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.
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.
- Boyd K. Eye Cancer. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/eye-cancer-list. Accessed March 11, 2019.
- Boyd K, Vemulakonda GA. Eye Lymphoma. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/eye-lymphoma-list. Accessed March 11, 2019.
- Grange LK, Kouchouk A, Dalal MD, Vitale S, Nussenbla RB, Chan CC, et al. Neoplastic masquerade syndromes in patients with uveitis. Am J Ophthalmol 2014;157:526‐31.
- Biswas J, Majumdar PD .Uveitis: An Update .Goto H.Intraocular lymphoma.2016. 93-100
- Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Experiment Ophthalmol. 2008;36:564-578.
- Cooper, E.L. & Riker, J.L. (1951) Malignant lymphoma of the uveal tract. American Journal of Ophthalmology, 34, 1153–1158.
- Qualman, S.J., Mendelsohn, G., Mann, R.B. & Green, W.R. (1983) Intraocular lymphomas. Natural history based on a clinicopathologic study of eight cases and review of the literature. Cancer, 52, 878–886.
- Salomão DR, Pulido JS, Johnston PB, Canal-Fontcuberta I, Feldman AL. Vitreoretinal presentation of secondary large B-cell lymphoma in patients with systemic lymphoma. JAMA Ophthalmol. 2013;131(9):1151-1158
- Coupland SE, Chan CC, Smith J. Pathophysiology or retinal lymphoma. Ocul Immunol Inflamm. 2009;17:227-237
- Chan CC, Gonzales JA. Primary Intraocular Lymphoma. New Jersey, London, Singapore, Beinjing, Shanghai, Hong Kong, Taipei: Worl Publishing Co. Pte. Ltd.,2007:1-267
- Coupland SE, Anastasssiou G, Bornfeld N, Hummel M, Stein H. Primary intraocular lymphoma of T-cell type: Report of a case and review of the literature. Graefes Arch Clin Exp Ophthalmol 2005;243:189-197
- Bardenstein DS. Intraocular lymphoma. Cancer Control. 1998;5:317–325.
- Freeman LN, Schachat AP, Knox DL, et al. Clinical features laboratory investigations, and survival in ocular reticulum sarcoma. Ophthalmology 1987;94: 1631-1639.
- Cohen IJ, Vogel R, Matz S, et al. Successful non-neurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB). Cancer. 1986;57:6–11.
- Wilkins CS, Goduni L, Dedania VS, Modi YS, Johnson B, Mehta N, Weng CY. Diagnostic and Therapeutic Challenge. Retina. 2021 Jul 1;41(7):1570-1576. doi: 10.1097/IAE.0000000000002820. PMID: 32332425.
- Hoffman PM, McKelvie P, Hall AJ, Stawell RJ, Santamaria JD. Intraocular lymphoma: a series of 14 patients with clinicopathological features and treatment outcomes. Eye 2003;17:513-521
- Zhang P, Tian J, Gao L. Intraocular lymphoma masquerading as recurent iridocyclitis: findings based on in vivo confocal microscopy. Ocul Immunol Inflamm 2018;26(3):362-364
- Akpek EK, Ahmed I, Hochberg FH, Soheilian M, Dryja TP, Jakobiec FA, Foster CS. Intraocular-central nervous system lymphoma: clinical features, diagnosis and outcomes. Ophthalmol 1999;106(9):1805-1810
- Katoch D, Bansal R, Nijhawan R, Gupta A. Primary intraocular central nervous system lymphoma masquerading as diffuse retinal vasculitis. BMJ Case Rep 2013;1-4
- Dalal M, Casady M, Moriarty E, Faia L, Nussenblatt R, Chan CC, Sen HN. Diagnostic procedures in vitreoretinal lymphoma. Ocul Immunol Inflamm. 2014 Aug;22(4):270-6.
- Casady M, Faia L, Nazemzadeh M, Nussenblatt R, Chan CC, Sen HN. Fundus autofluorescence patterns in primary intraocular lymphoma. Retina. 2014 Feb;34(2):366-72.
- Liu TY, Ibrahim M, Bittencourt M, et al. Retinal optical coherence tomography manifestations of intraocular lymphoma. J Ophthal Inflamm Infect 2012; 2: 215-218.
- Chan CC. Molecular pathology of primary intraocular lymphoma. Trans Am Ophthalmol Soc 2003;101:269-286
- Pulido JS, Salomão DR, Frederick LA, Viswanatha DS. MyD-88 L265P mutations are present in some cases of vitreoretinal lymphoma. Retina 2015;35(4):624-627
- Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 2013;15:93‐100.
- Kimura K, Usui Y, Goto H, et al. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol 2012; 56: 383-389.
- Wang Y, Shen D, Wang VM, Sen HN, Chan CC. Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 2011;12:5684‐97.
- Buggage RR, Whitcup SM, Nussenblatt RB, Chan CC. Using interleukin 10 to interleukin 6 ratio to distinguish primary intraocular lymphoma and uveitis. Invest Ophthalmol Vis Sci 1999;40:2462-2463
- Chan CC, Rubenstein JL, Coupland SE, et al. Primary vitreoretinal lympoma: A report from an international primary central nervous system lymphoma collaborative group symposium. The Oncologist. 2011;16: 1589-1599
- Berenbom A, Davila RM, Lin HS et al .Treatment outcomes for primary intra ocular lymphoma: implications for external beam radiotherapy. Eye 21: 1198-1201
- Isobe K, Ejima Y, Tokumaru S et al. Treatment of primary intraocular lymphoma with radiation therapy : a multi institutional survey in Japan . Leuk Lymphoma 47: 1800-1805
- De Smet MD, Vancs VS, Kohler D et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol 83: 448-451
- Frenkel S, Hendler K, Siegal T et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10years of experience . Br J Ophthalmol 92: 383-388
- Kitzmann AS, Pulido JS, Mohney BG. Intraocular use of rituximab. Eye. 2007; 21: 1524-1527.
- Pulido, J.S., Johnston, P.B., Nowakowski, G.S. et al. The diagnosis and treatment of primary vitreoretinal lymphoma: a review. Int J Retin Vitr 4, 18 (2018).
- Venkatesh R, Bavaharan B, Mahendradas P, Yadav NK. Primary vitreoretinal lymphoma: prevalence, impact, and management challenges. Clin Ophthalmol. 2019 Feb 14;13:353-364.
- Kalogeropoulos D, Vartholomatos G, Mitra A, Elaraoud I, Ch'ng SW, Zikou A, Papoudou-Bai A, Moschos MM, Kanavaros P, Kalogeropoulos C. Primary vitreoretinal lymphoma. Saudi J Ophthalmol. 2019 Jan-Mar;33(1):66-80.
- Grimm S.A., Pulido J.S., Jahnke K. Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group report. Ann Oncol. 2007;18:1851–1855.