Patient-derived xenograft mouse models to investigate tropism to the central nervous system and retina of primary and secondary central nervous system lymphoma.

AIMS: How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B-cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system. METHODS: We established a patient-derived central nervous system lymphoma xenograft mouse model and characterised xenografts derived from four primary and four secondary central nervous system lymphoma patients using immunohistochemistry, flow cytometry and nucleic acid sequencing technology. In reimplantation experiments, we analysed dissemination patterns of orthotopic and heterotopic xenografts and performed RNA sequencing of different involved organs to detect differences at the transcriptome level. RESULTS: We found that xenografted primary central nervous system lymphoma cells home to the central nervous system and eye after intrasplenic transplantation, mimicking central nervous system and primary vitreoretinal lymphoma pathology, respectively. Transcriptomic analysis revealed distinct signatures for lymphoma cells in the brain in comparison to the spleen as well as a small overlap of commonly regulated genes in both primary and secondary central nervous system lymphoma. CONCLUSION: This in vivo tumour model preserves key features of primary and secondary central nervous system lymphoma and can be used to explore critical pathways for the central nervous system and retinal tropism with the goal to find new targets for novel therapeutic approaches.

Retinal changes of primary vitreoretinal lymphoma after intravitreal methotrexate.

BACKGROUND: To identify retinal changes using spectral-domain optical coherence tomography (SD-OCT) and ultra-widefield images in eyes with primary vitreoretinal lymphoma (PVRL) during intravitreal methotrexate (MTX) treatment.  METHODS: This study retrospectively reviewed 111 eyes of 58 patients with vitreous cytology-proven confirmed PVRL, who received intravitreal injections of MTX. RESULTS: At the initial visit, the OCT manifestations included vitreous cells (105 eyes, 94.6%), intraretinal infiltration (44 eyes,39.6%), subretinal infiltration (45 eyes, 40.5%,), retinal pigment epithelium (RPE) abnormalities (66 eyes, 59.5%), disruption of the ellipsoid zone (58 eyes, 52.3%), subretinal fluid (4 eyes, 3.6%), RPE detachment (PED) (28 eyes, 25.2%), epiretinal membrane (ERM) (8 eyes, 7.2%), macular edema (10 eyes, 9%). After therapy, tumor regression was achieved in all eyes. Between the initial presentation and regression, the vitreous cells (94.6% vs. 0%, P < 0.001), intraretinal infiltration (39.6% vs. 0%, P < 0.001), RPE abnormalities (59.5% vs.19.8%, P < 0.001), PED (25.2% vs.0%, P < 0.001), and subretinal infiltration (40.5%vs.16.2%, P < 0.001) were significantly reduced. The fundus photography findings all improved after therapy. The mean Logarithm of the Minimum Angle of Resolution (logMAR) for the best corrected visual acuity (BCVA) at presentation was 0.79 ± 0.81 (range, 0-2.9), which improved to 0.70 ± 0.97 (range, 0-2.9, P = 0.01) at the final visit. CONCLUSIONS: SD-OCT combined with ultra-widefield imaging, which can reflect retinal changes, are valuable tools for monitoring the effect of PVRL treatment.

CXCR4, CXCR5 and CD44 May Be Involved in Homing of Lymphoma Cells into the Eye in a Patient Derived Xenograft Homing Mouse Model for Primary Vitreoretinal Lymphoma.

Background: Primary vitreoretinal lymphoma (PVRL), a rare malignancy of the eye, is strongly related to primary central nervous system lymphoma (PCNSL). We hypothesized that lymphoma cells disseminate to the CNS and eye tissue via distinct homing receptors. The objective of this study was to test expression of CXCR4, CXCR5, CXCR7 and CD44 homing receptors on CD20 positive B-lymphoma cells on enucleated eyes using a PCNSL xenograft mouse model. Methods: We used indirect immunofluorescence double staining for CD20/CXCR4, CD20/CXCR5, CD20/CXCR7 and CD20/CD44 on enucleated eyes of a PCNSL xenograft mouse model with PVRL phenotype (PCNSL group) in comparison to a secondary CNS lymphoma xenograft mouse model (SCNSL group). Lymphoma infiltration was evaluated with an immunoreactive score (IRS). Results: 11/13 paired eyes of the PCNSL but none of the SCNSL group were infiltrated by CD20-positive cells. Particularly the choroid and to a lesser extent the retina of the PCNSL group were infiltrated by CD20+/CXCR4+, CD20+/CXCR5+, few CD20+/CD44+ but no CD20+/CXCR7+ cells. Expression of CXCR4 (p = 0.0205), CXCR5 (p = 0.0004) and CD44 (p < 0.0001) was significantly increased in the PCNSL compared to the SCNSL group. Conclusions: CD20+ PCNSL lymphoma cells infiltrating the eye co-express distinct homing receptors such as CXCR4 and CXCR5 in a PVRL homing mouse model. These receptors may be involved in PVRL homing into the eye.

