Ebstein-Bar Virus (EBV)-Positive diffuse large B-cell vitreoretinal lymphoma: Two cases without overt immunocompromise and review of the literature

Abstract

Purpose

To describe 2 cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma of the vitreous and retina (LBCL-VR) in elderly patients without overt systemic immunocompromise and summarize previously published literature.

Observations

Two elderly Asian patients without overt immunocompromise were referred to our clinic for management of uveitis. The first patient, a 79-year-old man, had a history of presumed varicella zoster keratitis of the right eye (OD) and anterior and intermediate uveitis of the left eye (OS). The second patient, a 69-year-old female, had CMV-associated anterior uveitis OD. After initial improvement, both patients developed recurrent and persistent intraocular inflammation leading to a diagnostic vitrectomy. Cytopathology of the vitreous sample confirmed a diagnosis of EBV-positive LBCL-VR in both cases. Neither patient was immunosuppressed nor had evidence of CNS disease. Both patients received serial intravitreal methotrexate as treatment, and both remained free of local recurrence and extraocular dissemination of VRL at last follow up (3 and 1.5 years, respectively).

Conclusion

Vitreoretinal lymphoma (VRL) remains a challenging diagnosis. EBV-positive LBCL-VR is an exceedingly rare entity with distinctive demographic and immunologic features. In addition to overt immunocompromise, immunosenescence may also be associated with EBV-positive LBCL-VR. EBV status should be evaluated in all cases of LBCL-VR, especially in LBCL without mutations in MYD88 and/or CD79a.

1. Introduction

Vitreoretinal lymphoma (VRL) is a rare malignancy affecting the vitreous body, retina, subretinal space, and optic nerve.¹ Although VRL may be isolated to the eye, 42–92 % of patients develop central nervous system (CNS) disease.^2,3 VRL is most prevalent in immunocompetent adults over the age of 50, and has no racial predilection.^1,3 Large B-cell lymphoma (LBCL) of the vitreous and retina (LBCL-VR), is the most common type VRL, and the terms are frequently used interchangeably.⁴

Epstein-Barr virus (EBV) infection is common, with worldwide prevalence estimates over 95 %.⁵ Although EBV is a well-known driver of lymphoid neoplasia, by definition, LBCL-VR is EBV-negative.^4,5 EBV-positive LBCL-VR comprises a distinct entity, not well-characterized at this site and, perhaps, closely related to the EBV-positive diffuse large B-cell lymphoma of the CNS (EBV-positive CNS DLBCL).^3,4,6 EBV-positive CNS DLBCL occurs nearly universally in a setting of immunocompromise, which may be secondary to infection (e.g. Human Immunodeficiency Virus (HIV)), medications, or other malignancies.⁴ EBV-positive DLBCL can also occur in the CNS, lymph nodes, and extranodal sites in a setting of immunosenescence (i.e. decline of immune function associated with advanced age) and is more commonly in males (M:F ratio 2:1), typically of Asian, African, or Latin American descent, who have no underlying immune disorder/dysfunction.⁴

There have been few previously reported cases which fulfill the WHO5 diagnostic criteria for EBV-positive LBCL-VR.⁴ Four occurred in a setting of immunocompromise (HIV in two patients and rheumatoid arthritis in two patients). One case occurred in a 72-year-old man with no overt immunocompromise.⁷ Herein, we present two elderly Asian patients without overt immunocompromise with EBV-positive VRL. Both patients had a prolonged history of presumed anterior uveitis prior to diagnosis with EBV-positive LBCL-VR. These cases emphasize the diagnostic challenges of EBV-positive LBCL-VR and broaden our understanding of the complexity of VRL.

2. Case 1

A 79-year-old Asian male with past medical history of hypertension and hyperlipidemia presented to the eye emergency room for floaters and blurred vision in the right eye (OD). Prior ocular history was notable for an anterior and intermediate uveitis in the left eye (OS) complicated by uveitic glaucoma that responded to topical difluprednate therapy, and presumed varicella zoster virus (VZV) associated keratitis OD. The patient self-discontinued a suppressive dose of valacyclovir 1 g daily approximately 1 month prior to his current presentation.

