BASICS

DESCRIPTION

• Vitreoretinal lymphoma (VR lymphoma) is a high-grade type of non-Hodgkin’s lymphoma that involves the retina and vitreous.

• The term “primary intraocular lymphoma” is commonly used in the literature to refer to this condition. This term is somewhat of a misnomer and should be avoided as uveal lymphoma (a distinct clinical entity) can be primary and is also intraocular.

EPIDEMIOLOGY

Incidence

• VR lymphoma is rare with an estimated incidence of 30–50 cases per 10 million population.

• There has been an increase in the incidence of VR lymphoma within the past several decades in both the immunocompetent and immunocompromised populations.

RISK FACTORS

• Immunodeficiency states: Organ transplantation, HIV infection, and congenital immunodeficiency.

• Age: VR lymphoma primarily affects the middle-aged and elderly, although cases in children have been reported.

Genetics

See “Molecular gene analysis” under “Diagnostic tests and interpretation”.

ETIOLOGY

Infection by Epstein-Barr virus, herpesvirus, and Toxoplasma gondii has been implicated in the induction of primary central nervous system (PCNS) or VR lymphoma, but results are inclusive at this time.

COMMONLY ASSOCIATED CONDITIONS

• PCNS lymphoma: VR lymphoma is strongly associated with and is considered a subtype of PCNS lymphoma.

– It is estimated that of patients with PCNS lymphoma, 15–25% have VR lymphoma at diagnosis and another 25% develop VR lymphoma during subsequent follow-up.

– 60–80% of patients presenting with VR lymphoma will develop PCNS lymphoma.

• Systemic lymphoma: VR lymphoma secondary to systemic lymphoma is rare.

– Intraocular lymphoma secondary to systemic lymphoma generally affects the uvea (see “Choroidal metastasis” under “Differential diagnosis”).

DIAGNOSIS

HISTORY

• Patients present with symptoms of floaters or blurred vision.

• Eye pain, redness, and photophobia are uncommon.

PHYSICAL EXAM

• The most common features of VR lymphoma include chronic vitreous cellular infiltration and yellowish sub-retinal pigment epithelium (RPE) infiltrates in combination or as isolated findings.

– Sub-RPE infiltrates are initially small and focal and might resemble soft drusen but can enlarge and coalesce into larger plaques over time.

– Resolution of sub-RPE infiltrates is usually accompanied by residual RPE atrophy.

– Spontaneous resolution of sub-RPE infiltrates has rarely been reported.

• Other less common findings include anterior chamber reaction, keratic precipitates, vitreous hemorrhage, retinal vascular infiltration, and optic disc edema.

• 80% of cases are bilateral but ocular involvement can be asymmetrical.

• PCNS lymphoma generally affects the frontal lobe.

– Neurologic findings include behavioral and cognitive changes (most common), headache, seizure, hemiparesis, cerebellar dysfunction, and cranial nerve palsies.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• All patients with suspected VR lymphoma require cerebrospinal fluid (CSF) analysis to exclude PCNS lymphoma.

– 25% of patients with brain lésions identified on magnetic résonance Imaging (MRI) have lymphoma cells in their CSF.

Imaging

• All patients with suspected VR lymphoma require CNS imaging to exclude PCNS lymphoma.

– Brain lesions are low signal on T1-weighted and high signal in T2-weighted MRI images.

Diagnostic Procedures/Other

• Routine cytology: Allows evaluation of cell morphology (see under “Pathological findings”) (1).

• Immunophenotyping (immunohistochemistry): Uses monoclonal antibodies to analyze surface markers of lymphoma cells (CD19+, CD20+, CD22+, CD79a+, BCL-2+, MUM1/IRF4+, BCL-6+) to establish B-cell monoclonality.

– Can be performed on slide-mounted sample or with flow cytometry.

– Light-chain immunoglobulins (kappa or lambda) are other cell surface markers that can be studied by immunohistochemistry; ratio of kappa/lambda or lambda/kappa >3 is suggestive of B-cell lymphoma.

• Molecular gene analysis: Immunoglobulin heavy chain (IgH) gene rearrangement demonstrated by polymerase chain reaction can be used to establish monoclonality of B-cell lymphoma. t (14:18) translocation involving the bcl-2 gene has also been reported.

• Cytokine analysis: High levels of interleukin-10 (IL-10) are seen in the vitreous of eyes with RV lymphoma, whereas IL-6 (and IL-12) is increased in eyes with inflammatory conditions. IL-10:IL-6 ratio >1.0 is suggestive of B-cell lymphoma.

Pathological Findings

• Majority of VR lymphomas are B-cell non-Hodgkin lymphomas subtyped as diffuse large B-cell lymphoma, according to the World Health Organization lymphoma classification.

• The malignant cells are medium to large pleomorphic cells with high nuclear/cytoplasmic ratios and prominent nucleoli.

• Sample for analysis can be obtained from the vitreous (needle biopsy, vitrectomy) or from the sub-RPE infiltrates (needle biopsy, chorioretinal biopsy).

