Risk Analysis of Retinal Hemangioblastomas in Nonadvanced Stages of von Hippel–Lindau Syndrome Using Ultra-widefield Imaging: The ULTRA von Hippel–Lindau Study

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science Pub Date : 2025-06-09 DOI:10.1016/j.xops.2025.100846

Sebastiano Del Fabbro MD , Maria Vittoria Cicinelli MD , Rosangela Lattanzio MD , Soufiane Bousyf MD , Lorenza Bruno MD , Alessio Antropoli MD , Lorenzo Bianco MD , Elena Bruschi MD , Alessandro Arrigo MD , Giovanni Pipitone MD , Francesco Cei MD , Lucia Salerno MD , Alessandro Larcher MD , Andrea Salonia MD , Francesco Bandello MD , Maurizio Battaglia Parodi MD , the OSR VHL Program

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Abstract

Purpose

To investigate the longitudinal progression, risk factors, and complications associated with retinal hemangioblastomas (RHs) in nonadvanced stages of von Hippel–Lindau (VHL) syndrome using ultra-widefield (UWF) imaging.

Design

Single-center longitudinal cohort study.

Subjects

Caucasian patients with genetically confirmed VHL syndrome.

Methods

Annual evaluations included dilated fundus examinations, UWF pseudocolor fundus retinal images, UWF fluorescein angiography, and OCT. Genetic analysis classified VHL mutations. Baseline RH counts and anatomical distributions were recorded as central (juxtapapillary, macular), peripheral, or both. Longitudinal follow-up tracked new RH formation and visual acuity (VA) values.

Main Outcome Measures

Cumulative incidence, incidence rate ratios (IRRs), and risk factors of new RHs assessed using mixed-effects negative binomial regression models. Hazard of recurrent RHs evaluated through Cox frailty models and longitudinal changes in VA.

Results

Among 78 eyes of 43 patients (mean age: 47.8 ± 13.6 years), 110 RHs were documented at baseline, with 3 (3%) centrally located, 35 (32%) peripherally, and 72 (65%) spanning both zones. von Hippel–Lindau variants were investigated in 37 patients: 19 had missense variants (51%), and 18 had presumed null alleles (49%), including nonsense (10 of 37; 27%), frameshift (1 of 37; 3%), splice site (1 of 37; 3%), and exon deletion mutations (6 of 37; 16%). Over a median follow-up of 31 months (interquartile range: 27–109), 35 (43%) eyes developed new RHs, with an incidence rate of 0.22 RHs per eye-year (95% confidence interval: 0.17–0.27). By the last available examination, 26 eyes (34%) remained disease-free, whereas17 (23%) showed no progression of existing RHs. Age reduced the IRR of new RHs by 4.2% annually (P = 0.003), whereas higher baseline tumor burden and vascular leakage increased the IRR significantly (P < 0.001 and P = 0.03, respectively). Peripheral RHs were the strongest predictor of recurrence (hazard ratio = 16.4, P < 0.001), whereas older age remained protective (hazard ratio = 0.96, P = 0.04). Visual acuity (logarithm of the minimum angle of resolution) worsened from 0.05 ± 0.2 (Snellen equivalent: 20/22) at baseline to 0.11 ± 0.3 (Snellen equivalent: 20/25) at the final visit.

Conclusions

Peripheral RHs and vascular leakage are significant risk factors for RH progression and recurrence in VHL syndrome. Although older age provides a protective effect, close monitoring of high-risk eyes is essential to enable timely intervention and preserve vision.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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使用超宽视场成像分析非晚期von Hippel-Lindau综合征视网膜血管母细胞瘤的风险：ULTRA von Hippel-Lindau研究

目的应用超宽视场（UWF）成像技术探讨非晚期von Hippel-Lindau （VHL）综合征视网膜血管母细胞瘤（RHs）的纵向进展、危险因素及并发症。设计：单中心纵向队列研究。研究对象：基因证实的VHL综合征的高加索患者。方法年度评估包括眼底扩张检查、UWF假彩色眼底视网膜图像、UWF荧光素血管造影和oct。基线RH计数和解剖分布记录为中心（并列乳头，黄斑），外周，或两者兼而有之。纵向随访追踪新的RH形成和视力（VA）值。主要结局指标采用混合效应负二项回归模型评估新发RHs的累积发病率、发病率比（IRRs）和危险因素。结果在43例患者（平均年龄：47.8±13.6岁）的78只眼中，基线时记录了110只RHs，其中3只（3%）位于中心，35只（32%）位于周围，72只（65%）跨越两个区域。在37例患者中研究了von Hippel-Lindau变异：19例有错义变异（51%），18例有推定无效等位基因（49%），包括无义变异(37例中的10例；27%)，移码(1 / 37；3%)，剪接位点(1 / 37；外显子缺失突变(6 / 37；16%)。在中位随访31个月（四分位数范围：27-109）中，35只（43%）眼出现新的RHs，每眼年发病率为0.22（95%可信区间：0.17-0.27）。到最后一次检查时，26只眼睛（34%）仍然无病，而17只（23%）没有显示现有RHs的进展。年龄使新发RHs的IRR每年降低4.2% (P = 0.003)，而较高的基线肿瘤负荷和血管泄漏显著增加IRR (P <；0.001和P = 0.03)。外周RHs是复发的最强预测因子(风险比= 16.4,P <；0.001)，而老年仍然具有保护作用（风险比= 0.96,P = 0.04）。视力（最小分辨角的对数）从基线时的0.05±0.2（斯奈伦当量：20/22）恶化到最后一次就诊时的0.11±0.3（斯奈伦当量：20/25）。结论外周RH和血管渗漏是VHL综合征RH进展和复发的重要危险因素。虽然老年提供了保护作用，但密切监测高风险眼睛对于及时干预和保护视力至关重要。财务披露专有或商业披露可在本文末尾的脚注和披露中找到。

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