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Purpose: To report the clinical course of patients with diagnostic confirmation of choroidal lymphoma by anterior chamber paracentesis and aqueous fluid flow cytometry., Methods: Single-center case series., Results: Two patients with choroidal thickening were suspected to have choroidal lymphoma based on clinical findings and ultrasonographic evidence of extrascleral extension. In each case, anterior chamber paracentesis was performed due to the observation of the associated anterior chamber reaction. Flow cytometry detected the presence of a clonal B-cell population consistent with non-Hodgkin's lymphoma. In one case, external beam radiation therapy resulted in a complete therapeutic response. More invasive methods of ocular tissue biopsy were avoided., Conclusions: Definitive diagnosis in suspected cases of choroidal lymphoma remains challenging. Ocular fluid sampling may be a low morbidity and convenient alternative for confirming a suspected diagnosis in cases associated with cellular infiltration of the intraocular fluids.

Methotrexate (MTX) may induce immunosuppression and facilitate the onset of lymphoproliferative disorders (LPD). Most cases of MTX-LPD occur in patients with rheumatoid arthritis; the incidence is high in Japan. Vitreoretinal lymphoma (VRL) is a rare non-Hodgkin's lymphoma that can masquerade as steroid-resistant chronic uveitis, leading to fatal diagnostic delay. A 68-year-old woman exhibited optic disc swelling and retinal vasculitis causing floaters in the right eye. She was undergoing long-term MTX treatment for rheumatoid arthritis; she previously had been diagnosed with MTX-LPD, which regressed upon discontinuation of MTX. Steroid therapy was ineffective for optic disc swelling and retinal vasculitis; her best-corrected visual acuity decreased to 20/400. Vitreous biopsy revealed VRL, which was successfully treated with high-dose MTX-based systemic chemotherapy and intravitreal injections of MTX. To our knowledge, this is the first case report of VRL in a patient with an autoimmune disease who have a history of MTX-LPD.

The relationship between Epstein-Barr virus (EBV) infection and uveitis is unclear. We conducted an observational cross-sectional study to determine the prevalence of EBV in uveitis and to describe the clinical features of EBV-positive uveitis cases. This study was carried out at the F.I. Proctor Foundation at the University of California, San Francisco. All patients with suspected infectious uveitis who underwent unbiased metagenomic deep sequencing (MDS) were included. Demographics, testing information, and clinical features were documented. Eleven out of 288 patients with suspected infectious uveitis had EBV detected by RNA-seq in intraocular fluid. The prevalence of EBV in uveitis in our study sample is 4%. Three out of 11 EBV-positive eyes (27%) were found to have biopsy-proven vitreoretinal lymphoma. Future studies are needed to determine if EBV may drive the development of vitreoretinal lymphoma and if its presence should heighten the suspicion of vitreoretinal lymphoma.

Purpose: To describe a rare case of intraocular lymphoma that metastasized from cutaneous mycosis fungoides and transformed to large cell T cell lymphoma resulting in vitreoretinal pathology., Methods: Retrospective case report., Results: A 57-year-old male presented with 3 months of blurred vision in the right eye. He reported only a medical history of psoriasis. Examination revealed keratic precipitates and dense vitritis in the right eye. He was taken for a diagnostic vitrectomy. Histopathology showed that atypical lymphoid cells and flow cytometry were consistent with transformed large cell T-cell lymphoma. During follow-up, pre- and inner retinal lesions were noted throughout the posterior pole. Histopathology of the psoriatic lesions was consistent with mycosis fungoides. He was initiated on systemic and intravitreal methotrexate with improvement in vision., Conclusions: Ocular involvement in metastatic transformed T-cell lymphoma is extremely rare but can be present with vitritis and retinal deposits. Our patient responded well to intravitreal methotrexate therapy.