On initial examination, VA was 20/100 OD and 20/50 OS. IOP was 24 OD and 9 OS. Anterior segment examination OD revealed corneal epithelial pseudodendrites, 1+ anterior chamber (AC) cell, and 1–2+ anterior vitreous cell. Fundus examination OD did not show evidence of retinal lesions. Examination OS was unremarkable. An AC paracentesis was performed OD and the aqueous sent for PCR testing for herpes simplex virus (HSV), VZV, and cytomegalovirus (CMV). A targeted serologic work-up was requested, including complete blood count (CBC) with differential, comprehensive metabolic profile (CMP), QuantiFERON, Treponema pallidum antibodies, and angiotensin converting enzyme (ACE). The patient started on valacyclovir 1g TID and prednisolone 1 % q2h while awake OD for suspected herpetic uveitis. His aqueous PCR testing was negative for viral etiologies and serological work-up was unremarkable. The valacyclovir was discontinued. Over the following 6 weeks, the patient continued to have dense, persistent vitritis OD (Fig. 1). Optical Coherence Tomography (OCT) did not reveal any macular lesions in either eye (Fig. 1). Given the unrevealing work-up and non-response to local steroid therapy, there was concern for VRL and the patient underwent a diagnostic pars plana vitrectomy (PPV) OD.

Fig. 1.

Case 1, EBV-associated VRL in a 79-year-old Asian man. Wide field fundus and OCT retina images of right eye (A, B) showing significant media opacity in setting of dense vitritis and left eye (C, D) for comparison with clear media.

Cytopathologic evaluation of the vitreous fluid showed a dominant population of large, atypical lymphocytes in a background of prominent apoptosis and necrosis and few small lymphocytes and macrophages (Fig. 2). Immunohistochemical studies (IHC) showed that the large, atypical cells (80–90 % of lymphocytes) were CD20 positive B-cells, which were also positive for CD30, BCL2, and MUM1 and negative for CD5, CD10, BCL6, and c-MYC with a Ki-67 proliferative index of 80 %. The atypical lymphocytes were positive for EBV-encoded small RNA via in-situ hybridization (EBER-ISH). Targeted mutation studies using locked nucleic acid (LNA) probes showed no evidence of MYD88 L265P mutation (assay sensitivity 0.5 % for detecting MYD88 L265P mutation in a wild-type background). PCR for B-cell clonality was nondiagnostic due to absence of amplifiable DNA. The combined clinical, laboratory, cytomorphologic, IHC, ISH, and molecular genetic findings were compatible with EBV-positive DLBCL.

Fig. 2.

Case 1. EBV-associated VRL in a 79-year-old Asian man, cytopathologic findings. Large, atypical lymphocytes with irregular nuclear contours and scant cytoplasm (black arrow) in a background of apoptotic lymphocytes (red arrow) (A). Higher magnification highlights large, atypical lymphocytes (black arrow) in a background of numerous necrotic lymphocytes (white arrowhead). Note the few small morphologically normal lymphocytes (red arrow) and macrophages (black arrowhead) (B). The large, atypical lymphocytes and apoptotic/necrotic debris stain for B-cell marker CD20 (brown reaction product) (C). Rare small lymphocytes stain for T-cell marker CD3 (D). The large, atypical lymphocytes are negative for CD10 (E) and BCL6 (F) and are positive for MUM1 (G) and EBER-1 (H) with a brisk Ki-67 proliferative index (I).

[Stains: H&E (A, B), CD20 (C), CD3 (D), CD10 (E), BCL6 (F), MUM1 (G), EBV-encoded RNA by in situ hybridization (H), Ki-67 (I); x400 (A, C-I), x630 (B)].

