Primary vitreoretinal lymphoma (PVRL) is a rare but highly aggressive intraocular malignancy closely associated with primary central nervous system lymphoma (PCNSL). Characterized by vague symptoms and high rates of misdiagnosis, PVRL poses significant challenges to timely intervention. In a recent review published in Blood Science, researchers examine evolving diagnostic techniques, current treatment approaches, and future directions in the management of this disease.Diagnostic Approaches
（Blood Science. 7(2):e00233, June 2025.）
Diagnosing PVRL requires a combination of clinical evaluation, ocular imaging, cytological analysis, and molecular testing. Cytological examination of vitreous samples is the gold standard, but the yield is often low due to limited cellularity and prior corticosteroid treatment. To improve sensitivity, immunohistochemistry and flow cytometry are employed to detect B-cell markers such as CD19 and CD20. Molecular diagnostics, including immunoglobulin heavy chain (IgH) rearrangement analysis and mutation screening for MYD88 and CD79B, increase diagnostic specificity. The introduction of next-generation sequencing (NGS) has further enhanced the ability to detect pathogenic mutations and enables broader genetic profiling from small ocular fluid samples. Supportive biomarkers such as interleukin-10 (IL-10) and altered IL-10/IL-6 ratios in the aqueous humor aid in diagnosis. Imaging techniques such as optical coherence tomography (OCT) and fundus autofluorescence (FAF) provide structural insight, while MRI and cerebrospinal fluid (CSF) analysis are essential in cases where CNS involvement is suspected.
Treatment Strategies and Outcomes
（Blood Science. 7(2):e00233, June 2025.）
Treatment aims to achieve local disease control and prevent CNS dissemination. Local therapies include intravitreal methotrexate (MTX), intravitreal rituximab, and external-beam radiotherapy (EBRT). Methotrexate is typically administered weekly and tapered after disease control is achieved. Rituximab, which targets CD20, can be used either as monotherapy or in combination with MTX. EBRT is effective in achieving intraocular control, though it carries a risk of ocular toxicity. In cases where there is CNS involvement or high risk of dissemination, systemic high-dose methotrexate (HD-MTX) is commonly used, borrowing from PCNSL treatment protocols. Retrospective studies suggest that combining systemic and local therapies may delay CNS relapse and improve disease control. For patients with relapsed or refractory PVRL, autologous stem cell transplantation (ASCT) may offer benefit, particularly in younger and fit individuals. Reduced-intensity conditioning regimens are currently being explored to expand eligibility to older patients.
Safety Profile
While effective, all current treatment modalities carry potential risks. Intravitreal methotrexate may cause corneal epitheliopathy and intraocular inflammation, and repeated injections may pose challenges in terms of patient tolerance. Radiotherapy is associated with long-term complications such as cataract formation and retinal damage. Systemic HD-MTX can cause myelosuppression, nephrotoxicity, and neurotoxicity, particularly in elderly patients or those with preexisting comorbidities. ASCT, though promising for long-term control, is intensive and may not be suitable for all patients. Monitoring and managing these risks is essential to optimizing therapy.
Emerging Therapies and Innovations
In light of the limitations of existing treatments, several novel therapies are under investigation. Lenalidomide, an immunomodulatory agent, has shown encouraging activity in combination with rituximab for relapsed disease. Bruton’s tyrosine kinase inhibitors (BTKis) such as ibrutinib are being explored for their ability to block B-cell receptor signaling and have demonstrated promising responses in PCNSL, with potential applicability to PVRL. Immune checkpoint inhibitors and CAR T-cell therapies are also being considered, though data specific to PVRL are currently limited. Targeted therapies directed at pathways such as mTOR, PI3K, and BCL family proteins are in preclinical and early clinical phases, offering potential future treatment avenues. Additionally, artificial intelligence applications in ophthalmic imaging may soon enhance early diagnostic accuracy and treatment monitoring.
Conclusion
Primary vitreoretinal lymphoma remains a formidable diagnostic and therapeutic challenge due to its insidious onset, high risk of CNS dissemination, and limited treatment standardization. However, the landscape is evolving. Advances in molecular diagnostics, including NGS and cytokine profiling, are improving the speed and accuracy of diagnosis. Emerging therapies, particularly those targeting molecular pathways and immune mechanisms, hold promise for patients with relapsed or refractory disease. As highlighted in Blood Science, a multidisciplinary approach combining ophthalmology, hematology, oncology, and neurology is essential to improving outcomes. Continued innovation and collaboration across specialties will be key to transforming the prognosis of this rare but deadly malignancy.
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