Primary Vitreoretinal Lymphoma Therapy Monitoring: Significant Vitreous Haze Reduction After Intravitreal Rituximab.

BACKGROUND/AIMS: Intravitreal rituximab is an off-label treatment option for primary vitreoretinal lymphoma (PVRL). The objective of this study was to monitor the therapeutic response and safety profile of intravitreal rituximab in a cohort of PVRL patients. METHODS: In this retrospective, uncontrolled, open label, multicentre study, 20 eyes from 15 consecutive patients diagnosed with PRVL received at least one intravitreal injection of 1mg in 0.1ml rituximab. Biodata of the PVRL patients was recorded as well as visual acuity and vitreous haze score immediately before rituximab intravitreal injection and at follow-up examinations. Intravitreal rituximab safety data was also recorded. Additional rituximab injections were made during control visits on a pro re nata (PRN) regime using increased vitreous haze to indicate recurrence. RESULTS: There was significant vitreous haze reduction (p=0.0002) followed by significant improvement of visual acuity (mean best visual acuity before therapy 0.57 logMAR, after therapy 0.20 logMAR (p=0.0228) during the follow-up time up to 4 years. Only mild ocular side effects were reported. Median follow-up time was 565 days (range, 7-1253 days). CONCLUSION: Intravitreal rituximab therapy shows promising PVRL regression without any severe side effects. Although our clinical data support rituximab as intravitreal therapy in PVRL disease, further study is warranted.

A diagnostic challenge of primary Central nervous system lymphoma: from the eyes to the brain.

BACKGROUND: Being a subtype of primary central nervous system lymphoma (PCNSL), primary vitreoretinal lymphoma (PVRL) is a rare and fatal intraocular malignancy manifesting as blurred vision and floaters, and is usually combined with, or eventually progresses to, central nervous system lesions. The diagnosis of PVRL/PCNSL remains challenging because of the nonspecific clinical features and diagnostic dependency on biopsy. CASE PRESENTATION: In this paper, we present the clinical, imaging, laboratory, brain biopsy, and vitreous biopsy findings of a 56-year-old immunocompetent woman who presented with blurred vision of the left eye, but which rapidly evolved into lesions of the central nervous system. The dramatic changes on brain imaging and the undiagnostic brain and vitreous biopsy results presented great challenges for the diagnosis. PCNSL was eventually presumed according to comprehensive consideration of the disease progression pattern, the characteristic neuroimaging, and molecular hints. CONCLUSIONS: PCNSL is a highly invasive tumor, and timely diagnosis is the key point in clinical practice. However, the requirement for biopsy and the existence of sentinel lesions impedes the diagnosis. Therefore, follow-up and repeated biopsy is always necessary for a definitive diagnosis. This case indicates that a complete evaluation of neuroimaging, ophthalmic testing, cytologic examination of the cerebrospinal fluid, diagnostic vitrectomy, and brain biopsy are essential for diagnosis of PCNSL. Moreover, molecular and cytokine analyses are useful adjuncts to the diagnostic cytology. Of note, the analysis of cytokine levels (IL-10/IL-6) is an important auxiliary diagnostic strategy in the diagnosis of diffuse large B-cell lymphoma.

Gene expression profiling of primary vitreoretinal lymphoma.