Systemic oncologic workup for lymphoma, including magnetic resonance imaging (MRI) of the brain and orbits with and without contrast, cerebrospinal fluid (CSF) cytology, testicular ultrasound, and chest/abdomen/pelvis computed tomography (CT) scan with contrast, was negative. PCR for EBV DNA on whole blood was positive (1206 copies/mL), while no EBV DNA was identified in the CSF. HIV studies (p21 antigen and HIV-1 and HIV-2 antibodies) were negative. This systemic workup supported the diagnosis of EBV-positive LBCL-VR.

The patient was initiated on serial intravitreous methotrexate (MTX) 400 μg monthly injections receiving a total of 12 injections OD over one year, with improvement in vision to 20/40 OD. Five years after the initial presentation, three years following diagnosis with VRL, the patient has no evidence of recurrent or disseminated lymphoma.

3. Case 2

A 69-year-old Asian woman with history of locally treated endometrial cancer (hysterectomy and vaginal cuff brachytherapy) in complete remission was referred to our clinic for long-standing, recurrent hypertensive anterior uveitis OS. She was first diagnosed with hypertensive anterior uveitis, suspected to be Posner Schlossman syndrome, approximately 2.5 years prior to initial presentation, 2 months following her cataract surgery, which responded well to topical steroids. She experienced 2 more flares of uveitis while tapering off drops but had since been quiet on long standing difluprednate 0.05 % twice daily for approximately 2 years. She sought a second opinion with a uveitis specialist to try and taper off topical corticosteroids.

At her initial presentation to our clinic, VA was 20/50 OD and 20/60 OS. IOP was 6 OD and 23 mmHg OS. Anterior segment examination and DFE OD were unremarkable. Anterior segment examination OS revealed numerous granulomatous keratic precipitates, 2+ AC cells, and DFE OS showed 2+ vitreous cells. OCT of the macula was unremarkable OU. Laboratory studies, including CBC with differential, CMP, QuantiFERON, Treponema pallidum antibodies, and ACE were within normal limits. An AC paracentesis was performed and the aqueous sent for PCR testing for HSV, VZV, and CMV. Her aqueous PCR testing returned positive for CMV (156,000 copies/mL) and she was diagnosed with chronic hypertensive CMV-associated anterior and intermediate uveitis OS. She was started on oral valganciclovir 900 mg BID and continued on difluprednate 0.05 % QID OS.

The patient had gradual improvement in her intraocular inflammation with complete resolution on follow-up 9 months later. VA improved to 20/20 OS and IOP was 15 OS. She was asked to taper the valganciclovir to 450 mg BID and to taper the difluprednate 0.05 % to BID. The patient was lost to follow-up for 4 months. When she returned, there was notable worsening of intraocular inflammation with 3+ AC cell and 3+ anterior vitreous cells while still on difluprednate BID OS and valganciclovir 450 mg BID. There was no evidence of retinitis, vasculitis, or choroiditis OU. The valganciclovir was increased back to 900 mg BID and the difluprednate 0.05 % back to QID OS. On follow-up, her anterior chamber cell had resolved, but her vitreous cell appeared worse. The decision was made to proceed with diagnostic vitrectomy OS. Cytopathologic examination of the vitreous fluid showed medium-to-large, atypical lymphocytes in a background of apoptotic/necrotic cells, small lymphocytes, and macrophages (Fig. 3). Immunohistochemical stains showed that the atypical lymphocytes were CD20 positive B-cells, which were also positive for CD30 and MUM1 (post-germinal cell marker) and negative for CD5, germinal center cell markers CD10 and BCL6, and c-MYC. Proliferation marker Ki-67 was primarily expressed in the nuclei of atypical medium-to-large cells. The atypical lymphocytes were positive for EBV-encoded small RNA via in-situ hybridization. PCR studies showed a clonal rearrangement in the immunoglobulin heavy chain (IgH) gene. Targeted mutation studies showed no evidence of MYD88 L265P mutation. PCR for CMV DNA was positive, but below the quantifiable limit (<1423 copies/mL). The patient underwent additional work-up to assess her immune status that included normal CD4 and CD8 counts, and negative HIV and HTLV-1/2 testing. MRI brain and orbits with and without contrast did not show evidence of CNS lymphoma. Repeat CT chest, abdomen, and pelvis did not show evidence of local or metastatic malignancy. CSF cytology and cytometry showed no evidence of malignant cells. The combined clinical, imaging, laboratory, cytomorphologic, immunohistochemical, ISH, and molecular genetic study findings were compatible with EBV-associated VRL, with the differential diagnosis including EBV-positive LBCL-VR and chronic inflammation-associated large B-cell lymphoma of vitreous and retina (CI-LBCL-VR).

