Primary intraocular lymphoma often poses a diagnostic dilemma with presentation like vitritis, intermediate uveitis or subretinal plaque-like lesions. Diagnosis is often challenging in such cases, and this is why it is often one of the diseases referred to as a masquerade syndrome.
- 1 Disease
- 2 Management
- 3 Additional Resources
- 4 References
Vitreoretinal lymphoma (as primary introacular lymphoma is now known) is the most common introacular lymphoproliferative disease. The term vitreoretinal lymphoma distinguishes it from other introcular lymphoproliferations including choroidal lymphomas (which do not have any association with central nervous system disease) and iris or ciliary body lymphomas. The term intraocular lymphoma was first introduced more than 60 years ago. However, prior to the advent of immunohistochemistry, vitreoretinal lymphomas were known as reticulum cell sarcomas, microgliomas, perithelial sarcomas or lymphosarcomas. It is considered a variant of primary central nervous system (CNS) lymphomas and may occur only in the eye initially (thus a primary vitreoretinal lymphoma) or contemporaneously with CNS disease. Rarely, a vitreoretinal lymphoma can be classified as secondary when it arises due to metastasis from a systemic lymphoma.
Vitreoretinal lymphomas represent < 1% of all intraocular tumors, 4-6% of all intracranial tumors and 1-2% of all extra nodal non-Hodgkin’s lymphomas. Involvement of the CNS is common, developing in 35-90% along the course of the disease. Women are more commonly affected than men and patients generally present in 4th to 6th decade, although a case as young as 15 years has been reported. Eighty to ninety percent patients will have bilateral disease, although initial presentation may be unilateral or asymmetric.
On examination , anterior segment is may exhibit anterior chamber cells as well as keratic precipitates in both the primary presentation as well as in recurrences. Confocal microscopy of such "keratic precipitates" has demonstrated features that recapitulate atypical large lymphocytes with large nuclei and minimal cytoplasm. These cells can even layer and present as a hypopyon; in these situations, the eye is generally more quiet than it would be with a hypopyon from an infectious etiology.
The manifestation of the disease can be either as vitreous inflammation, subretinal lesions, or both. Vitreous opacities may be seen extending from posterior pole to periphery which may move on movement of the eye producing an image like aurora in the sky caused due to the reactive inflammatory cells in vitreous.
Subretinal lesions may begin as small, yellow to white mounds, which enlarge and expand and further coalesce to produce large yellow sub retinal masses with brown pigmentation in the center known as leopard skin pigmentation. These lesions may become atrophic and shrink with treatment and the passage of time.
The lesions may involve optic disc producing an optic nerve head swelling. Vasculitis with retinal hemorrhages can also be seen. Sheathing of the vessels may be seen which could be reactive or due to lymphoma cells infiltration.
The patient usually presents with the complaints of blurring of vision, floaters, or a combination of both.
Vitreoretinal lymphoma can be challenging to diagnose due to its uncommon occurrence and the similarities it shares with other uveitic conditions. Diseases that should be considered on the differential diagnosis include chronic endophthalmitis, syphilis, tuberculosis, Behcet disease, birdshot chorioretinopathy, secondary intraocular lymphoma, primary uveal lymphoma, and birdshot chorioretinopathy. Patients may be initially be treated with topical or systemic corticosteroids under the presumption that their presentation represents a posterior uveitis. Because lymphomatous cells are responsive to steroids, the "uveitis" may improve, only to recur with decrease in the dose of steroids or discontinuation of therapy. A diagnostic and therapeutic vitrectomy may result without a diagnosis of a lymphomatous process, particularly when a patient is still using topical or systemic corticosteroids. A study from the National Eye Institute found that patients underwent a mean of 2.1 procedures prior to a diagnosis of vitreoretinal lympoma. Furthermore, they found an average of 13.9 months from onset of symptoms to a confirmed histopathological diagnosis.
Hypofluorescence may be seen due to blockage of dye by the tumor cells as well as granular hyperfluorescence and late staining due to damage to the retinal pigment epithelium. The contrast between hypo- and hyperfluorescence has been noted to be reminiscent of leopard spots, but is certainly not pathognomonic for the disease. A leopard spot pattern denoted by hypofluorescent round spots has been observed in 43% of cases. 
Optical coherence tomography
Granular subretinal lesions (between Bruch's membrane and the retinal pigment epithelium) can be seen when subretinal lesions exist. OCT can be used to monitor progression or regression of the lymphoma.