The characteristics of tumor cells of primary vitreoretinal lymphoma (PVRL) have not been defined, although researches have shown that most cases are of diffuse large B-cell lymphoma (DLBCL). To determine the subtype and biological characteristics of tumor cells of PVRL, we performed a gene expression profiling analysis. RNA was extracted from the vitreous fluid of 7 PVRL patients and from nodal samples of 10 DLBCL patients: 6 of germinal center B-cell (GCB) type and 4 of activated B-cell (ABC) type determined by Hans' criteria. Six PVRL samples showed gene expression profiles that were similar to each other. The patterns were different from those of the ABC-type nodular DLBCL but relatively close to those of the GCB-type nodular DLBCL. Interestingly, all of the 6 examined PVRL samples had either MYD88L265P or mutation in the immunoreceptor tyrosine-based activation motif (ITAM) region of CD79B. Five PVRL patients with similar gene expression profiles were treated with a standardized regimen: intravitreal administration of methotrexate (MTX) followed by six courses of systemic high doses of MTX. As a result, 2 patients had CD79B mutations and showed early central nervous system (CNS) progression. Patients without CNS progression did not have this mutation. In conclusion, PVRL had unique genetic features: an expression pattern different from ABC-type and relatively close to GCB-type DLBCL. CD79B mutations showed potential to serve as prognostic markers for CNS progression.

Longitudinal observation of OCT imaging is a valuable tool to monitor primary vitreoretinal lymphoma treated with intravitreal injections of methotrexate.

BACKGROUND: Developing objective and repeatable indicators to evaluate the efficacy of PVRL treatment is important. The quantification of vitreous cells is a traditional criterion; however slight changes are difficult to ascertain. Spectral domain optical coherence tomography (SD-OCT) is objective, repeatable, and easily explained. The purpose of this study is to provide a longitudinal observation of OCT in PVRL treated with intravitreal injections of methotrexate (MTX) and to evaluate the utility of OCT in monitoring responsiveness of PVRL to treatment. METHODS: The medical records of patients with biopsy-positive PVRL attending our hospital between January 2016 and September 2017 who received intravitreal injections of MTX were included in this study. Pre- and post-treatment OCT images were reviewed independently by two researchers. RESULTS: Of the 24 cases reviewed, 10 patients (18 eyes) were included. SD-OCT abnormalities at the initial visit included vitreous cells (18/18), OR (outer retina) fuzzy borders (12/18), PED (pigment epithelium detachments) (9/18), subretinal hyperreflective infiltration (3/18), intraretinal infiltration (8/18), and SRF (subretinal fluid) (4/18). Post induction treatment, SRF in cases with RD (retinal detachment) was absorbed, and subretinal fibrosis appeared. Other lesions were significantly reduced. Post consolidation treatment, OR fuzzy borders, PED and SRF disappeared in 2 eyes, intraretinal infiltration disappeared in 1 eye, and other abnormalities further improved. Additionally, retinal fibrosis was observed in 3 eyes. One month post maintenance treatment, all abnormalities observed at the first visit vanished. At the last visit, OCT showed subretinal fibrosis and in 3 eyes (16.7%), the disruption of outer retina in 9 eyes (50%) and thinning of the whole layer in 4 eyes (22.2%). CONCLUSIONS: Our observations reveal that characteristic OCT features in PVRL patients can reduce gradually and finally vanish with therapy. We propose that SD-OCT may be employed to monitor the responsiveness of PVRL to treatment, which may influence decision making in the management of this disease.

Masqueraders of multiple evanescent white dot syndrome (MEWDS).