Purpose: The purpose of this study is to investigate matrix metalloproteinases (MMPs) expression in human intraocular lymphoma (IOL)., Methods: Two enucleated eyes and seven cell-block samples obtained from patients with IOL who underwent vitrectomy were used. Immunopathological examinations were performed for detection of MMP-2, MMP-9, and TIMP-4 expressions., Results: In the enucleated eye with primary IOL (PIOL), MMP-2 was negative, and MMP-9 and TIMP-4 were positive in the lymphoma cells, while in the enucleated eye with secondary IOL (SIOL), all the molecules were positive. Among the cell-block samples with PIOL, the positive rate in lymphoma cells of MMP-2, MMP-9, and TIMP-4 was 75%, 100%, and 75%, respectively. In the cell-block samples with SIOL, the positive rates of MMP-2, MMP-9, and TIMP-4 were all 100%., Conclusions: MMP-2, MMP-9, and TIMP-4 were expressed in lymphoma cells using the specimens of human IOL, suggesting that MMPs may play an important role in the development of IOL.

Purpose: To report a case of primary vitreoretinal lymphoma (PVRL) showing recurrence after spontaneous regression, diagnosed with the aid of next-generation sequencing (NGS)., Methods: Retrospective case report., Results: A 61-year-old immunocompetent Korean woman presented with subretinal lesions suspected of PVRL, which resolved spontaneously in 2 months. After 8 months, the lesion recurred and diagnostic vitrectomy was performed. The cytologic examination of the vitreous was indeterminate as there was only minimal vitreous opacity present at the time of surgery. NGS identified significant mutations including single nucleotide variants in MYD88 L265P, which is a unique hallmark of VRL, in vitreous sample, and the diagnosis of PVRL was made., Conclusion: This case showed PVRL can spontaneously regress almost completely, then recur, so careful ophthalmic and systemic follow-ups are warranted. When cytological confirmation is challenging due to the minimal disease involvement in the vitreous, NGS is effective in confirming the mutation profiles of PVRL.

Purpose: To establish diagnostic criteria for vitreoretinal lymphoma (VRL) using cytology and laboratory tests from vitreous samples: interleukin (IL)-10/IL-6 ratio, immunoglobulin (Ig) H gene rearrangement, and clonal B-cells on flow cytometry., Methods: Fifty-six patients with and 39 without VRL were included. We assessed the sensitivity and specificity of each test and those of diagnostic criteria based on combinations of these tests., Results: The sensitivity values for malignant cytology, IL-10/IL-6 > 1, IgH gene rearrangement, and flow cytometry were 0.554, 0.821, 0.732, and 0.625 with specificity of 1.000, 1.000, 0.846, and 0.974, respectively. When the diagnostic criteria were set at malignant cytology or at two or more of of four tests (atypical cells, IL-10/IL-6 > 1, IgH gene rearrangement, and flow cytometry), the sensitivity and specificity values for accurate diagnosis were 0.929 and 1.00, respectively., Conclusion: Malignant cytology or positive results for two or more of four tests may be adequate for VRL diagnosis.

Purpose: Diagnosis of intraocular lymphoma (IOL) is usually achieved by histopathological analysis. However, it may lead to inconclusive results due to the scarcity of malignant cells obtained by biopsy, hence leading to delayed diagnosis. We report two cases of IOL with pseudo-hypopyon, a rare feature of IOL, as their initial ocular feature, diagnosed using a multidisciplinary diagnostic approach. Common clinical features of IOL with pseudo-hypopyon were also investigated., Methods: Retrospective case series and literature review., Results: Two cases of IOL, a 78-year-old female and a 59-year-old male, whom had been diagnosed with systemic B-cell lymphoma developed pseudo-hypopyon and visual impairment during the course of their chemotherapy. Diagnosis of IOL was achieved from anterior chamber aspiration samples with supplementary diagnostic tools including flow cytometric immunophenotyping, interleukin and IgH gene rearrangement analysis in addition to the conventional histopathological analysis. Generally, pseudo-hypopyon was more commonly seen in secondary IOL and may associate with hyphema and high intraocular pressure., Conclusion: Pseudo-hypopyon is a rare feature of IOL, more commonly seen in secondary IOL, which can be accompanied by hyphema and high intraocular pressure. Supplementary diagnostic tools such as flow cytometric immunophenotyping, interleukin analysis, and immunogloblin H gene rearrangement analysis are useful for supporting the diagnosis of IOL with pseudo-hypopyon.