Fig. 3.

Case 2. EBV-associated VRL in a 69-year-old Asian woman, cytopathologic findings.

A mixed population of medium-to-large lymphocytes with irregular nuclear contours, focally prominent nucleoli, and scant cytoplasm (black arrow) in a background of pink necrotic debris, small lymphocytes (arrowhead), and macrophages (red arrow) (A). The atypical lymphocytes and apoptotic/necrotic debris stain for B-cell marker CD20 (brown reaction product) (B). Small lymphocytes stain for T-cell marker CD3 (brown reaction product) (C). The intact atypical lymphocytes are EBER-1 positive (blue reaction product) (D).

[Stains: H&E (A), CD20 (B), CD3 (C) EBV-encoded RNA by in situ hybridization (D); all images x400].

The patient was referred to the ocular oncology service who initiated serial monthly intravitreal MTX 400 μg injections. On the most recent follow-up, 6 months after diagnosis of EBV-associated VRL, there was no evidence of disease recurrence and VA was 20/20 OU. The patient's valganciclovir was successfully tapered to 900 mg daily, with plans to continue suppressive dosing for at least another 6 months.

4. Discussion

We present two patients without overt immunocompromise who developed EBV-positive LBCL-VR. EBV-positive LBCL-VR is exceedingly rare with few reported cases in the literature, the majority of which occurred in immunocompromised or significantly immunosuppressed patients (Table 1).7, 8, 9, 10, 11 Our two cases herein are similar in demographics to the patient presented by Wang et al.,⁷ with all three patients having Asian ethnic ancestry and likely immunosenescence secondary to advanced age at 79, 69, and 72 years old (Table 1).

Table 1.

Pertinent clinical features of reported EBV-positive vitreoretinal lymphoma (VRL) and potential cases.