PURPOSE: To describe disorders that can masquerade as multiple evanescent white dot syndrome (MEWDS). DESIGN: Retrospective, multicenter case series. PARTICIPANTS: Patients who presented with clinical findings compatible with a diagnosis of MEWDS but were ultimately diagnosed with an alternative inflammatory, infectious, or neoplastic disorder. METHODS: Clinical records and multimodal imaging findings including fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and OCT angiography (OCTA) were analyzed. MAIN OUTCOME MEASURES: Inclusion criteria to be defined as a masquerade syndrome for MEWDS included the presence of disseminated grayish-white outer retinal spots that were hyperautofluorescent on FAF and associated with ellipsoid zone (EZ) disruption on OCT. RESULTS: Twenty-two eyes of 13 patients were identified. All patients presented with the classic findings of MEWDS listed above. A MEWDS-like presentation was bilateral in nine of 13 patients (69%). Final diagnosis was determined on the basis of additional investigations including serologies and biopsy. These diagnoses included syphilis (three patients), lymphoma (three patients), idiopathic multifocal choroiditis (two patients), idiopathic retinal phlebitis (one patient), idiopathic acute zonal occult outer retinopathy (one patient), sarcoidosis (one patient), tuberculosis (one patient), and cancer-associated retinopathy (one patient). The outer retinal lesions and imaging findings resolved with treatment for the associated systemic disorders. CONCLUSIONS: Widespread grayish-white outer retinal spots associated with hyperautofluorescence on FAF and disruption of the EZ on OCT are not pathognomonic for MEWDS. A high index of suspicion must be maintained for masqueraders of MEWDS, which can include serious inflammatory, infectious, and neoplastic disorders.

Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL-PCNSL. PATIENTS AND METHODS: Patients with refractory/relapsed (R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%). RESULTS: Fifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9-51.2) in assessable patients and 32.0% (95% CI 21.9-51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8 < 1.6, P = 0.03). CONCLUSIONS: The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. CLINICAL TRIALS NUMBER: NCT01956695.

Two cases of primary vitreoretinal lymphoma: a diagnostic challenge : The supporting role of multimodal imaging in the diagnosis of primary vitreoretinal lymphoma.

PURPOSE: To report two cases of primary vitreoretinal lymphoma (PVRL), which presented as intermediate and posterior uveitis. METHODS: Combined clinical assessment, multimodal imaging with spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, brain magnetic resonance imaging and vitreous and retinal biopsy. Case 1 was a 48-year-old woman who complained of visual loss in her right eye secondary to a diffuse vitreous opacification and multiple chorioretinal lesions. Case 2, a 74-year-old man, presented with low vision in his right eye due to a wide chorioretinal lesion at the posterior pole, vitreous opacification and posterior uveitis in both eyes. RESULTS: Diffuse large B cell lymphoma was histologically diagnosed in the cerebellum in the first case and in chorioretinal tissue in the second patient. Atypical lymphoid cells were detected and allowed to make a diagnosis of primary central nervous system lymphoma in case 1 and PVRL in case 2. CONCLUSION: PVRL often masquerades ad intermediate or posterior uveitis. The management of the patients needed a team of pathologists, haematologists and ophthalmologists to achieve the correct diagnosis and choose the more appropriate therapy. Some peculiar characteristics on multimodal imaging, even in atypical cases of PVRL, should raise suspicious for PVRL and lead to a diagnostic vitrectomy and/or retinal biopsy.

Optical coherence tomography manifestations of primary vitreoretinal lymphoma.

BACKGROUND: Primary vitreoretinal lymphoma (PVRL), a subset of primary central nervous system lymphoma (PCNSL), is a high-grade malignant tumor that shows various chorioretinal findings. Optical coherence tomography (OCT) is useful for detecting these lesions, and various abnormalities on OCT images have been reported. The purpose of this report was to investigate retrospectively the OCT manifestations of various disease stages and compare the manifestations of pretreatment, recurrent, and chronic cases. METHODS: We reviewed the medical charts and OCT images of 38 consecutive cases with PVRL. When abnormalities were detected on OCT images, the patients were classified based on the treatment of the primary disease: pretreatment if not treated, recurrent if treated previously, and chronic when chronic changes. RESULTS: Twenty-six eyes (20 cases) had abnormalities in the post-pole OCT images, i.e., 16 eyes (12 cases) were in the pretreatment group, seven eyes (five cases) were in the recurrent group, and five eyes (five cases) were in the chronic group. Two eyes (two cases) had abnormalities on OCT in the pretreatment and recurrent or chronic stages. The pretreatment and recurrent groups had subretinal or retinal pigment epithelium (RPE) level abnormalities more often than intraretinal changes. Twelve of 16 pretreated eyes and all seven eyes with recurrent disease had subretinal or RPE level abnormalities. One pretreatment case and three recurrent cases had atypical OCT manifestations of intraretinal (round lesions) or epiretinal changes (villous-shaped lesions). CONCLUSIONS: Although pretreatment cases and recurrent cases showed similar OCT abnormalities and the specific changes in the various disease stages were unclarified, collecting OCT data from various disease stages will facilitate detection of typical OCT changes of PVRL and lead to early diagnosis and treatment.

