Rapid, Spontaneous Resolution of Prominent Subretinal Infiltrate in Vitreoretinal Lymphoma

Abstract

Purpose:

This case report describes a patient with vitreoretinal lymphoma who subacutely developed a large, peripapillary subretinal infiltrate that rapidly and spontaneously resolved.

Methods:

A case report is presented.

Results:

A 65-year-old Asian-American woman was referred for evaluation of a dense, peripapillary subretinal infiltrate in the left eye. A diagnostic vitrectomy revealed large, atypical lymphocytes with irregularly shaped nuclei, and mutational testing was positive for myeloid differentiation primary response 88 (MYD88). Prior to surgery, the patient’s subretinal infiltrate had begun to resolve spontaneously, a process that continued after surgery without initiation of systemic or local ocular therapy.

Conclusions:

Patients with vitreoretinal lymphoma may present with transient, subretinal infiltrates that can resolve without treatment.

Introduction

Vitreoretinal lymphoma (VRL) represents a subset of intraocular lymphoma and can be primary to the eye, with or without central nervous system (CNS) involvement, or secondary to systemic lymphoma elsewhere in the body. ^{1 -4} The most common presenting symptoms of VRL are blurry vision and floaters, and the most common presenting signs are vitreous cell and subretinal pigment epithelium (subRPE) infiltrates. While underrecognized, subretinal infiltrates also commonly occur. Anterior segment involvement including the presence of anterior chamber cells and keratic precipitates is present in some cases but is nonspecific, contributing to VRL’s reputation as a masquerade syndrome. ^5,6 Consequently, VRL is often misdiagnosed as uveitis and treated with topical anti-inflammatory or systemic immunosuppressive therapy, resulting in a delayed average time to diagnosis of 21 to 40 months. ^7,8

Unlike uveal lymphoma, which tends to be an indolent extranodal marginal zone lymphoma, VRL is typically a high-grade, aggressive diffuse large B-cell lymphoma (DLBCL). ^{9 -11} In addition, 56% to 90% of patients with primary VRL ultimately develop CNS involvement in 8 to 29 months, and median overall survival is worse in patients with CNS involvement. ^4,12,13 To appropriately diagnose and treat this condition that has a high propensity for CNS involvement, it is important to recognize the full spectrum of VRL presentations.

This case report describes a patient with VRL who was subsequently diagnosed with systemic DLBCL. She subacutely developed a large, peripapillary subretinal infiltrate that then rapidly and spontaneously resolved. This unique presentation adds to the spectrum of clinical features seen in VRL.

Methods

Case Report

A 65-year-old Asian-American woman presented to an outside ophthalmologist complaining of blurry vision and floaters in both eyes for 1 year and acute onset of flashes in the left eye for 1 week. She was diagnosed with a hemorrhagic posterior vitreous detachment (PVD) in the left eye and was instructed to follow up in 1 month. At her 1-month follow-up, a new lesion was noted in her left eye and she was referred to our institution for evaluation. Her medical history was notable for hypertension and her ocular history was otherwise unremarkable. On review of systems, she endorsed having a near syncopal episode 3 weeks prior and occasional frontal sinus headaches for the past year.

Her visual acuity was 20/20 in the right eye and 20/40 in the left eye. Confrontation visual field testing was full in the right eye and showed inferotemporal field loss in the left eye. Ishihara color vision test results were normal (10 of 10 plates) in the right eye and reduced (5 of 10 plates) in the left eye. Slitlamp examination showed an absence of anterior chamber cells in both eyes but revealed 1+ vitreous cell in the right eye and 2+ vitreous cell with a PVD in the left eye. Dilated fundus examination was notable for numerous small, discrete subRPE lesions in the periphery of the right eye and a large peripapillary, white subretinal infiltrate with numerous small, discrete subRPE lesions in the superior macula and periphery of the left eye (Figure 1A). Fundus autofluorescence showed hyperautofluorescence in the areas of subretinal and subRPE lesions (Figure 2A), and fluorescein angiography demonstrated late staining of these lesions with no leakage (Figure 2, B and C).

Figure 1.

