Beyond the Optic Nerve: Unmasking Occult Intraretinal Lymphoma via Chorioretinal Biopsy

Introduction

Lymphomatous optic neuropathy (LON) is a rare but vision-threatening manifestation of central nervous system (CNS) lymphoma, characterized by the direct infiltration of malignant cells into the optic nerve. It can occur as a primary process or, more commonly, as a secondary spread from systemic non-Hodgkin’s lymphoma, such as diffuse large B-cell lymphoma (DLBCL). Early diagnosis is critical to preserving vision and life, yet detection remains a significant clinical challenge.

Current clinical guidelines for the diagnosis of vitreoretinal and optic nerve lymphoma heavily rely on neuro-imaging and cerebrospinal fluid (CSF) analysis. However, classical CNS surveillance modalities, including magnetic resonance imaging (MRI) and standard lumbar puncture cytology, are not always reliable in detecting early or isolated infiltration. In the absence of definitive findings on standard workup, clinicians face a dilemma regarding the timing and necessity of invasive procedures.

This case report discusses a patient with a history of DLBCL who presented with progressive optic neuropathy despite negative neuro-imaging and cerebrospinal fluid analysis. The case illustrates the limitations of standard CNS surveillance in detecting occult infiltration and highlights the necessity of tissue biopsy for definitive diagnosis.

Case Presentation

A 64-year-old female presented for evaluation for six weeks of left eye decreased vision. Her medical history was significant for hypertension, autoimmune hepatitis (status-post liver transplant), and DLBCL. Her oncologic history included treatment with R-CHOP (dose-reduced for hepatic insufficiency) and intrathecal methotrexate, which she had completed three months prior. Extensive surveillance for disease recurrence, including three lumbar punctures, a PET scan, CT and MRI of the brain, and two bone marrow biopsies, had been performed and confirmed remission of disease.

On examination, the patient’s vision was 20/20 in the right eye and light perception in the left eye (previously 20/25 three months prior). The left eye was also noted to have a relative afferent pupillary defect and a generalized constricted visual field.

Dilated funduscopic examination of the left eye revealed vitreous haze and severe optic disc edema. The optic nerve head was pale with obscured margins. Posterior segment assessment demonstrated scattered retinal infiltrates involving both the macula and periphery, alongside clinical findings consistent with a new central retinal artery occlusion.

Ancillary Testing

Next Steps

The patient's neuro-oncology team strongly recommended obtaining a tissue biopsy to facilitate definitive diagnosis and treatment planning. Consequently, in the setting of rapid clinical progression, a guarded visual prognosis, and OCT evidence of new infiltrative lesions, a diagnostic chorioretinal biopsy was performed. The specimen was submitted for surgical pathology analysis with utilization of CD20 immunohistochemical staining to evaluate for B-cell lineage pathology.

Discussion

Lymphomatous optic neuropathy demands a high index of suspicion in immunosuppressed patients or those with a history of lymphoma who present with unexplained optic neuropathy, as these cases typically follow a fulminant course of rapidly progressive, severe vision loss. A major diagnostic hurdle is the tendency for intraocular lymphoma to masquerade as uveitis, often showing temporary response to corticosteroids, which can delay definitive diagnosis by months or years[1]. Furthermore, classical CNS surveillance modalities often lack the sensitivity required to detect isolated ocular disease; cerebrospinal fluid cytology has a reported sensitivity ranging from only 2% to 32% in these contexts and is rarely positive in cases without overt CNS spread. In the case presented, multiple lumbar punctures and MRI scans failed to identify malignant cells despite active disease progression. For patients with better visual potential, less invasive diagnostics should be considered before biopsy, such as aqueous or vitreous sampling for the MYD88 and L265P mutations, which has demonstrated sensitivities of approximately 67% and 75% respectively[2]. Additionally, cytokine analysis with an IL-10/IL-6 ratio greater than 1.0 serves as a robust biomarker for intraocular lymphoma, with sensitivity reported between 81-92%[3].

References

1. Ahle G, Touitou V, Cassoux N, et al. Optic Nerve Infiltration in Primary Central Nervous System Lymphoma. JAMA Neurol. 2017;74(11):1368–1373.
2. Zhang, X., Peng, X., Liang, D. et al. Clinical guidelines for the diagnosis and treatment of vitreoretinal lymphoma in Chinese patients (2024). Eye and Vis 12, 20 (2025).
3. Hiemcke-Jiwa LS, ten Dam-van Loon NH, Leguit RJ, et al. Potential Diagnosis of Vitreoretinal Lymphoma by Detection of MYD88 Mutation in Aqueous Humor With Ultrasensitive Droplet Digital Polymerase Chain Reaction. JAMA Ophthalmol. 2018;136(10):1098–1104.