Recurrent pseudohypopyon in association with primary vitreoretinal lymphoma: a case report.

BACKGROUND: Primary vitreoretinal lymphoma (PVRL) is a rare and fatal ocular malignancy that is mostly classified as diffuse large B cell lymphoma (DLBCL). PVRL is often fatal because of its association with the central nervous system (CNS). PVRL frequently masquerades as uveitis and sometimes recurs in clinical findings as keratic precipitates (KPs) and subretinal lesions. Pseudohypopyon is one of the clinical findings of the local recurrence of PVRL and is treated with radiotherapy; however, the effectiveness of local control with an intravitreal injection of methotrexate (MTX) has not yet been determined. We herein present a case of recurrent vitreoretinal lymphoma that repeatedly developed pseudohypopyon and treated with intravitreal MTX. CASE PRESENTATION: A 64-year-old woman was diagnosed with PVRL involving primary central nervous system lymphoma (PCNSL). She received radiotherapy to the whole brain and a local ocular treatment, which resulted in temporary remission of the disease. Pseudohypopyon was detected during the follow-up. It was 2-mm high, viscous, and swollen in the center. Anterior chamber biopsy revealed the presence of atypical lymphocytes, indicating the recurrence of DLBCL. Pseudohypopyon was treated with intravitreal methotrexate and completely disappeared. Pseudohypopyon has since repeatedly appeared and been treated with intravitreal MTX each time. The recurrence of PVRL with KPs and subretinal invasion was treated with intravitreal MTX each time. Recurrence with pseudohypopyon was not simultaneous with KPs or subretinal invasion. No CNS involvement was detected during the observation period. CONCLUSIONS: Pseudohypopyon is one of the signs of recurrent vitreoretinal lymphoma. Although pseudohypopyon was temporarily controlled with intravitreal MTX, this treatment did not completely induce its remission.

Occlusive Vasculitis Following Intravitreal Rituximab Injection for Primary Vitreoretinal Lymphoma.

PURPOSE: We report three cases of occlusive vasculitis following intravitreal rituximab therapy for biopsy-proven primary vitreoretinal lymphoma (PVRL), one of which was following an injection of the biosimilar Riabni (rituximab-arrx, AmGen) and two of which were following an injection of Rituxan (rituximab, Genentech). METHODS: Case series. RESULTS: Three cases of occlusive vasculitis confirmed with fluorescein angiography are reported 5 days, 8 days, and 3.5 weeks following intravitreal injection of rituximab. The initial vision was poor (20/500, 20/150, and light perception), but vision recovered to baseline in two cases, and remained poor in the case of combined artery and vein occlusion. CONCLUSION: Occlusive vasculitis is a rarely reported but potential complication of intravitreal rituximab therapy in patients who have been previously treated with the agent and may have delayed onset. A low threshold for fluorescein angiography as a diagnostic test for post-injection vision loss and prompt treatment with topical and/or oral steroids should be considered.

Primary Vitreoretinal Lymphoma Presenting Solely with Asymptomatic Peripheral Drusenoid Lesions.

Introduction: Primary vitreoretinal lymphoma (PVRL) is a rare malignant tumor that typically involves the retina, vitreous, or optic nerve head. PVRL often occurs concurrently with central nervous system lymphoma. Here, we present the first report of a patient with biopsy-confirmed PVRL presenting solely with asymptomatic peripheral drusenoid lesions. Case Presentation: A woman in her 70s presented with new elevated amelanotic yellow lesions with overlying pigment in both of her eyes not previously seen prior to cataract surgery. Over the next 4 months, there was waxing and waning of lesions which resolved and first appeared in the right eye and then the left. A diagnostic vitrectomy of the left eye revealed B-cell lymphoma. The patient elected for initial treatment with radiation therapy of both orbits. A new lesion was identified in her right eye nearly 18 months after starting maintenance therapy with ibrutinib, following which systemic chemotherapy with methotrexate was initiated. Conclusion: Elevated clinical suspicion for a malignant process is needed for patients with progressive new retinal lesions in older age. Local radiation therapy to the orbits alone may not be sufficient to prevent progression despite initial presentation showing confinement of disease to the intraocular space.