Fundus photography and optical coherence tomography (OCT) images of the left eye showing resolution of subretinal infiltrate over 1 month. (A–C) Images taken at presentation, (D–F) at 1-week follow-up (prediagnostic vitrectomy), (G–I) at 2-week follow-up (postdiagnostic vitrectomy), and (J–L) at 4-week follow-up. OCT images (B), (E), (H), and (K) correspond to scans through the superior subretinal, peripapillary infiltrate. OCT images (C), (F), (I), and (L) correspond to scans through the fovea, initially showing an absence of any significant subretinal infiltrate with subsequent appearance of a transient subretinal lesion.

Figure 2.

Autofluorescence and fluorescein angiography (FA) imaging of the left eye at presentation. (A) Hyperautofluorescence corresponding to the superior peripapillary subretinal infiltrate and the superior macular and nasal peripheral subretinal pigment epithelium infiltrates. (B) An early FA. (C) A late FA showing late staining of the peripapillary subretinal infiltrate.

Optical coherence tomography confirmed the subretinal location of the prominent peripapillary lesion (Figure 1B) with much smaller sub-RPE deposits in the superior macula (Figure 1C) and elsewhere showed no evidence of overlying retinitis. A laboratory evaluation including rapid plasma reagin, fluorescent treponemal antibody absorption, QuantiFERON-TB Gold, and toxoplasma serology testing had negative results. Magnetic resonance imaging of the brain and orbits revealed mild enhancement around the left optic nerve sheath that was greater than that of the right optic nerve sheath and scattered periventricular and subcortical T2/fluid-attenuated inversion recovery hyperintensities, both of which were consistent with probable CNS involvement. The patient was scheduled for a diagnostic pars plana vitrectomy (PPV).

At her preoperative examination 1 week after initial presentation, the peripapillary subretinal lesion demonstrated central clearing with migration into the macula and involvement of the subfoveal space (Figure 1, D-F). Postoperatively, the patient was prescribed prednisolone acetate and moxifloxacin eye drops to use 4 times per day in the operated eye.

Results

Cytology from the PPV showed large, atypical lymphocytes with irregularly shaped nuclei and prominent nucleoli, and myeloid differentiation primary response 88 (MYD88) mutational testing was positive for the leucine-to-proline substitution at position 265, confirming the diagnosis of VRL. At her postoperative visits 2 weeks (Figure 1, G-I) and 4 weeks (Figure 1, J-L) from initial presentation, the peripapillary subretinal infiltrate had completely resolved and the fovea-involving subretinal component had largely resolved prior to initiation of systemic or local ocular therapy. Cytology, flow cytometry, and gene rearrangement studies from cerebrospinal fluid were unremarkable, but a positron emission tomography scan showed fluorodeoxyglucose-avid lesions in multiple lymph nodes, including the right frontal sinus. This was biopsied and pathology confirmed DLBCL.

The patient was subsequently treated with 8 cycles of systemic high-dose methotrexate; 8 cycles of rituximab; 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); and autologous stem cell transplant (ASCT) 7 months after initial presentation. She achieved a complete response (ocular, CNS, and sinus) with systemic therapy alone. At last follow-up (9 months from initial presentation), the patient remained stable with no evidence of vitreous cell, subretinal infiltrates, or subRPE infiltrates. Given the improvement in ophthalmic findings with systemic therapy, no intravitreal therapy was administered. She remains under close ocular surveillance.

Conclusions

Here, we present a patient with VRL who had a large, prominent, superior peripapillary subretinal infiltrate that migrated to the macula and then spontaneously resolved prior to treatment. Of note, this patient was evaluated by a retina specialist 1 month prior to evaluation at our institution with no apparent lesion at this time. This suggests that subretinal VRL involvement can develop subacutely and can resolve over a short period of time. Concurrently, the patient had peripheral small, discrete subRPE infiltrates that changed over time during the transient appearance of her prominent subretinal lesion; some resolved completely, whereas others appeared and persisted for several months after starting treatment with systemic therapy. While this patient was initially diagnosed with a hemorrhagic PVD, she likely had lymphoma cells involving the vitreous from the start of her initial symptoms. We presume that the subretinal infiltrate represents lymphomatous cells, but we did not biopsy the subretinal space. This subretinal material could also represent an immune reaction to lymphoma cells in the vitreous or a paraneoplastic reaction to lymphoma, among other possibilities.

