Primary Vitreoretinal Lymphoma

Synonyms

PVRL, ,

Overview

Primary vitreoretinal lymphoma (PVRL) is a rare form of primary central nervous system (CNS) lymphoma (PCNSL) arising in the intraocular compartment without brain involvement. Despite its apparent indolent clinical course, PVRL can cause permanent vision loss and CNS relapse, the major cause of death in patients with PVRL. The pathophysiology of PVRL is unknown. As in PCNSL, the transformation of the tumor cells likely originates outside the CNS, before the cells migrate to the eye and proliferate within an immune-permissive microenvironment. PVRL exhibits a biased immunoglobulin repertoire, suggesting underlying antigen selection. The diagnosis remains challenging, requiring close coordination between ophthalmologists and cytologists. Because of their rarity and fragility in the vitreous, lymphoma cells cannot always be identified. Interleukin levels, molecular biology, and imaging are used in combination with clinical ophthalmological examination to support the diagnosis of PVRL. Multi-institutional prospective studies are urgently needed to validate the equivocal conclusions regarding treatments drawn from heterogeneous retrospective or small cohort studies. Intravitreal injection of methotrexate or rituximab or local radiotherapy is effective at clearing tumor cells within the eyes but does not prevent CNS relapse. Systemic treatment based on high-dose methotrexate chemotherapy, with or without local treatment, might reduce this risk. At relapse, intensive consolidation chemotherapy followed by stem cell transplantation can be considered. Single-agent ibrutinib, lenalidomide, and temozolomide treatments are effective in patients with relapsed PVRL and should be tested as first-line treatments. Therapeutic response assessment based on clinical examination is improved by measuring cytokine levels but still needs to be refined.

Symptoms

The disease’s insidious onset coupled with vague complaints from patients with PVRL are among the factors that make early diagnosis difficult. The differential diagnosis is broad and includes other ocular lymphomas, non-lymphomatous neoplastic conditions, and non-neoplastic conditions of the retina.

Symptoms. Nonetheless, a variety of clinical observations aid in diagnosis of PVRL. Typically, the disease mimics a steroid-resistant chronic uveitis with associated vitritis. The most common ocular complaints reported by patients include blurred vision, painless loss of vision, floaters, red eye, and photophobia. If PVRL presents concurrently with CNSL, there may be behavioral changes and neurological findings such as hemiparesis and ataxia.

Signs. On exam, clinical signs may overlap with those of chronic posterior uveitis. Anterior chamber signs may include mild cells and flare, but more typically, these signs are absent.

Vitritis is common in PVRL and may manifest as an “aurora borealis” effect as cells gather along vitreal fibers, especially in the superior peripheral vitreous. In addition, the vitreous cells in PVRL tend to be larger and less abundant than those found in typical vitritis. Although it is not common, the classic “leopard spot” collection of subretinal pigmented lesions that coalesce over time may appear on funduscopic examination. Retinal whitening, as seen in viral retinitis, is not a hallmark of this disease. Rarely, PVRL may be associated with exudative retinal detachment, a fundus mass, or concurrent optic nerve swelling.

Diagnosis

A patient who is 50 years or older with steroid-resistant uveitis or persistent vitritis, minimal fundus changes, and generally preserved visual acuity should raise suspicion for PVRL.

Imaging. Ophthalmic imaging studies, though not specific or diagnostic, may help validate clinical suspicion of the disease. Fluorescein and indocyanine green angiography may exhibit localized hypofluorescent spots from subretinal infiltrate or hyperfluorescent window defects. Features present in other posterior uveitic conditions are not commonly seen, including perivascular staining, vessel leakage, cystoid macular edema, or optic nerve swelling.

Fundus autofluorescence patterns are typically normal but may highlight clinically observed areas of brown “leopard spots” as bright hyperautofluorescence. Chronic changes to the RPE may instead produce focal areas of dark hypoautofluoresence.

New findings that have been identified on optical coherence tomography include cellular infiltrates in the vitreous, focal pockets of subretinal hyper-reflective material between the RPE and Bruch’s membrane, and small pockets of RPE detachments.

Ophthalmic ultrasound is helpful to demonstrate choroidal thickening and rule out intraocular or orbital mass lesions as seen in choroidal lymphoma.

Laboratory testing. Once PVRL is considered in the differential diagnosis, more common causes of ocular inflammation should be eliminated, and directed systemic laboratory testing is usually needed. Definitive diagnosis requires identification of malignant lymphoid cells in the eye.

When vitritis is the predominant clinical sign, diagnostic pars plana vitrectomy to obtain both undiluted and partially diluted vitreous specimens is preferable to aqueous fluid collection or bedside vitreous tap. If multifocal white subretinal deposits are seen with minimal vitreous cells, a diagnostic vitrectomy may be combined with full-thickness chorioretinal biopsy or needle aspiration of subretinal material. Repeat biopsies may be required.

In all cases, specimens must be processed immediately and preferably hand-delivered by the operating surgeon to the laboratory for prompt analysis. After careful discussion with the pathologist, the surgeon should be certain that testing facilities are available for cytopathology.

Although cytopathology is most sensitive for detecting abnormal lymphoid cells, biomolecular analyses are available to bolster the diagnosis of B-cell PVRL, including detectable CD20, CD79, and PAX5. In rare cases, T-celldominated lymphoma may reveal CD3 and CD8 markers. Flow cytometric analysis may identify clonal B-cell populations on the basis of cell surface markers. Further tests include immunohistochemistry and elevated IL-10 to IL-6 ratio greater than 1, but clinicians should be aware of the low sensitivity of this method of testing.

If the diagnosis is confirmed, a team approach with a medical oncologist trained in treatment of CNS lymphoma is recommended to help coordinate systemic testing, including neuroimaging and lumbar puncture.

Prognosis

Relapse rates for PVRL are variable depending on treatment and follow-up. Despite advances in treatment and diagnosis, prognosis for those with PVRL/PCNSL remains dismal, with progression-free survival around 1 year and overall survival under 3 years. Although ocular therapy alone can achieve local control, it has little effect on overall survival.

Treatment

Management of PVRL remains controversial, but it generally employs a multimodal approach including systemic therapy, radiotherapy, and intravitreal chemotherapy monitored by an oncologist. Systemic high-dose methotrexate (MTX)-based chemotherapy is used to treat both ocular and CNS disease. Many clinicians favor systemic therapy even for apparently isolated ocular disease, out of concern that subclinical CNS disease may be present concurrently.

Local ocular therapy may be used as monotherapy or as part of a combination that includes external beam radiotherapy to both globes and intravitreal MTX and rituximab. The involvement of both eyes does not preclude the use of local therapy, but systemic therapy should be considered.