VRL Report [Ref]	Demographics			Management						Outcomes
	Age (y), Gender	PMH	Meds	Affected Eye(s)	Visual Acuity (OD,OS)	Anterior Findings	Posterior Findings	Initial Dx	Initial Tx (response)	Time to VRL Dx (y)	VRL Tx	Local Recurrence (Time from VRL Dx, y)	Dissemination of Lymphoma (Time from VRL Dx in y)
Zafar et al. (Case 1)	79M	None	None	OD	20/100	OD: corneal pseudodendrites, 1+ anterior chamber (AC) cell	OD: 1–2+ anterior vit cell, vit debris	Suspected herpes viral anterior/intermediate uveitis	Topical CS and Valacyclovir (no response)	2.5	iVit MTX OD	None (3)	None (3)
						OS: cataracts	OS: drusen
Zafar et al. (Case 2)	69F	Endo AdenoCA (2y prior)	None	OS	20/60	OD: no cell	OD: unremarkable	Possner-Schlossman crisis → anterior/intermediate uveitis (CMV-associated)	Topical CS + oral valacyclovir (with initial response, then worsened with taper)	4	iVit MTX OU	None (0.5)	None (0.5)
						OS: granulomatous keratic precipitates (KP), 2+ AC cell	OS: 2+ anterior vit cells
Sun et al.10	64M	RA (15y)	MTX	OU	20/32, 20/15	OU: KP, AC cell	OD: Mild Vit opacity, limited view	Anterior/intermediate uveitis	Topical CS and levofloxacin (OD no response, OS positive response)	0.25	iVit MTX	None (0.5)	None (0.5)
			Tacro			→ OD KP, AC cell; OS: normal	OS: normal
			Tocil
Nagata et al.9	39F	RA (10y)	MTX	OD	0.01 (Snellen equivalent 20/2000)	Hypopyon, KP, PS	Dense vitreous opacities	Behcet's disease, HLA-B27 associated uveitis, or RA-associated uveitis	Topical + ST CS (initial response → recurred)	4	iVit MTX, systemic chemo	Not available (NA)	Optic nerve involvement (0)
			TNFi
Mittra et al.8	38M	HIV c/b CNS Toxo (3y prior)	None	OS	20/20	OD: clear AC	OD: 2+ anterior vit cells, hazy view, focal retinitis, chorioretinal scars, atrophy	CMV retinitis → multifocal Toxo > atypical CMV retinitis or VRL lymphoma	Oral pyrimethamine + azithromycin (OD positive response, recurrence) → intravitreal ganciclovir (OD response) → intravitreal clindamycin (OS no response)	NA	Radiation (OS)	None (NA)	None (0)
						OS: RAPD, clear AC	OS: trace cells, epiretinal membrane
Wang et al.7	72M	None	None	OS (	HM	Corneal leukoplakia	Vitreous opacities (cloud-like), diffuse white retinal surface nodules, retinal vascular sheathing, retinal hemorrhages	Infectious endophthalmitis (fungal)	Post-PK: Topical CS + immunologic therapies (symptomatic following discontinuation) → topical levofloxacin, ganciclovir, tacrolimus, loprednol; oral valacyclovir	1.5	iVit MTX	None (0.3)	None (0)
						Endothelial decompensation → corneal graft edema, 3+ cells, fibrin, diffuse white iris surface nodules, conjunctival hyperemia
Ruiz-Bilbao et al.11	37M	HIV c/b Toxo (unsp.) and PCP pneu-monia, IVDU, Hep B, Hep C, Mono, splenec-tomy	IVMP	OS	NA	NA	Severe vitritis, chorioretinitis lesions, perilesional vasculitis → retinal necrosis, optic atrophy without vitritis	EBV uveitis	IV ganciclovir (no response) → PPV, intravitreal foscarnet, IV foscarnet → patient left hospital against medical advice	1.5 (post-mortem)	NA (expired)	NA	1.3 (CNS; corpus callosum, frontal lobe)

EBV-positive LBCL-VR is regarded as a distinct entity from the conventional LBCL-VR. Unlike the conventional LBCL-VR, EBV-positive LBCL-VR is more likely to be CD30-positive, lacks the high-frequency MYD88 and CD79A mutations seen in a conventional LBCL-VR and, by definition, is EBV-positive. In fact, the presence of EBV has been reported to be mutually exclusive with either MYD88 and/or CD79a mutations.¹² Since MYD88 mutation testing has emerged as a valuable diagnostic modality for VRL, absence of MYD88 mutation in VRL may prompt consideration of EBV-positive LBCL-VR.

EBV-positive LBCL-VR has protean clinical manifestations (Table 1). The masquerading nature and variable clinical course of EBV-positive LBCL-VR often confounds the management of these patients, the majority of whom are immunosuppressed. Table 2 lists the pathologic and laboratory results of reported EBV-positive LBCL-VR and potential cases. Supplementary Table 1 highlights the molecular markers from Table 2 and their clinical relevance.

Table 2.

Pathologic and laboratory results of reported EBV-positive vitreoretinal lymphoma and potential cases.