Five previous case reports have described a waxing-and-waning course of VRL lesions. Shah and colleagues reported on 3 patients who had multiple evanescent white-dot syndrome–like presentations of VRL, in which the patients had multifocal, small, white deep retinal or subretinal lesions that changed locations over the course of 1 to several months. ¹⁴ Mantopoulos and Cebulla described a patient with spontaneous regression of large, subRPE infiltrates over a 3-month period. ¹⁵ Kase and colleagues reported on a patient with VRL who underwent enucleation for a blind eye that showed a subretinal lymphocytic infiltration after atypical lymphoid cells were found on a vitreous biopsy prior to enucleation. ¹⁶ Tan and colleagues described a patient with a subretinal infiltrate that spontaneously resolved after 6 weeks who later underwent a brain biopsy showing DLBCL. ¹⁷ Pakdel and colleagues reported 2 cases of VRL with subretinal infiltrates that regressed soon after diagnostic PPV. They hypothesized that this could have been from PPV-induced T-cell inflammation, which caused suppression of neoplastic B lymphocytes. ¹⁸

Our case is unique in that the patient had extensive and sequential multimodal imaging that showcased the migratory and transient nature of a prominent subretinal lesion that regressed without treatment over a 1-month period. Moreover, our patient showed partial resolution of the subretinal lesion prior to PPV and vitreous biopsy. This self-resolving nature of VRL has now been characterized in multiple reports including ours. In addition, cases of extraocular lymphoma involving the conjunctiva and orbit have shown spontaneous regression as well. ^{19 -21} Although the mechanism is not entirely clear, local immune regulation may play a role in controlling lymphomatous proliferation: Inflammation induced by lymphoma cells may lead to upregulation of natural killer- and T lymphocytes that suppress B lymphocytes. ^22,23

While the varying presentation of VRL contributes to the difficulty in diagnosing this disease, another reason for its delayed diagnosis is the low yield of cytology from a vitreous biopsy. When vitreous cell is present, cytology from vitreous biopsy yields positive results in 47% of cases, but when vitritis is absent, the yield drops to only 10%, suggesting that cytology from vitreous biopsy alone is not always pragmatic. ⁵ Other supportive diagnostic tests include flow cytometry, gene rearrangement studies, cytokine assays for interleukin (IL)-10 and -6 levels, and MYD88 gene analysis. While diagnostic for lymphoma, flow cytometry using B-cell and T-cell markers has a relatively low sensitivity of 36%, whereas the immunoglobulin heavy chain gene rearrangement study to detect monoclonal B-cell populations has a higher sensitivity of 64%. ²⁴ For detecting VRL of T-cell type, gene rearrangement studies of T-cell receptors can aid in the diagnosis of this rarer form of VRL. ²⁵ Testing of IL-10 to IL-6 ratios greater than 1.0 has been used to support the diagnosis of primary VRL with a sensitivity of 74% and specificity of 75%. ^26,27

More recently, studies have found that a characteristic missense mutation in the MYD88 gene resulting in a change of leucine to proline at position 265 of the universal adapter protein is found in 82% of all VRL cases and 87% of primary VRL cases. ^28,29 When vitreous biopsy is inconclusive, a transvitreal chorioretinal biopsy can also be performed to obtain a tissue diagnosis. ³⁰ From the diagnostic PPV, our patient had a combination of positive cytological findings in addition to positive testing results for MYD88 to confirm the diagnosis of VRL.

Treatment of VRL depends on the extent of disease and whether lymphoma is confined to the eye or present elsewhere in the body. For ophthalmic treatment, local external beam radiotherapy ³¹ or intravitreal therapy with methotrexate ^{32 -34} or rituximab ^{35 -38} may be used. When there is concurrent CNS involvement, systemic high-dose methotrexate is commonly used either as a single agent or as part of combination therapy. ^{39 -41} For systemic DLBCL, combination therapy with R-CHOP is often given as first-line treatment. ⁴² More recently, ASCT ⁴³ and Bruton tyrosine kinase inhibitors ^44,45 have been used for treatment of systemic lymphoma. Our patient underwent multiple rounds of methotrexate, rituximab, and R-CHOP, in addition to ASCT, and achieved both a complete metabolic response based on repeated positron emission tomography scan imaging and a complete ocular response.

Patients with VRL may present with transient, subretinal infiltrates that can resolve without treatment. Recognizing this form of VRL presentation is important for prompt diagnostic evaluation of the eye, CNS, and elsewhere for lymphoma and the initiation of appropriate local and/or systemic therapy.