Transient Bacillary Layer Detachment During the Disease Course of Primary Vitreoretinal Lymphoma.

PURPOSE: To report the clinical course and the retinal imaging features of a case of cytology-proven primary vitreoretinal lymphoma (PVRL) presenting with a transient bacillary layer detachment (BALAD) during the disease course. METHODS: Observational case report. RESULTS: A 50 year-old woman was referred to us with a 2-month history of vitritis in both eyes, poorly responding to oral prednisolone. After discontinuation of oral prednisolone, worsening of vitritis and the appearance of multiple creamy-like subretinal infiltrates in the mid-peripheral retina of both eyes, along with the exclusion of common causes of intermediate/posterior uveitis, made us consider PVRL. Aqueous humor sampling detected MYD88 L265P mutation, and subsequent diagnostic pars plana vitrectomy in the left eye yielded a positive cytology for large B cell lymphoma consistent with PVRL. During the disease course, optical coherence tomography of the macula showed a BALAD in the right eye, which resolved during follow-up. CONCLUSION: Our case indicates that BALAD is a possible rare manifestation of PVRL, and this should be considered in the differential diagnosis process in order to avoid diagnostic delays.

Diagnostic methods for primary vitreoretinal lymphoma: A systematic review.

Primary vitreoretinal lymphoma is a potentially aggressive intraocular malignancy with poor systemic prognosis and sometimes significant diagnostic delays as it may masquerade as chronic uveitis. Despite the variety of diagnostic techniques, it is unclear which modality is most accurate in the diagnosis of PVRL. A systematic literature search was conducted on Ovid MEDLINE, EMBASE and the Cochrane Controlled Register of Trials for studies published between January, 2000, and June, 2023. Randomized controlled trials (RCTs) reporting on the following diagnostic tools used to diagnose patients with PVRL were included: cytology, flow cytometry, MYD88 L265P mutation, CD79B mutation, interleukin 10/interleukin-6 (IL-10/IL-6) ratio, polymerase chain reaction (PCR) for monoclonal immunoglobulin heavy chain (IgH) and immunoglobulin kappa light chain (IgK) rearrangements, and imaging findings. The aggregated sensitivity of each diagnostic modality was reported and compared using the chi-squared (χ2) test. A total of 662 eyes from 29 retrospective studies reporting on patients diagnosed with PVRL were included. An IL-10/IL-6 ratio greater than 1 had the highest sensitivity (89.39%, n = 278/311 eyes, n = 16 studies) for PVRL, where the sensitivity was not significantly different when only vitreous samples were drawn (88.89%, n = 232/261 eyes, n = 13 studies) compared to aqueous samples (83.33%, n = 20/24, n = 2) (p = 0.42). Flow cytometry of vitreous samples gave a positive result in 66/75 eyes (88.00%, n = 6 studies) with PVRL, and monoclonal IgH rearrangements on PCR gave a positive result in 354/416 eyes (85.10%, n = 20 studies) with PVRL. MYD88 L265P and CD79B mutation analysis performed poorly, yielding a positive result in 63/90 eyes (70.00%, n = 8 studies) with PVRL, and 20/57 eyes (35.09%, n = 4 studies) with PVRL, respectively. Overall, our systematic review found that an IL-10/IL-6 ratio greater or equal to one may provide the highest sensitivity in identifying patients with PVRL. Future studies are needed to employ multiple diagnostic tools to aid in the detection of PVRL and to further establish nuanced guidelines when determining the optimal diagnostic tool to use in diverse patient populations.

Case report: Intraretinal hyperflow microinfiltration lesions on swept-source optical coherence tomography angiography as a potential biomarker of primary vitreoretinal lymphoma.

