Primary intraocular lymphoma: clinical features, diagnosis, and treatment

Commentary Primary Intraocular Lymphoma: Clinical Features, Diagnosis, and Treatment Chi-Chao Chan Section of Immunopathology Laboratory of Immunology National Eye Institute National Institutes of Health Bethesda, MD

Primary intraocular lymphoma (PIOL) is a subtype of primary central nervous system lymphoma that originates and locates inside the eye.1-6 Primary intraocular lymphoma does not include lymphomas located in ocular adnexa of the orbit, lacrimal gland, and conjunctiva. It also excludes metastatic lymphomas of the eye that arise from the lymphoid system outside the central nervous system. Primary intraocular lymphoma often masquerades as intraocular inflammation or uveitis; therefore the disease is easily misdiagnosed, resulting in inappropriate treatment, high morbidity, and mortality. In this issue of Clinical Lymphoma, 2 neurooncologists, Hormigo and DeAngelis, review the clinical features, diagnosis, and treatment of PIOL.7 The comprehensive review covers rather complete clinical aspects that have been recently published by several representative groups of ophthalmologists. In general, the authors are in agreement with the summaries made by the ophthalmologists.

Primary Intraocular Lymphoma Although PIOL is a rare disease, its incidence has dramatically increased in the past 15 years.8 In an uveitic referral clinic, Rothova et al reported 1.1% of all uveitic patients had PIOL.5 This figure is close to our statistics of over 1000 patients at the Uveitis Clinic of the National Eye Institute (R. R. Buggage, MD, and R. L. Nussenblatt, MD, unpublished data, 2003). Primary intraocular lymphoma is aggressive, with a poor prognosis. Therefore, it is important for the ophthalmologists and internists to recognize, diagnose, and treat the disease promptly. Typical clinical manifestations include blurred vision and floaters. Ophthalmic examination reveals vitreitis and subretinal infiltrates, which require

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not only slit-lamp evaluation of the anterior segments of the eye but also fundoscopic examination to evaluate the posterior segments including the vitreous and retina. Hence, a dilated fundus examination is required for the diagnosis of PIOL.

Diagnosis Because 60%-80% of PIOL patients will develop central nervous system lymphoma,9-11 we recommend neuroimaging and examination of the cerebrospinal fluid prior to a more invasive diagnostic procedure, the diagnostic vitrectomy in the worse eye.1 Prompt processing of the vitreous specimen and evaluation of the cytology by an experienced cytologist and/or ophthalmic pathologist are needed. Molecular analysis detecting immunoglobulin gene rearrangements in the tumor cells and ocular cytokine levels showing elevated interleukin (IL)-10 with an IL-10:IL-6 ratio > 1.0 are helpful adjuncts for the diagnosis. We have recently analyzed 35 patients with vitreal cytokines in PIOL and 64 with uveitis. For the PIOL group, the geometric mean IL-10:IL-6 ratio was 5.23 (95% CI, 2.13-12.86). The geometric mean ratio for the uveitis group was 0.23 (95% CI, 0.15-0.36). By the 2-sample t test, the difference in geometric means between groups was significant with P < 0.001. Correct classification by the ratio > 1.0 cutoff rule for these patients was accomplished 74.7% of the time. The sensitivity of the cutoff rule for PIOL diagnosis was 74.3%, and the specificity was 75.0%.12

Mechanisms of Lymphomagenesis There are multiple mechanisms of lymphomagenesis. Immunoprivileged environments play a critical role in permitting PIOL to develop within the eye and central nervous system although it might be eliminated systemically. On the other hand, an infectious antigen-driven polyclonal B-cell lymphoproliferation could be the initial phase of a process leading, in a variable time, into a true clonal disease.13 Particular genetic background and envi-

ronmental factors could play a role in the development of a malignant phenotype, while a specific infectious microorganism may not seem to be relevant in this setting. This means that the infectious microorganism alone might not be responsible for lymphoid tumors and that additional events, ie, those encompassing genetic, immunologic, and microenvironmental factors, are probably necessary in order to induce malignant B-cell phenotype. Proof of this phenomenon in PIOL is still lacking and requires further investigation.

Treatment Hormigo and DeAngelis present their ample experience and discussion in the treatment of primary central nervous system lymphoma and PIOL;7 they agree with the experience of Plotkin and Batchelor.14 They also describe recent limited data on the treatment of recurrent PIOL with intravitreal methotrexate.7 Recurrent ocular disease is difficult to treat. This may attribute to lower levels of methotrexate in the vitreous compared with the aqueous.15 In addition to the complications from multiple intravitreal injections, local high doses of methotrexate could damage limbal stem cells and induce corneal toxicity. Intensive chemotherapy followed by hematopoietic stem cell rescue may be considered as an effective therapy in patients with refractory and recurrent PIOL.16 Optimal treatment for PIOL becomes a great challenge to both the oncologist and ophthalmologist. 1. Buggage RR, Chan CC, Nussenblatt RB. Ocular manifestations of central nervous system lymphoma. Curr Opin Oncol 2001; 13:137-142. 2. Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin Ophthalmol 2002; 13:411-418. 3. Gill MK, Jampol LM. Variations in the presentation of primary intraocular lymphoma: case reports and a review. Surv Ophthalmol 2001; 45:463-471. 4. Read RW, Zamir E, Rao NA. Neoplastic masquerade syndromes. Surv Ophthalmol 2002; 47:81-124. 5. Rothova A, Ooijman F, Kerkhoff F, et al. Uveitis masquerade syndromes. Ophthalmology 2001; 108:386-399. 6. Tuaillon N, Chan CC. Molecular analysis of primary central nervous system and primary intraocular lymphoma. Curr Mol Med 2001; 1:259-272. 7. Hormigo A, DeAngelis LM. Primary intraocular lymphoma: clinical features, diagnosis and treatment. Clin Lymphoma 2003; 4:22-29.

8. Eby NL, Grufferman S, Flannelly CM, et al. Increasing incidence of primary brain lymphoma in the US. Cancer 1988; 62:2461-2465. 9. Whitcup SM, de Smet MD, Rubin BI, et al. Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 1993; 100:1399-1406. 10. Peterson K, Gordon KB, Heinemann MH, et al. The clinical spectrum of ocular lymphoma. Cancer 1993; 72:843-849. 11. Akpek EK, Ahmed I, Hochberg FH, et al. Intraocular-

central nervous system lymphoma: clinical features, diagnosis, and outcomes. Ophthalmology 2003. In press. 12. Wolf LA, Reed GF, Buggage RR, et al. Levels of IL-10 and IL-6 in the vitreous are helpful for differential diagnosis of primary intraocular lymphoma and ocular inflammation. Ophthalmology 2003 (In press). 13. Barth TF, Bentz M, Dohner H, Moller P. Molecular aspects of B-cell lymphomas of the gastrointestinal tract. Clin Lymphoma 2001; 2:57-64. 14. Plotkin SR, Batchelor TT. Advances in the therapy of

primary central nervous system lymphoma. Clin Lymphoma 2001; 1:263-275. 15. Batchelor TT, Kolak G, Ciordia R, et al. High-dose methotrexate for intraocular lymphoma. Clin Cancer Res 2003; 9:711-715. 16. Soussain C, Suzan F, Hoang-Xuan K, et al. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol 2001; 19:742-749.

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