From the Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
Supported by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: firstname.lastname@example.org
Iris neovascularization in eyes with retinoblastoma suggests advanced intraocular tumor or the presence of extensive retinal detachment.1 Hence, iris neovascularization typically portends poor prognosis for globe salvage and future vision.2 In cases of unilateral advanced retinoblastoma with iris neovascularization, enucleation is generally advised. Chemoreduction is often preferred in cases of bilateral retinoblastoma with iris neovascularization in which both eyes might require enucleation, with the goal to save at least one eye.2 Chemoreduction, using vincristine, etoposide, and carboplatin, has been shown in several large reports to be effective in retinoblastoma control, particularly in eyes with less advanced tumor.3 The role of chemoreduction for eyes with retinoblastoma-related iris neovascularization has been described in a few cases in the literature.2 We report a case of bilateral retinoblastoma with iris neovascularization that showed complete resolution and globe salvage following chemoreduction.
A 30-month-old girl was noted by her parents to have deviation of the left eye for 1 year. She was diagnosed as having left esotropia and treated with amblyopia patching of the fellow eye for 1 year. One month before presentation, the parents noted a white reflex in the left eye and magnetic resonance imaging disclosed a large, heterogeneous, enhancing intraocular mass with additional enhancement in the anterior chamber of the left eye and a smaller nodule in the right eye. There was no optic nerve or extraocular extension. A diagnosis of bilateral retinoblastoma was suspected and she was referred for management.
On examination, visual acuity was fix-and-follow in the right eye and no fix or follow in the left eye. Intraocular pressures measured 13 mm Hg in both eyes. Leukocoria was noted in the left eye (Figure). There was iris neovascularization in the left eye. Fundus examination revealed three retinocytomas (spontaneously arrested retinoblastomas) in the right eye, located in the macula, ora serrata, and inferiorly. All were 6 mm in diameter or smaller. There was no subretinal fluid, subretinal seed, or vitreous seed in the right eye and it was classified as group B retinoblastoma. Fundus examination of the left eye revealed a large retinoblastoma measuring 24 mm in basal diameter with total retinal detachment and diffuse vitreous and subretinal hemorrhage, classified as group E. B-scan ultrasonography showed a solid tumor with calcium measuring 14.4 mm in thickness and confirmed the retinal detachment.
Figure. A 30-Month-Old Girl with Small Presumed Retinocytomas in the Right Eye and Advanced Retinoblastoma with Iris Neovascularization in the Left Eye. (A) Anterior Segment Photograph of the Left Eye Showing Massive Tumor and Retinal Detachment Behind the Clear Lens. (B) Iris Fluorescein Angiography Depicting Dye Leakage from Iris Neovascularization. (C) Fundus Image Revealing Group E Retinoblastoma. (D) After Chemoreduction, the Leukocoria Had Disappeared. (E) No Sign of Iris Neovascularization on Iris Fluorescein Angiography. (F) Complete Tumor Regression and Resolution of the Retinal Detachment Is Found.
Given the bilaterality of disease, the plan was to treat with chemoreduction with possible future enucleation in the left eye if there was a poor response. Six cycles of chemoreduction using vincristine (0.9 mg/m2), carboplatin (336 mg/m2), and etoposide (90 mg/m2) was employed. As early as 1 month following chemoreduction cycle #1, there was dramatic regression of the large retinoblastoma in the left eye with resolution of retinal detachment and the iris neovascularization had completely resolved with normal intraocular pressures. At 3 months of follow-up, there was no evidence of iris neovascularization and the tumors in both eyes were stable.
