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Carlos Bianciotto, MD; Carol L. Shields, MD; Brian Kang, BS; Jerry A. Shields, MD

Arch Ophthalmol. 2008;126(4):578-579.

Iris melanoma is uncommon, representing only 2% of all uveal melanomas.¹ In a series of 169 consecutive patients with iris melanoma, Shields et al² indicated that elevated intraocular pressure was found in 30% of cases. The main mechanism for the elevated pressure was mechanical obstruction of aqueous outflow from solid tumor or seeding. In that series, there were no eyes with secondary neovascular glaucoma. We report herein the unique association of neovascular glaucoma with chronic iris melanoma and discuss its management.

Report of a Case
A 64-year-old man was referred with a documented 12-year history of a slowly enlarging pigmented iris lesion in the left eye. The right eye had longstanding poor vision secondary to ocular histoplasmosis with a foveal scar diagnosed at age 15 years. At his initial visit, the visual acuities were 20/300 OD and 20/150 OS. On slitlamp examination of the left eye, a nodular, pigmented tumor with prominent intrinsic vascularity was noted in the inferior iris and measured 8 mm in the largest diameter and 1.9 mm in thickness, with corneal endothelial touch (Figure 1). There was no ciliary body component by ultrasound biomicroscopy. Associated ectropion uveae, cataract, and profound iris neovascularization of the entire iris were found. Intraocular pressures were 17 mm Hg OD and 24 mm Hg OS, despite using topical and oral antiglaucoma medications. Angle involvement with tumor seeding and neovascularization were noted on gonioscopy. Fundus examination showed bilateral peripheral histoplasmosis chorioretinal lesions with a large atrophic foveal scar in the right eye.

View larger version (53K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. A 64-year-old man was referred with an enlarging iris melanoma and secondary neovascular glaucoma in his only seeing eye. A, The melanoma occupied the inferior portion of the iris and diffuse neovascularization on the entire iris surface was noted. B, Ultrasound biomicroscopy depicted a solid iris mass touching the endothelium.

A diagnosis of enlarging iris melanoma in the left eye with secondary cataract and neovascular glaucoma was rendered. Due to contralateral amblyopia, enucleation was avoided, and because of extensive tumor seeding, surgical resection was not considered. Plaque radiotherapy combined with a single injection of 1.25 mg of intravitreal bevacizumab (0.05 mL at a concentration of 25 mg/mL) (Avastin; Genentech, Inc, San Francisco, California) was advised for treatment of the melanoma and resolution of the iris neovascularization. At the time of radiotherapy, fine-needle aspiration biopsy of the melanoma for genetic testing was performed.

Microsatellite array disclosed chromosome 3 monosomy. At 15 months' follow-up, the iris neovascularization and glaucoma were completely resolved with an intraocular pressure of 6 mm Hg while the patient was receiving no medications, and the residual melanoma scar remained regressed and flat (Figure 2).

View larger version (68K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Treatment involved intravitreal bevacizumab and plaque radiotherapy. A, Application of the radioactive plaque over the cornea for a total dose of 8000 cGy to the melanoma (the conversion of centigray to rad is 1:1). B, Fifteen months after treatment, the tumor remained regressed and the iris neovascularization completely resolved. A dense cataract is present. Cataract surgery is planned.

Comment
The assumption that tumor growth and metastasis are angiogenesis dependent was initially proposed by Folkman³ in 1971. Recent research in tumor microvasculature has emphasized vascular endothelial growth factor (VEGF) as a mediator of tumor angiogenesis.⁴

Iris melanoma demonstrates VEGF expression.^4-5 Lee et al⁴ reported an iris melanoma with VEGF expression using immunohistochemical staining of an anti-VEGF antibody. Sahin et al⁵ described weak VEGF expression (staining of < 25% of cells) in 2 of 3 iris melanomas using a similar technique.

Bevacizumab is a recombinant humanized anti-VEGF IgG₁ monoclonal antibody approved as an antiangiogenic agent for the treatment of metastatic colorectal cancer in combination with chemotherapy.⁶ It has also been proven to increase survival rates when used in association with chemotherapy for the treatment of non–small-cell lung cancer. A phase 2 clinical trial of bevacizumab in patients with metastatic skin melanoma showed prolonged disease stabilization in 25% of the patients.⁷ From an ophthalmology standpoint, intravitreal bevacizumab has been used for age-related macular degeneration and iris neovascular glaucoma.⁸

The management of iris melanoma with elevated intraocular pressure is challenging and generally requires enucleation.² In this case, the bevacizumab was used in combination with plaque radiotherapy, which resulted in rapid resolution of the neovascular glaucoma as well as the tumor. The precise effect of bevacizumab on the melanoma remains speculative.

AUTHOR INFORMATION
Correspondence: Dr C. L. Shields, Ocular Oncology Service, Ste 1440, Wills Eye Institute, 840 Walnut St, Philadelphia, PA 19107 (carol.shields{at}shieldsoncology.com).

Financial Disclosure: None reported.

Funding/Support: This work was supported by the Retina Research Foundation of the Retina Society in Capetown, South Africa (Dr C. L. Shields), the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (Dr J. A. Shields), a donation from Michael, Bruce, and Ellen Ratner, New York, New York (Drs J. A. Shields and C. L. Shields), Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania (Dr C. L. Shields), the LuEsther Mertz Retina Research Foundation, New York (Dr C. L. Shields), and the Eye Tumor Research Foundation, Philadelphia (Drs C. L. Shields and J. A. Shields).

REFERENCES
1. Shields CL, Shields JA, Materin M, Gershenbaum E, Singh AD, Smith A. Iris melanoma: risk factors for metastasis in 169 consecutive patients. Ophthalmology. 2001;108(1):172-178. FULL TEXT | ISI | PUBMED 2. Shields CL, Materin MA, Shields JA, Gershenbaum E, Singh AD, Smith A. Factors associated with elevated intraocular pressure in eyes with iris melanoma. Br J Ophthalmol. 2001;85(6):666-669. FREE FULL TEXT 3. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186. ISI | PUBMED 4. Lee ES, Baratz KH, Pulido JS, Salomao DR. Expression of vascular endothelial growth factor in iris melanoma. Arch Ophthalmol. 2006;124(9):1349-1350. FREE FULL TEXT 5. Sahin A , Kiratli H, Tezel GG, Soylemezoglu F, Bilgic S. Expression of vascular endothelial growth factor a, matrix metalloproteinase 9 and extravascular matrix patterns in iris and ciliary body melanomas. Ophthalmic Res. 2007;39(1):40-44. FULL TEXT | ISI | PUBMED 6. Hurwitz H, Fehrenbacher J, Novotny W; et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342. FREE FULL TEXT 7. Varker KA, Biber JE, Kefauver C; et al. A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma [published online ahead of print May 30, 2007]. Ann Surg Oncol. 2007;14(8):2367-2376. FREE FULL TEXT 8. Davidorf FH, Mouser JG, Derick RJ. Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection. Retina. 2006;26(3):354-356. FULL TEXT | ISI | PUBMED

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