– The obtained sample should be handled with care and transferred to the laboratory as quickly as possible to minimize degeneration of fragile lymphoma cells.

– Use of cell culture media instead of saline can increase the diagnostic yield.

– Prior steroid treatment can induce lysis of lymphoma cells. Discontinuing steroid use before biopsy may increase the diagnostic yield.

– The malignant cells are accompanied by large numbers of non-neoplastic cells (small reactive lymphocytes, histiocytes) and necrotic debris making detection of lymphoma cells more challenging.

– Multiple tissue biopsies may be required to establish the correct diagnosis.

DIFFERENTIAL DIAGNOSIS

• Inflammatory/infectious conditions (Multifocal choroiditis, bird-shot chorioretinitis, acute posterior multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome, Vogt-Koyanagi-Harada syndrome, toxoplasmosis, sarcoidosis, tuberculosis, syphilis, viral retinitis, etc)

– RV lymphoma is the most common cause of masquerade syndrome and should be considered in the differential diagnosis of chronic ocular inflammatory conditions in the elderly.

– VR lymphoma can initially and temporarily respond to steroid treatment with decrease in vitreous cells and improvement of symptoms leading to misdiagnosis of inflammatory condition.

• Choroidal metastasis: Multifocal choroidal metastasis can simulate the sub-RPE infiltrates of lymphoma but lacks the vitreous cellular infiltration.

• Choroidal lymphoma: Is a distinct entity and although most cases present with diffuse homogenous choroidal thickening, some can manifest yellowish–orange multifocal choroidal infiltrates that can be confused with the sub-retinal infiltrates of VR lymphoma. Features of choroidal lymphoma that help differentiate it from VR lymphoma include:

– Can be associated with anterior epibulbar (subconjunctival) extension of lymphoma manifesting as salmon patches

– Does not manifest significant vitreous cellular infiltration

– B-scan ultrasound generally shows acoustically hollow diffuse choroidal thickening with occasional posterior epibulbar (extraocular) extension of tumor. In contrast, eye wall thickening seen on B-scan ultrasonography of VR lymphoma is generally focal and less pronounced with no extraocular extension.

– In contrast to VR lymphoma, which is high-grade and aggressive, choroidal lymphoma is low-grade and slowly progressive with good life prognosis.

– Has no association with PCNS lymphoma but can be associated with systemic non-Hodgkin’s lymphoma, especially in some bilateral cases

TREATMENT

MEDICATION

PCNS Lymphoma

First Line

• Patients with PCNS lymphoma are usually treated with high-dose intravenous methotrexate (MTX) with or without intrathecal chemotherapy or whole-brain radiation.

– Combined chemotherapy and radiotherapy offers a better life prognosis compared with radiotherapy alone but is associated with high rates of delayed neurotoxicity especially in patients >60 years of age.

Second Line

• Newer agents used for systemic treatment of PCNS lymphoma, usually in combination with high-dose MTX, include:

– Rituximab (anti-CD20 antibody)

– Ifosfamide/trofosfamide (nitrogen mustard alkylating agents)

VR Lymphoma

• There is no general agreement on the optimal treatment for VR lymphoma.

• Patients with combined VR and PCNS lymphoma require systemic/CNS therapy as described above.

• Treatment options for patients with isolated VR lymphoma include systemic chemotherapy, local ocular therapy (radiation, intravitreal injection), or a combination of both (2).

First Line

• Low-dose EBRT (35–40 Gy) has been shown to be very effective in treatment of VR lymphoma (3).

– Radiation complications are generally mild and tolerable and include dry eye, cataract, and radiation retinopathy.

Second Line

• Intravitreal MTX (400 mcg/0.1 mL) has been used successfully for treatment of VR lymphoma (4).

– Requires multiple injections of intravitreal MTX over many months.

– Is associated with complications such as corneal keratopathy, cataract, neovascular glaucoma, and inflammatory reaction

– Intravitreal rituximab (1 mg/0.1 mL) has been used in limited number of patients but long-term safety and efficacy is not yet known (5) .

SURGERY/OTHER PROCEDURES

Complete pars plana vitrectomy not only provides enough vitreous sample for diagnostic procedures (see under “Diagnostic tests & interpretation”), but also allows earlier visual rehabilitation in patients with severe vitreous haziness.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

• All patients with isolated VR lymphoma are at high risk for development of PCNS lymphoma and require long-term CNS monitoring.

• Regardless of the method of treatment, all patients with treated VR lymphoma require close ocular monitoring for early detection of lymphoma recurrence and for treatment complications.

PATIENT EDUCATION

Patients should report any onset of new or recurrent ocular symptoms (see in “Symptoms” under “Diagnosis”) or neurologic symptoms (see in “Physical exam” under “Diagnosis”) without delay.

• www.fighteyecancer.com

• www.eyecancerinfo.com

PROGNOSIS

• Presence of PCNS lymphoma imparts a poor prognosis for life (2–3 years).

• Extensive macular sub-RPE infiltrates lead to development of macular RPE alterations and are associated with poor a visual prognosis.

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