Iris neovascularization was found in 44% of 106 eyes with retinoblastoma as described by Walton and Grant, who concluded that the presence of iris neovascularization was a risk factor for advanced disease with possible tumor invasion into the choroid and optic nerve.4 Similarly, Eagle reported the presence of iris neovascularization in 167 (43%) of 387 enucleated eyes with retinoblastoma.5 In that series, it was found that the incidence of iris neovascularization was greater (71%) in eyes with high-risk features when compared with those without high-risk features (34%).5 In a study by Pe’er et al. of 146 enucleated eyes with retinoblastoma, iris neovascularization was found in 96 (66%) eyes and there was also a significant association between iris neovascularization and other characteristic signs of advanced retinoblastoma, such as tumor size (P = .0004), optic nerve invasion (P = .0008), tumor necrosis (P = .0001), and calcification (P = .002).6
Intraocular malignancies, such as retinoblastoma, melanoma, and medulloepithelioma, as well as the retinal detachment that they produce, can be a source of vascular endothelial growth factor (VEGF).6,7 Pe’er et al. found that VEGF was secreted by hypoxic retinoblastoma, especially those in advanced, necrotic stages.6 All eight representative eyes chosen for in situ hybridization analysis of VEGF showed strong signals of VEGF mRNA in retinoblastoma cells.6 They speculated that VEGF and other factors function as mediators of ischemia-induced iris neovascularization in eyes with retinoblastoma.6
Elevated levels of VEGF and VEGF receptors in the retina, choroid, and iris of eyes with retinoblastoma may explain breakdown of the blood–retinal barrier and induce preretinal and iris neovascularization.8 Management of eyes with VEGF-induced neovascularization typically focuses on the use of a VEGF inhibitor, but this is not appropriate for eyes with retinoblastoma because this could lead to seeding of the malignancy from the intravitreal injection. In eyes with malignancy, the target is classically management of the malignancy with hope for resolution of the source of VEGF. In our case, tumor control with chemoreduction resulted in resolution of the retinoblastoma and retinal detachment with visible resolution of the iris neovascularization.
However, a unique situation arises when a patient presents with bilateral advanced retinoblastoma. In such a circumstance, globe retention of at least one eye is desirable, especially if both eyes manifest group D or E retinoblastoma.9 In a study of 76 eyes with group E retinoblastoma managed with chemoreduction, Shields et al. explored management of chemoreduction alone or chemoreduction plus prophylactic low dose external beam radiotherapy (P-EBRT).9 At 5 years of follow-up, globe salvage with chemoreduction alone (33%) was statistically less than that with chemoreduction plus P-EBRT (80%) (relative risk = 3.33, 95% confidence interval = 2.03 to 5.46).9 Therefore, globe retention with advanced retinoblastoma (group E) is best achieved with chemoreduction and low dose P-EBRT (P < .001).9
There have been previous case reports with observations of iris neovascularization resolution following treatment of retinoblastoma, as in our case.2 In one study, two cases of advanced bilateral retinoblastoma with iris neovascularization showed complete resolution of the iris neovascularization after chemoreduction.2 This observation is important, particularly for children who manifest bilateral iris neovascularization with hope for retention of at least one eye without iris neovascularization-related glaucoma.
In this case, iris neovascularization showed dramatic complete resolution, clinically and angiographically, early in the treatment of the malignancy. So, the old dictum of “enucleation for eyes with retinoblastoma and iris neovascularization” could be changing in this era of chemoreduction.
- Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008:293–317.
- Shields CL, Sun H, Manquez ME, Leahey A, Meadows AT, Shields JA. Resolution of iris neovascularization following chemoreduction of advanced retinoblastoma. Arch Ophthalmol. 2006;124:1196–1197. doi:10.1001/archopht.124.8.1196 [CrossRef]
- Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280. doi:10.1016/j.ophtha.2006.06.018 [CrossRef]
- Walton DS, Grant WM. Retinoblastoma and iris neovascularization. Am J Ophthalmol. 1968;65:598–599.
- Eagle RC Jr, . High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med. 2009;133:1203–1209.
- Pe’er J, Neufeld M, Baras M, et al. Rubeosis iridis in retinoblastoma: histologic findings and the possible role of vascular endothelial growth factor in its induction. Ophthalmology. 1997;104:1251–1258.
- Missotten GS, Notting IC, Schlingemann RO, et al. Vascular endothelial growth factor A in eyes with uveal melanoma. Arch Ophthalmol. 2006;124:1428–1434. doi:10.1001/archopht.124.10.1428 [CrossRef]
- Stitt AW, Simpson DA, Boocock C, et al. Expression of vascular endothelial growth factor (VEGF) and its receptors is regulated in eyes with intra-ocular tumours. J Pathol. 1998;186:306–312. doi:10.1002/(SICI)1096-9896(1998110)186:3<306::AID-PATH183>3.0.CO;2-B [CrossRef]
- Shields CL, Ramasubramanian A, Thangappan A, et al. Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes. Ophthalmology. 2009;117:544–551. doi:10.1016/j.ophtha.2008.10.014 [CrossRef]