Primary intraocular lymphoma often poses a diagnostic dilemma with presentation like vitritis, intermediate uveitis or sub retinal plaque like lesions (1). Diagnosis is often challenging in such cases.(1,) 2 It stands true its name of a masquerade Syndrome
- 1 Disease
- 2 Diagnosis
- 3 Management
- 4 Additional Resources
- 5 References
The term intra ocular lymphoma was first used more than 60 years ago (3,4) From its first description, it has got many misnomers like reticulum cell sarcoma , microglioma, perithelial sarcoma and lymphosarcoma. It is a rare and malignant condition which is a variant of primary central nervous system lymphoma. Intra ocular lymphoma can be classified as Primary which can be oculo-CNS and primarily ocular or Secondary when it spreads to the eye from a systemic malignancy. (2)
The primary intraocular lymphoma has been classified based on the precise location in the eye. The most common subtype is primary vitreoretinal lymphoma which is generally a diffuse large B cell Lymphoma , the other type is the primary uveal lymphoma (5 )which is generally extra nodal marginal B cell lymphoma. The primary lymphoma generally involves the retina, while secondary dissemination leads to involvement of the choroid.
Intraocular lymphomas represent < 1% of all intra ocular tumors (6), 4-6% of all intracranial tumours and 1-2% of all extra nodal non Hodgkin’s lymphomas.(7) Involvement of central nervous system (CNS) is common which develops in 35-90% along the course of the disease. Women are more affected than men (6) and patients generally present in 4th to 6th decade(7), though a case as young as 15 years has been reported (8). Eight to ninety percent patients have bilateral disease though initial presentation may be unilateral.( 7)
On examination , anterior segment is usually quiet although keratic precipitates with mild to moderate number of cells and flare may be present. This feature if seen, usually implies relapse more than primary presentation (2).
The manifestation of the disease can be either vitreal or as sub retinal lesions. 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 (2) caused due to the reactive inflammatory cells in vitreous.
The sub-retinal lesions to begin with are small, yellow white mounds, which enlarge and expand and further coalesce to produce large yellow sub retinal masses with brown pigmentation in the centre known as leopard skin pigmentation. These lesions may become atrophic and small with treatment and the passage of time.
The lesions may involve optic disc producing an optic nerve head swelling. Vasculitis with retinal haemorrhages 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.
The difficulty lies in diagnosing the disease due to its uncommon occurance and masquerading as uveitis.So the patients are usually put on steroids which hampers in the dagnostic efficacy of vitreous biopsy
Fundus Fluorescence Angiography
Hypofluorescence may be seen due to blockage of dye by the tumour cells as well as granular hyperfluorescence and late staining due to damage to the retinal pigment epithelium.
Optical coherence tomography
Graular lesions at sub retinal pigment epithelium level can be seen in early stages. So can be used to monitor progression or regression of the lymphoma .9 (Figure 3)
For diagnosis, diagnostic vitrectomy using a three port vitrectomy is indicated which may also play a therapeutic role. Small gauge vitrectomy cutters(25G) can suffice and the yield of vitrectomy can be increased by taking an undiluted specimen ( 0.5- 1 ml) that too at a low cut rate .
The sample is evaluated for:
- Cytokine measurement
- PCR for gene rearrangements
- Surface markers of tumour cells.
Even after taking the appropriate measures it may yield positive results in only 48% of the cases.
Cytological examination is the gold standard for diagnosis 10 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.(11) The reason was a false negative result is that vitreous cells may be mixed with necrotic and inflammatory cells. (Figure 4)
Next in line in the battery of tests is cytokine evaluation. IL-10 is increased, IL-6 which is an inflammatory marker is low as compared to secondary ocular lymphoma. The importance lies in a high IL10 /IL 6 ratio (5,9.)
Microdissection and PCR analysis can also be done to identify Ig H gene rearrangements using FR2A, FR3A, CDR3 as primers (12). Molecular analysis is currently gaining up for diagnosis. Cell markers can be studied to identify the type of tumour (CD20 , CD3 CD79a).
Gadolium enhanced MRI of CNS and whole body PET-CT is necessary for initial systemic examination. Once intraocular lymphoma is diagnosed, these work up’s should be done periodically.
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 (15). A total dose of 30-40 Gy, divided in the fractions of 1.5 to 2 Gy is given.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. (16) Local Chemotherapy
In unilateral cases intravitreal methotrexate has been used in the dosage of 400 g 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. (17) 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 (18)
Intravitreal rituximab which is anti CD 20 monoclonal antibody can be used in the dosage of 1mg /.1 ml in cases which are unresponsive or cannot tolerate methotrexate. (19)
For isolated ocular lymphoma’s 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.
Intravenous high dose methotrexate is commonly used for oculo-CNS lymphomas.
Currently there is no prophylactic method that completely prevents the onset of CNS Lymphopma subsequent to intra ocular lymphoma. When survival outcome of oculo –CNS Lymphoma is compared with ocular lymphoma, no significant difference is seen (20).
- American Academy of Ophthalmology. Ocular Pathology/Oncology: Primary intraocular and central nervous system (CNS) lymphoma Practicing Ophthalmologists Learning System, 2017 - 2019 San Francisco: American Academy of Ophthalmology, 2017.
1. 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.
2. Biswas J, Majumdar PD .Uveitis: An Update .Goto H.Intraocular lymphoma.2016. 93-100
3. Cooper, E.L. & Riker, J.L. (1951) Malignant lymphoma of the uveal tract. American Journal of Ophthalmology, 34, 1153–1158.
4. 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.
5. 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
6. Bardenstein DS. Intraocular lymphoma. Cancer Control. 1998;5:317–325.
7. Freeman LN, Schachat AP, Knox DL, et al. Clinical features laboratory investigations, and survival in ocular reticulum sarcoma. Ophthalmology 1987;94: 1631-1639.
8. 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.
9. Liu TY, Ibrahim M, Bittencourt M, et al. Retinal optical coherence tomography manifestations of intraocular lymphoma. J Ophthal Inflamm Infect 2012; 2: 215-218.
10. Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 2013;15:93‐100.
11. 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.
12. 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.
13. Peterson K, Gordon KB, Heinemann MH, et al. The clinical spectrum of ocular lymphoma. Cancer. 1993;72;843–849.
14. Cho BJ, Yu HG. Risk factors for intraocular involvement in patients with primary central nervous system lymphoma. J Neurooncol. 2014;120:523–529.
15. Berenbom A, Davila RM, Lin HS et al .Treatment outcomes for primary intra ocular lymphoma: implications for external beam radiotherapy. Eye 21: 1198-1201
16. 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
17. De Smet MD, Vancs VS, Kohler D et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol 83: 448-451
18. Frenkel S, Hendler K, Siegal T et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10years of experience . Br J Ophthalmol 92: 383-388
19. Kitzmann AS, Pulido JS, Mohney BG. Intraocular use of rituximab. Eye. 2007; 21: 1524-1527.
20. Grimm SA, McCannel CA, Omuro AM et al. Primary CNS Lymphoma with intra ocular involvement .International PCNSL Collaborative Group Report.Neurology 71: 1355-1360.