	Pathology Findings					Systemic Results
VRL Report [Ref]	Specimen	Cytology	IHC/ISH	Flow Cytometry	Molecular Studies Interleukin Levels	Blood	CSF
Zafar et al. (Case 1)	Vit	Atypical lymphocytes Size: Large, monomorphic + apoptosis + necrosis	CD20 + CD30 + BCL2 + MUM1 + CD5 - CD10 - BCL6 - c-MYC - Ki-67: 80 % EBER +	No monoclonal B-cell population	MYD88 L265P Negative B-cell clonality studies (IgH, kappa): Nondiagnostic	EBV DNA Positive	EBV DNA Negative No malignant cells
Zafar et al. (Case 2)	Aqueous Vit	Atypical lymphocytes Size: medium to large, polymorphic + apoptosis + necrosis	CD20 + CD30 + MUM1 + CD5 - CD10 - BCL6 - c-MYC - EBER + CMV Ag -	Inconclusive	MYD88 L265P Negative B-cell clonality studies (IgH, kappa): Positive Aqueous CMV DNA: 156,000 copies/mL Vit CMV DNA: <1423 copies/mL	n.a.	No malignant cells
Sun et al.10	Vit	Atypical lymphocytes Size: large	CD20 + BCL2 + MUM1 + CD5 - BCL6 - Ki67: 58 % EBER + EBNA2 + EBV LMP1 - IMP3 -	CD20 + CD19 + CD38 + IgA + Ig light chain + HLA-DR + CD5 -	B-cell clonality studies (IgH): Positive T-cell clonality studies TCR: Positive EBV DNA - Positive IL-10: 35 pg/mL IL-6: 551 pg/mL	EBV DNA Negative “Blood tests for EBV antibodies, anti-EBV capsid antigen, anti-EBNA, and anti-early antigen D IgG indicated prior infection.”	n.a.
Nagata et al.9	Vit	Abnormal lymphoid cells Size: Moderately large + nucleoli - Cyt vacuoles - Cyt granules	EBV LMP1 +	CD20 + CD19 + CD10 - CD5 +	EBV (unsp.) Positive B-cell clonality studies (IgH, kappa): Positive IL-10: 32 pg/mL IL-6: 288 pg/mL	n.a.	n.a.
Mittra et al.8	Vit, RBx	Vit: Mixed population of lymphocytes and histiocytes RBx: Abnormal lymphoid cells (ILM to OPL)	Vit: Testing - RBx: CD20 + CD45 + EBV LMP1 + EBER +	n.a.	n.a.	n.a.	No malignant cells
Wang et al.7	Aqueous., Vit, Iris	Iris: DLBCL	Iris: CD20 + CD3 - MUM1 + CD10 - BCL6 - Melan A - S-100 - HMB45 - EMA - CD68 - BCL2 + (90 %) CD5 - BCL1/Cyclin D1 - CD19 + CD30 + (70 %) Ki-67: 70 % EBER + (80 %) c-MYC IHC: + (40 %) c-MYC ISH:	n.a.	Aqueous EBV (PCR): Positive IL-10: 7.7 × 104 pg/mL IL-6: 171 pg/mL Vit: chr 6 loss (CNV)	n.a.	n.a.
Ruiz-Bilbao et al.11	Aqueous, Vit, CNS tumor (post-mortem)	Aqueous/Vit: Inconclusive CNS tumor: DLBCL	EBER +	Aqueous/Vit: Inconclusive	EBV PCR: Positive in aqueous and Vit	EBV DNA Positive	EBV DNA Negative

Ag = antigen; CMV = cytomegalovirus; CNS = central nervous system; CNV = copy number variation; DLBCL = diffuse large B-cell lymphoma; DNA = deoxyribonucleic acid; EBNA2 = Epstein–Barr nuclear antigen 2; EBER = Epstein-Barr encoded small ribonucleic acid; EBV = Epstein-Barr Virus; EMA = epithelial membrane antigen; HLA-DR = human leukocyte antigen – DR isotype; IHC = immunohistochemical staining; Ig = immunoglobulin; IL-6 = interleukin-6; IL-10 = interleukin-10; ILM = inner limiting membrane; ISH = in-situ hybridization; Ki-67 = proliferation marker Ki-67; LMP1 = latent membrane protein 1; n.a. = not available; OPL = outer plexiform layer; PCR = polymerase chain reaction; RBx = retina biopsy; Ref = reference; Vit = vitreous; VRL = vitreoretinal lymphoma.

