Primary Vitreoretinal Lymphoma: A Comprehensive Retrospective Analysis of 65 Cases at Two European Centers

Introduction. Primary vitreoretinal lymphoma (PVRL) is a distinct subset of primary central nervous system lymphoma (PCNSL), characterized by its emergence within the intraocular environment without initial brain involvement. The pathogenesis of PVRL remains unclear, though it is hypothesized to originate outside the CNS, subsequently migrating to ocular regions where an immune-permissive microenvironment facilitates its manifestation. Diagnostically, PVRL presents significant challenges due to its clinical mimicry of uveitis and the fragility of lymphoma cells in the vitreous. The treatment of PVRL is demanding as well, with diverse and heterogeneous strategies, encompassing localized intravitreal therapy, radiotherapy, systemic chemotherapy, and targeted therapy. However, as a rare disease, data on PVRL are limited, and prospective trials are largely absent. Through collaboration between two European centers, we conducted a comprehensive retrospective analysis of PVRL cases to evaluate treatment outcomes and relapse behavior, aiming to enhance understanding of this challenging condition.

Methods. A retrospective analysis of PVRL cases was performed at the University Hospital Tübingen and the Medical University Graz. Electronic health records were analyzed for demographic data, clinical presentation, diagnostic procedure, treatments and outcome, relapse manifestations and adverse events. Descriptive statistics are provided for the entire cohort and center-specific cohorts. Statistical comparisons using SPSS were performed where possible.

Results. A total of 65 cases with intraocular lymphoma involvement were identified (Tübingen n=34, Graz n=31), comprising 40 cases of primary vitreoretinal lymphoma (PVRL), 9 cases of primary central nervous system lymphoma (PCNSL) with later ocular involvement, 5 cases of PCNSL with simultaneous eye infiltration, and 11 cases of systemic diffuse large B-cell lymphoma (DLBCL) at initial diagnosis. The mean age at diagnosis was 72.7 years (range 49-96), 55.4% were female, and the median follow-up time was 18 months. The median time to diagnosis from the onset of the first symptoms was 31 days (range 1-2805). There was considerable heterogeneity in treatment modalities and clinical management. Intravitreal (itv.) treatment primarily involved Rituximab (n=34), Methotrexate (n=19), or combinations thereof (n=5). Intravitreal Methotrexate resulted in clinically significant keratopathy in 11 of 12 cases (91.7%), while Rituximab caused increased intraocular pressure in 9 of 34 cases (26.4%). Intravitreal treatment (n=58) resulted in 55.2% complete responses, and 34.6% partial responses, without a significant difference between modalities. A total of 69.2% (n=45) of patients received systemic chemotherapy at some point, including 11 patients who received systemic immunochemotherapy despite having exclusive eye manifestations. Despite intensive therapy, 70% of cases developed a single documented relapse of any kind, while 52.4% developed a second relapse, considering high rates of patients lost to follow-up (n=25).

Conclusions. This retrospective analysis of a large cohort highlights the significant heterogeneity in treatment approaches for PVRL. The study found no significant differences in overall outcomes between intravitreal rituximab and intravitreal methotrexate. However, each treatment had distinct adverse effects, with methotrexate causing keratopathy and rituximab associated with increased intraocular pressure. Despite diverse treatment strategies, the high rate of relapses underscores the need for standardized treatment protocols. Future prospective trials are essential to optimize therapeutic strategies and improve long-term outcomes for PVRL patients, addressing both intraocular disease control and CNS relapse prevention.