Purpose: To describe the morphological patterns of keratic precipitates (KPs) in vitreoretinal lymphoma (VRL) using in vivo confocal microscopy (IVCM)., Methods: Six eyes of three biopsy-proven VRL patients were included. KPs were identified and analyzed on IVCM., Results: On examination, pigmented KPs in four eyes, white central KPs in two eyes and anterior chamber cells with flare in six eyes and pseudo hypopyon in one eye were identified. A typical floral pattern of KPs on IVCM was noted in all eyes. Three eyes each showed the complete and incomplete floral patterns, respectively. Resolution of KPs on IVCM was noted after chemotherapy., Conclusion: In addition to the routinely used clinical and imaging markers like the visual acuity, presence of lymphomatous cells in the vitreous and optical coherence tomography findings, the presence and appearance of KPs on IVCM can also be considered as a useful, diagnostic and treatment monitoring marker in VRL.

Purpose : To describe the epidemiology, clinical characteristics, diagnosis and treatment of human immunodeficiency virus (HIV)-related primary vitreoretinal lymphoma (PVRL). Methods : Narrative literature review. Results : HIV-related PVRL occurs in persons who are relatively young and generally have very low CD4+ T-cell counts. Vitritis with subretinal or sub-retinal pigment epithelial infiltrates is typical. Vitreous cytology remains the gold standard for diagnosis, supplemented by flow cytometry and genetic analyses of tumor cells, and measurement of aqueous or vitreous interleukin-10 levels. Concurrent brain involvement also may establish the diagnosis. Treatment includes antiretroviral therapy (ART), systemic chemotherapy (usually methotrexate-based) and local ocular treatment (intravitreal methotrexate, intravitreal rituximab, external beam radiotherapy). Systemic chemotherapy is of uncertain value for PVRL without other central nervous system involvement. Prognosis is poor, but has improved significantly compared to the pre-ART era. Conclusions : Ophthalmologists should consider the diagnosis of PVRL in HIV-positive individuals who present with intermediate or posterior uveitis.

Primary ocular lymphomas are typically confined to either the eye or the orbit. Rarely, in immune-competent patients, lymphomas affect both the eye and the orbit simultaneously. Mucosa-associated lymphoid tissue (MALT) lymphomas are the most common ocular lymphomas. They usually present primarily in the orbit but sometimes can present primarily in intraocular tissue. MALT lymphomas that occur initially in the uvea can sometimes spread to the adjacent orbit. We report a case of progressively enlarging MALT lymphoma in a 62-year-old immune-competent patient causing a severe mass effect in the orbit and simultaneously presenting with intraocular involvement. There was radiographic evidence of lymphoma confined to the orbit with intraocular involvement. The simultaneous presentation makes it difficult to determine if the lymphoma initially presented in the orbit or intraocular tissue, although the orbital component was more impressive. The case also includes a literature review of simultaneous orbital and intraocular MALT lymphomas. The patient responded to systemic chemotherapy with regression in size of the lymphoma, relief of the mass effect seen in the orbit, and the regression of the intraocular involvement.

Purpose: To compare the clinical features and treatment outcomes of different types of vitreoretinal lymphoma (VRL) that presents primarily, secondarily, or concurrently in association with CNS lymphoma., Methods: We retrospectively reviewed the medical records of 53 patients with VRL pathologically confirmed between 2000 and 2014 in two of the largest tertiary hospitals in Korea., Results: The proportions of primary, secondary, and concurrent VRL were 26%, 34%, and 40%, respectively. The primary VRL group had retinal infiltration most frequently (68%) among all groups and presented with the worst visual acuity at diagnosis (P = 0.035). The diagnostic delay was significantly shorter in patients with secondary VRL (1.4 months; P < 0.001). Median overall survival was 31 months in the entire cohort, and it was shortest in the concurrent VRL/CNS lymphoma group (18 months; P = 0.007)., Conclusions: Ocular presentation and survival times may be different in VRL patients according to the association with CNS involvement.

Purpose: To emphasize the application prospects of in vivo confocal microscopy (IVCM) in distinguishing intraocular lesions from inflammatory and neoplastic diseases., Methods: Retrospective case report., Results: A patient with neoplastic masquerade syndrome initially underwent IVCM examination. After six separate intravitreal injections of 400 mg/0.1 ml methotrexate, IVCM revealed a complete remission of intraocular lymphoma., Conclusions: Although IVCM findings alone are not enough to diagnose intraocular neoplasm with absolute certainty, they can provide useful indication for distinguishing between intraocular inflammatory diseases and neoplasms.