Primary vitreoretinal lymphoma (PVRL) is often associated with central nervous system involvement, contributing to a heightened mortality rate, thus imaging features that are characteristic enough to be potential biomarkers of PVRL are important, either in diagnosis or in assessment of disease activity. This report details the case of a 68-year-old male who presented with blurred vision in both eyes persisting for 2 months. Fundus examination demonstrated vitreous opacity and multiple subretinal yellow nodular lesions of varying sizes in the peripheral fundus of both eyes. Multiple vertical hyperreflective lesions in the neural retina of posterior pole, indistinct outer retina borders in the fovea, and hyperreflective lesions in the sub-retinal pigment epithelium (RPE) space of the peripheral retina were demonstrated on swept-source optical coherence tomography (SS-OCT) of the left eye. Hyperflow signals corresponding to the vertical hyperreflective lesions were detected on swept-source optical coherence tomography angiography (SS-OCTA) images of retinal deep capillary plexus (DCP) layer. Notably, the hyperflow signals, precisely located around retinal vessels from the nerve fiber layer to the outer plexiform layer, were postulated to stem from the dilation of infiltrated retinal vessels. Vitreous pathological results of the left eye confirmed the diagnosis of PVRL. Treatments with intravitreal methotrexate injections led to a marked improvement of best-corrected visual acuity (BCVA) and regression of the hyperflow microinfiltration lesions demonstrated on SS-OCTA. In conclusion, SS-OCTA effectively delineated the vertical hyperreflective lesions and corresponding hyperflow signals in the posterior pole macular region of a patient with PVRL. These lesions significantly diminished following intravitreal methotrexate injections. We speculated that the specific hyperflow signals on SS-OCTA could act as a potential biomarker of PVRL, and SS-OCTA holds promise in facilitating early diagnosis and monitoring therapeutic responses in PVRL cases.

Hyper-N-glycosylated SEL1L3 as auto-antigenic B-cell receptor target of primary vitreoretinal lymphomas.

Primary vitreoretinal lymphoma (PVRL) is a rare subtype of DLBCL and can progress into primary central nervous system lymphoma (PCNSL). To investigate the role of chronic antigenic stimulation in PVRL, we cloned and expressed B-cell receptors (BCR) from PVRL patients and tested for binding against human auto-antigens. SEL1L3, a protein with multiple glycosylation sites, was identified as the BCR target in 3/20 PVRL cases. SEL1L3 induces proliferation and BCR pathway activation in aggressive lymphoma cell lines. Moreover, SEL1L3 conjugated to a toxin killed exclusively lymphoma cells with respective BCR-reactivity. Western Blot analysis indicates the occurrence of hyper-N-glycosylation of SEL1L3 at aa 527 in PVRL patients with SEL1L3-reactive BCRs. The BCR of a PVRL patient with serum antibodies against SEL1L3 was cloned from a vitreous body biopsy at diagnosis and of a systemic manifestation at relapse. VH4-04*07 was used in both lymphoma manifestations with highly conserved CDR3 regions. Both BCRs showed binding to SEL1L3, suggesting continued dependence of lymphoma cells on antigen stimulation. These results indicate an important role of antigenic stimulation by post-translationally modified auto-antigens in the genesis of PVRL. They also provide the basis for a new treatment approach targeting unique lymphoma BCRs with ultimate specificity.

Clinical Outcomes in Vitrectomized versus Non-vitrectomized Eyes in Patients with Primary Vitreoretinal Lymphoma.

AIM: To evaluate if there is a difference in the clinical course of primary vitreoretinal lymphoma (PVRL) in vitrectomized versus non-vitrectomized eyes. METHODS: Observational multicenter retrospective case series of patients diagnosed with PVRL between 2007 and 2019, at three tertiary centers. The main outcomes were relapse rates, inflammatory parameters, and best-corrected visual acuities (BCVA). Statistical methods used were an adjusted generalized estimating equation model, and a proportional Cox model. RESULTS: Eighty patients (150 eyes) were followed for a median of 1.7 years. At presentation, there were no clinical differences between the groups. The relapse rate was 0.091/eye-year (EY) for vitrectomized eyes and 0.087/EY for non-vitrectomized eyes (p = .35). Vitrectomized eyes had better BCVA than non-vitrectomized eyes (p < .001). CONCLUSIONS: Vitrectomy had no effect on the relapse rate in eyes with PVRL. However, the decrease in vitreous cell and debris led to vitrectomized eyes having better visual acuity than non-vitrectomized eyes.