Retinal Capillary Hemangioblastomas in VHL
Case studies suggest a novel therapeutic may be able to treat these vision-threatening ocular tumors.
Corrina P. Azarcon, MD, DPBO; Imaan Zera Kherani, MD; and Amin Kherani, MD, FRCSC, FASRS
Retina Today
Von Hippel-Lindau (VHL) is an autosomal dominant neurocutaneous syndrome characterized by the growth of vascular tumors throughout the body, including the kidneys, pancreas, brain, spine, and eyes. This rare genetic mutation is found in one out of 36,000 individuals, and at least 900 cases have been reported in Canada.1,2 A key mechanism of VHL involves angiogenesis in normoxic conditions due to inactivation of the VHL protein via germline mutations of the VHL tumor suppressor gene. The inactivated VHL protein loses its ability to degrade hypoxia-inducible factors (HIF), leading to the formation of stable HIF subunits, activation of HIF-mediated transcription, and VEGF production.2-5 OCULAR TUMORS ASSOCIATED WITH VHL Ocular manifestations affect approximately half of patients with VHL and are diagnosed at a mean age of 26 years.6,7 Retinal capillary hemangioblastomas (RCHs) are the most common, with an 80% chance after age 80.2,7,8 RCHs typically present unilaterally or bilaterally in the peripheral retina or juxtapapillary area. These lesions can lead to vision-threatening complications, such as retinal nonperfusion and exudative or tractional retinal detachments (RDs).7,9 Treatment of RCHs is indicated when the vision is compromised; otherwise, small peripheral tumors are monitored.10,11 Ablative treatment modalities, such as laser, cryotherapy, transpupillary thermotherapy, photodynamic therapy, plaque brachytherapy, and external beam radiotherapy, are employed in cases of tumor progression.2 Surgical resection may be warranted for larger tumors, and intravitreal anti-VEGF therapy may be used as an adjunctive treatment to control exudation and retinal edema.2,11 While smaller and peripheral tumors respond well to local treatment, large or juxtapapillary tumors may be refractory.11 Belzutifan (Welireg, Merck), a small-molecule HIF-2α inhibitor that effectively blocks HIF pathway activation, inhibits VEGF-driven angiogenesis and tumor progression. This novel drug is already approved for nonsurgical renal cell carcinoma, central nervous system (CNS) hemangioblastomas, and pancreatic neuro-endocrine tumors in patients with VHL.12,13 While RCHs have not been specifically identified as an indication for the initiation of belzutifan, reports are beginning to shed light on its potential benefits for patients with RCH who are also dealing with other VHL-associated tumors.14-16 In this report, we present a patient with VHL and bilateral RCHs alongside systemic tumors, whose ocular tumors responded favorably to treatment with oral belzutifan. CASE REPORT A 30-year-old woman with genetically confirmed VHL syndrome has been followed for 2 decades in our retina clinic due to RCHs. She established care with our institution at 11 years of age, at which time she was asymptomatic and had a VA of 20/20 OU. She was diagnosed with a peripapillary RCH in her left eye, which was initially observed. Over the next 4 years, her vision gradually worsened to a VA of 20/100 OS secondary to tumor growth, bleeding, and exudation. Intravitreal anti-VEGF injections resulted in temporary improvement of the retinal edema.