Purpose: To describe clinical manifestations, diagnostic approaches, therapy, and outcomes of biopsy-proven intraocular lymphoma., Methods: Review of tertiary referral center records between 2005 and 2015., Results: A total of 51 eyes of 26 patients were included; mean age of onset was 60.42 years. Common ocular complaints included floaters (42%) and blurred vision (35%); 62% of patients had ocular and central nervous system involvement; 11% had systemic lymphoma; and 27% had only ocular involvement. Vitreous analysis was positive for malignant cells in 77% of patients on initial biopsy, and in 100% of patients on repeat biopsy. In total, 20/26 patients received systemic and topical treatment before IOL diagnosis was made; 25 patients received intravitreal methotrexate and/or rituximab; one patient received intracameral rituximab. All patients achieved remission by their final visit., Conclusions: Intraocular lymphoma often masquerades as intraocular inflammation, resulting in delayed or misdiagnosis with subsequent inappropriate management. Optimal therapy is a challenge for oncologists and ophthalmologists.

Purpose: To report on the clinical data of seven patients with T-cell intraocular lymphoma (IOL)., Methods: Retrospective case series., Results: Seven immunocompetent patients, 12 eyes, 6 women, with T-cell-IOL were included from five countries. Mean age was 53.5 years (range: 25-82). Four patients had systemic-ocular lymphoma, two had CNS-ocular lymphoma, and one had systemic-CNS- ocular lymphoma. Vitritis was the most frequent clinical sign, followed by anterior uveitis and serous retinal detachment. Cytopathologic examination was performed on all ocular specimens (vitreous in six and iris mass biopsy in one patient). Adjunctive diagnostic procedures included immunohistochemistry, molecular tests, and cytokine profiling of vitreous samples. Treatment modalities included systemic chemotherapy (five patients), intravitreal methotrexate (three patients), globe radiotherapy, and intrathecal chemotherapy. Mean survival from diagnosis was 21.7 months (range: 2-69). Two patients are still alive., Conclusions: T-cell IOL has variable clinical manifestations and prognosis. Systemic involvement, SRD, and vitreoretinal involvement were frequently observed.

Purpose: To examine spectral-domain optical coherence tomography (SD-OCT) patterns in intraocular lymphoma (IOL)., Methods: Records of 13 patients (21 eyes) with IOL were retrospectively reviewed. SD-OCT was evaluated at initial visit and during follow-up., Results: SD-OCT images at initial visit demonstrated disruption of the ellipsoid zone (8 eyes, 38.1%) and hyperreflective nodules at the retinal pigment epithelium (RPE) level (5 eyes, 23.8%). During follow-up, disruption of the ellipsoid zone (10 eyes, 47.6%) and hyperreflective nodules at the RPE level (7 eyes, 33.3%) were noted. In 5 eyes showing hyperreflective nodules at the RPE level, the hyperreflective nodules were reduced after treatment with intravitreal methotrexate., Conclusions: Hyperreflective nodules in the outer retina and disruption of the ellipsoid zone were observed in nearly one-half of patients with IOL over time. SD-OCT may allow for early detection of small macular abnormalities and aid in monitoring of treatment efficacy in this disease.

Purpose: To present a population of patients sharing atypical manifestations of vitreoretinal lymphoma (VRL)., Methods: Institutional case series in a single tertiary center. Patients with cytologically proven VRL, referred between November 2009 and May 2010, were retrospectively reviewed. Diagnosis of VRL was based on cytology of vitreous samples, immunohistochemistry, and molecular biology. Patients with confirmed VRL and clinical features different from the typical manifestations were included. Demographical and clinical characteristics of these patients were studied., Results: Twelve cases of VRL were diagnosed. Four cases (2M/2F) were considered atypical (A-VRL) in their presentations. Mean age for typical lymphoma (T-VRL) was 71.9 years (range: 62-87 years); mean age for A-VRL was 54 years (range: 50-59 years)., Conclusions: Diagnosis of VRL is challenging and diagnostic delay is frequent. The authors describe a series of patients sharing common characteristics, such as a younger age (p = 0.05), severe anterior chamber reaction, mild or no vitritis, and possible fulminant evolution.