area of residual neovascularization of the angle (Fig. 3A); intraocular pressure never increased to more than 16 mm Hg. Over the same period, the tumor underwent fibrotic changes, with chorioretinal atrophy and hyperpigmentation at the posterior margin (Fig. 3B). Ten months after initial treatment, findings on clinical examination were stable, with visual acuity of 20/30 in the right eye.
Figure 3. (A) After Treatment with Cryotherapy and Two Intravitreal Injections of Bevacizumab, Neovascularization of the Iris Resolved Almost Completely. (B) The Vasoproliferative Tumor Appeared Less Vascular, with Chorioretinal Atrophy and Hyperpigmentation of the Posterior Margin. Note Resolution of Lipid Exudates.
The systemic manifestations neurofibromatosis type 1 are caused by the development of hamartomas of neural crest origin. Retinal tumors, such as astrocytic hamartoma, combined hamartoma of the retina and retinal pigment epithelium, and retinal capillary hemangioma, are rarely seen in association with neurofibromatosis type 1.12 To the authors’ knowledge, vasoproliferative tumor of the retina has not been reported in association with neurofibromatosis type 1. Although the origin of vasoproliferative tumor is not well characterized, histopathologic examination shows proliferation of primarily glial cells, which are known to be of neural crest origin, with secondary vasoproliferation.1 Therefore, vasoproliferative tumor may represent a rare manifestation of neurofibromatosis type 1. Interestingly, the current patient also had a large cutaneous hemangioma (Fig. 2). Because neurofibromatosis type 1 is relatively common, with a prevalence of approximately 1 in 3,000,13 it is possible that the presence of vasoproliferative tumor in the current case is merely a chance occurrence.
The treatment of vasoproliferative tumor depends on the size, location, and secondary effects of the tumor. Small, asymptomatic tumors without exudate or maculopathy can be closely observed. When vision is threatened, treatment with transconjunctival cryotherapy is often used but may need to be repeated.4 Other effective treatments include plaque brachytherapy,4,8,9 laser photocoagulation,4 photodynamic therapy,10,11 and transscleral local resection.1
Cryotherapy can increase the risk of exudative retinal detachment,14 which may worsen neovascularization transiently. Additionally, regression of anterior and posterior segment neovascularization after cryotherapy is not immediate. Vascular endothelial growth factor levels have been shown to be elevated in the vitreous in many pathologic conditions that lead to neovascular glaucoma,15 and anti-vascular endothelial growth factor therapy offers the possibility of rapid regression of anterior segment neovascularization.16 Whether vasoproliferative tumors are vascular endothelial growth factor dependent is not known, although in one published case, adjunctive use of an anti-vascular endothelial growth factor agent (bevacizumab) led to regression of the vasoproliferative tumor.17 The current functionally monocular patient had florid neovascularization of the iris and angle. Therefore, anti-VEGF therapy was added to cryotherapy as a temporizing measure to prevent complete angle closure while awaiting the response to cryotherapy. The patient required one subsequent injection of bevacizumab, without additional cryotherapy, to attain regression of the neovascularization of the iris and the tumor.
This report describes a case of retinal vasoproliferative tumor in a patient with neurofibromatosis type 1. The administration of anti-vascular endothelial growth factor therapy, alone or in combination with other treatments, may provide a new therapeutic approach in the treatment of vasoproliferative tumor and associated complications.
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