Interestingly, our second patient had a diagnosis of chronic hypertensive anterior uveitis for years which was eventually diagnosed as CMV-associated anterior uveitis OS with a positive response to topical corticosteroids and valganciclovir. However, nearly 1 year after the diagnosis of CMV-associated anterior uveitis, she began developing signs of worsening intraocular cell after tapering the topical corticosteroids and valganciclovir and was eventually diagnosed as EBV-positive LBCL-VR. The clinical history of CMV-associated uveitis preceding the diagnosis of VRL raises consideration of LBCL-CI. It is hypothesized that chronic inflammation in a confined space may induce local immunodeficiency by the production of interleukin (IL)-10, promoting escape from immunosurveillance of EBV-transformed B-cells.⁸ It is possible that in our second patient, chronic CMV infection facilitated an emergence of a clonal EBV-transformed B-cell population. Further, although this patient had no known systemic immune dysfunction besides the remote history of locally treated uterine cancer, long-term topical steroid administration for chronic uveitis may have contributed to emergence of lymphoma. An alternative hypothesis is that the patient had simultaneous EBV-associated lymphoma from the onset, masquerading as uveitis.

The diagnosis of EBV-positive LBCL-VR is challenging. Standard infectious organism panels performed on intraocular fluid do not currently include EBV, including at our institution, which may contribute to under-recognition of this virus as a causative agent of both intraocular inflammation and neoplasia.⁵ Further confounding the picture is the fact EBV DNA has been found in healthy controls and aqueous antibody titers are considerably insensitive.¹³ While modern techniques such as PCR are more specific, they are unable to differentiate between active and dormant EBV infection.¹⁴ EBV also frequently coexists with other pathogens making it difficult to determine its specific role in uveitis.¹⁴ EBV testing is, therefore, best reserved for atypical presentations, similar to the cases reported in this study. As highlighted in Table 2, cytology and ancillary studies on vitreous fluid can be limited by low cellularity, leading to inconclusive or false negative results, further delaying diagnosis. While we included in this review only cases of LBCL-VR which were confirmed to be EBV-driven by positive EBER-ISH and EBV latent membrane protein-1 (LMP-1) IHC studies, there are other reported cases that also raise consideration of an EBV-associated lymphoma, but lack supporting ancillary studies to conclusively document an EBV-driven lymphoid neoplasm.15, 16, 17, 18, 19

Non-ocular EBV-positive DLBCL is usually managed by combination chemotherapy with rituximab, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (R-CHOP) as the first line treatment.⁴ EBV-positive DLBCL, however, responds more poorly to treatment with lower survival rates than EBV-negative DLBCL. Given the rarity of this lymphoma in the vitreous and retina, information on the optimal therapy and prognosis of EBV-positive LBCL-VR is lacking. In our 2 cases and those previously reported, patients were treated with intravitreal MTX, radiation, or systemic chemotherapy and while patients appear to have responded well to these treatments, limited follow-up prevents conclusions at this time.

In conclusion, we report two elderly Asian patients without overt immunocompromise with EBV-positive LBCL-VR, adding to the limited literature on this unique type of VRL. These cases underscore the importance of early recognition and incorporation of appropriate ancillary diagnostic studies for characterization of VRL to guide appropriate treatment strategies, while raising awareness of EBV as a potential driver in the pathogenesis of VRL in broader patient populations. Further research is warranted to elucidate the mechanisms underlying EBV-positive LBCL-VR and to optimize therapeutic outcomes.

CRediT authorship contribution statement

Sidra Zafar: Writing – review & editing, Writing – original draft, Data curation. Ari H. August: Writing – review & editing, Data curation. Tatyana Milman: Writing – review & editing, Data curation, Conceptualization. Jordan D. Deaner: Writing – original draft, Conceptualization.

Patient consent

Written consent to publish this case series has not been obtained. This report does not contain any personal identifying information.

Authorship

All authors attest that they meet the current ICMJE criteria for authorship.

Funding

Supported in part by an unrestricted grant from the J. Arch McNamara Retina Research Fund for Wills Eye Hospital and Mid Atlantic Retina.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the supplementary data to this article: