Diagnostic and therapeutic challenges in primary vitreoretinal lymphoma: a practical clinical approach.

Abstract

Background: Primary vitreoretinal lymphoma (PVRL) is a rare but aggressive subtype of extranodal diffuse large B-cell lymphoma and is closely related to primary central nervous system lymphoma (PCNSL). Its ability to masquerade as chronic posterior uveitis frequently leads to delayed diagnosis and inappropriate treatment, with significant prognostic implications.

Methods: A narrative review was performed following a comprehensive search of the PubMed/MEDLINE and Cochrane Library databases, encompassing publications from 2000 through 2025 and including randomized controlled trials, observational studies, prospective and retrospective studies, and systematic reviews. The search strategy incorporated the following keywords: "primary vitreoretinal lymphoma", "intraocular lymphoma", "diagnostic vitrectomy", "MYD88 mutation", "IL-10/IL-6 ratio", "intravitreal methotrexate", "rituximab", "CNS involvement", "optical coherence tomography". Two authors independently conducted study selection and eligibility assessment.

Results: Heightened clinical awareness remains pivotal for diagnosing PVRL, particularly when vitritis is partially responsive to steroids, when involvement is bilateral or asymmetric, and when subretinal pigment epithelial infiltrates are present. Multimodal imaging - including optical coherence tomography (OCT), fundus autofluorescence (FAF), and fluorescein angiography (FA) - facilitates early recognition and supports clinical suspicion. Diagnostic vitrectomy with cytology, immunohistochemistry, cytokine analysis (IL-10/IL-6 ratio), and molecular testing (IgH rearrangement, MYD88 L265P mutation) significantly increases diagnostic accuracy. Due to the strong association with central nervous system (CNS) involvement, neuroimaging is mandatory at diagnosis and during follow-up. Treatment options include intravitreal methotrexate and/or rituximab, systemic high-dose methotrexate-based chemotherapy, and radiotherapy. Emerging therapies in PVRL focus on targeted agents, including intravitreal biologics, BTK inhibitors, and personalized molecular-based treatments. The optimal strategy remains controversial and should be individualized based on CNS status and patient characteristics.

Discussion: Primary vitreoretinal lymphoma remains a diagnostic challenge due to its ability to mimic chronic inflammatory eye disorders and the frequent delay in establishing a definitive diagnosis. The integration of multimodal imaging, vitreous cytology, immunohistochemistry, cytokine profiling, and molecular testing has significantly improved diagnostic accuracy. However, management remains complex because of the close association with CNS involvement and the absence of universally accepted treatment protocols. Current therapeutic approaches, including intravitreal chemotherapy, systemic methotrexate-based regimens, and targeted therapies, require individualized selection based on disease extension and patient characteristics. Future advances in molecular diagnostics and personalized treatment strategies may contribute to earlier detection, improved disease control, and better long-term outcomes.

Conclusions: Prompt diagnosis, combined with a structured diagnostic approach, is essential to improving outcomes in PVRL. Close collaboration among ophthalmologists, hematologists, neurologists, and pathologists is mandatory for optimal patient management.