Many patterns of fundus autofluorescence exist in intraocular lymphoma. A study from the National Eye Institute found that granularity on FAF was associated with active lymphoma in 61% of their cases. 
For diagnosis, the gold standard is cytopathologic inspection of ocular fluid or chorioretinal biopsies. Small gauge vitrectomy may help with the yield and it is important to obtain an undiluted specimen (0.5 - 1 ml) at a low cut rate.
The sample may then be evaluated for:
- Directed polymerase chain reaction (PCR) for gene rearrangements in immunoglobulin heavy chain genes or (if T-cell lymphoma is suspected) T-cell receptor genes
- Directed PCR for mutation in the MYD88 gene involving codon L265P
- Cytokine measurement
Even after taking the appropriate measures, this can still yield false negative results.
Cytological examination is the gold standard for diagnosis which shows large atypical lymphoid cells with pleomorphic nuclei, scant basophilic cytoplasm and prominent nucleoli. However, Kimura et al showed that cytology was sufficient in only 48% of cases. The reason for such low yields includes the fact that lymphomatous cells may necrose and be misinterpreted.
Directed PCR can also be performed to identify IgH gene rearrangements using FR2A, FR3A, and CDR3 primers. While fine needle or laser capture microdissection is a technique that can help in procuring a relatively pure population of large, atypical lymphocytes, few ocular pathologists routinely perform such a procedure. Immunohistochemistry employing cell markers such as CD20 , CD3, CD79a, and PAX5 can help identify the cell type. Directed PCR for the MYD88 gene (codon L265P) can also be diagnostic of a DLBCL vitreoretinal lymphoma.
Cytokine evaluation assessing for interleukin (IL)-10 compared to IL-6 may also be considered as corroborating a suspicion of lymphoma. IL-10 is an immunosuppressive cytokine while IL-6 is an inflammatory cytokine; an elevated IL-10 /IL-6 ratio is suggestive of lymphoma, although there is a relatively lower diagnostic sensitivity with this test.  Aqueous levels of IL-10 are used by some to monitor for recurrence.
Gadolium enhanced MRI of the brain should be performed to evaluate for intracerebral disease. Care should be coordinated with a neuro-oncologist.
The treatment can be aimed as local therapy which can be radiotherapy to the eye or intracameral / intravitreal agents like (methotrexate and rituximab) or as systemic therapy which can be external beam radiotherapy or systemic chemotherapy.
EBRT(External Beam Radiotherapy)
In cases of bilaterality, EBRT is the most effective treatment. A total dose of 30-40 Gy, divided in the fractions of 1.5 to 2 Gy is often used.The side effects associated are dermatitis, punctate keratopathy , cataract and radiation retinopathy. The 2-year overall and disease-free survival rates were reported to be 74% and 58% respectively.
In unilateral cases, intravitreal methotrexate has been used in the dosage of 400 µg/0.1cc twice weekly for 4 weeks , followed by 1 weekly for 4 weeks, followed by 1 monthly for 12 months. It is used as a primary therapy as an alternative to radiotherapy or for cases of relapse. The risks associated are conjunctival injection and keratopathy. Sometimes these can be very severe which warrants the use of alternatives. Clinical remission is achieved after mean of 6.4 +/- 3.4 injections
Intravitreal rituximab which is a chimeric anti CD20 monoclonal antibody can be used in the dosage of 1mg /0.1 ml in cases which are unresponsive or cannot tolerate methotrexate.
For isolated ocular lymphoma, local chemotherapy and or radiotherapy can be done. In cases of systemic involvement or CNS lymphoma, systemic chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or rituximab-CHOP is done.
Other systemic agents that have been investigated include pomalidomide, stem cell transplantation, or ibrutinib, with or without local therapy.
In cases with CNS involvement, rituximab may be used in conjunction with high dose methotrexate. 
Currently there is no prophylactic method that completely prevents the onset of CNS lymphoma subsequent to vitreoretinal lymphoma. Patients with vitreoeretinal lymphoma must undergo careful and regular surveillance for development of CNS involvement. While the mortality rates vary widely in the literature, the 5-year overall survival rate of primary vitreoretinal lymphoma is less than 25%. In a multicenter study involving 7 different countries, the investigators found that local ocular therapy may help with the tumor control, but did not impact overall survival. In that particular study, the overall survival and median progression-free survival were reported to be 31 and 18 months, respectively.
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