Primary Vitreoretinal Lymphoma

Primary vitreoretinal lymphoma is a rare subtype of primary central nervous system lymphoma, a diffuse large B-cell lymphoma that begins in the vitreous, retina or optic nerve. It often presents as a chronic uveitis that does not respond to treatment, and most patients develop brain involvement within a few years.

It forms about 1% of intraocular tumours and about 4% to 6% of primary CNS lymphoma, with an incidence of about 1 in 2,000,000 people each year. Median age at diagnosis is 60 to 65, with a slight female predominance. About 60% to 90% of patients develop CNS lymphoma, and about 15% to 25% of patients with primary CNS lymphoma have ocular involvement.

Immunosuppression (HIV infection, transplant) is a risk factor. Many cases occur in immunocompetent adults. Epstein-Barr virus is associated in immunosuppressed patients.

Pathophysiology. Tumour cells are large, atypical B-cells (CD20, CD79a, PAX5 positive) with a non-germinal centre phenotype in most cases. MYD88 L265P mutation occurs in about 70% to 80%, with CD79B and CARD11 variants and frequent IL10 expression. The vitreous shows raised interleukin-10 relative to interleukin-6.

Prognosis. Median survival is about 4 to 5 years with modern therapy, falling when CNS disease develops (the main cause of death). Ocular disease may recur in the other eye and after treatment.

• Painless blurred vision, floaters and reduced acuity, usually bilateral and asymmetric.
• Vitreous haze and cells without much anterior chamber inflammation, creamy yellow white subretinal infiltrates (leopard spot pattern), retinal pigment epithelial detachments, vasculitis and optic nerve swelling.
• Poor response to corticosteroids for presumed uveitis, with a transient response that masks the diagnosis.
• Headache, cognitive change, focal deficits, seizures or personality change when brain lymphoma is present.

Red flags.

• Rapidly progressive visual loss.
• New neurological symptoms in a patient with uveitis (CNS involvement).

• Ophthalmological examination with slit lamp and dilated fundus, optical coherence tomography, fundus autofluorescence, fluorescein angiography and ocular ultrasound.
• Diagnostic vitrectomy (preferred, with undiluted sample transported rapidly to the laboratory) or chorioretinal biopsy, with cytology, flow cytometry, immunohistochemistry, MYD88 L265P PCR and immunoglobulin heavy chain gene rearrangement. Stop corticosteroids for 2 weeks before biopsy when possible.
• Vitreous cytokines: interleukin-10 to interleukin-6 ratio over 1 supports the diagnosis.
• MRI of the brain and spine with gadolinium, lumbar puncture with CSF cytology and flow cytometry, CT of the chest, abdomen and pelvis or PET-CT, and testicular examination (and ultrasound in men) for primary extra-CNS lymphoma.
• HIV, hepatitis B and C serology, FBC, LDH, creatinine and liver tests.

Differential diagnosis.

• Infectious uveitis (toxoplasmosis, syphilis, tuberculosis, cytomegalovirus, fungal)
• Non-infectious uveitis (sarcoidosis, Behçet disease, birdshot chorioretinopathy)
• Metastatic lymphoma from systemic disease and leukaemic infiltration
• Choroidal metastasis and amelanotic melanoma

Management combines local ocular therapy with systemic therapy to prevent CNS relapse. It is chosen in a multidisciplinary team with a neuro ophthalmologist and haematologist.

Local therapy for isolated ocular disease.

• Intravitreal methotrexate: methotrexate 400 micrograms in 0.1 mL by intravitreal injection twice weekly for 4 weeks (induction), then weekly for 8 weeks (consolidation), then monthly for 9 months (maintenance); maximum 400 micrograms for each injection and each eye; monitoring: corneal epitheliopathy, intraocular pressure, cataract, endophthalmitis, retinal toxicity and clinical response at each visit; adjustment: lubricating drops for corneal toxicity, widen the interval or stop for persistent keratopathy, delay injection during active ocular or periocular infection
• Intravitreal rituximab 1 mg in 0.1 mL by intravitreal injection once weekly for 4 weeks, then every 2 weeks for 2 to 4 doses, as an alternative or addition when methotrexate toxicity or resistance occurs; maximum 1 mg for each injection and each eye; monitoring: intraocular pressure, inflammation, retinal toxicity and endophthalmitis; adjustment: stop for severe intraocular inflammation, delay during active infection.
• Ocular radiotherapy 30 to 40 Gy in 15 to 20 fractions to both eyes is an option for bilateral disease, with a risk of cataract and radiation retinopathy.

Systemic therapy for CNS involvement or to prevent it.

• High dose methotrexate: methotrexate 3.5 g/m2 IV over 2 to 4 hours every 14 days for 4 to 8 cycles, with leucovorin 25 to 50 mg IV or orally every 6 hours beginning 24 hours after the start of methotrexate and continued until the methotrexate level is under 0.1 micromol/L; hydration with at least 3 L/m2 each day and urinary alkalinisation to pH 7 or higher; maximum methotrexate 3.5 g/m2 each cycle in this regimen; monitoring: creatinine and methotrexate levels at 24, 48 and 72 hours, FBC, liver tests, urine pH, mucositis; adjustment: omit when creatinine clearance is under 50 mL/min and reduce the dose in proportion at 50 to 79 mL/min, avoid NSAIDs, penicillins, proton pump inhibitors and co-trimoxazole around each dose because they delay clearance, give glucarpidase 50 units/kg IV once when the level is over 1 micromol/L at 36 hours or creatinine rises, drain pleural effusion or ascites before dosing
• Consolidation with high dose chemotherapy and autologous stem cell rescue, or whole brain radiotherapy at a reduced dose (23.4 Gy), is considered after response in fit patients.

Supportive measures. Pneumocystis prophylaxis with intensive therapy, antiemetics, and monitoring of renal function and urine pH.

Monitoring. Ophthalmological examination every 1 to 2 months in the first year, then every 3 months. MRI of the brain every 3 months for 2 years, then every 6 months. Review for relapse in the other eye and CNS.

Referral and escalation.

• Referral to an ocular oncology centre and neuro oncology or haematology on suspicion.
• Urgent admission for neurological symptoms or methotrexate toxicity (delayed clearance, renal failure).

Special groups.

• Older adults: lower intensity systemic therapy and local ocular treatment, with fitness assessment before high dose methotrexate.
• Renal impairment: high dose methotrexate is avoided, and local therapy is favoured.
• HIV-related disease: antiretroviral therapy with attention to interactions.
• Pregnancy: rare, and managed by a multidisciplinary team with local ocular therapy.