Purpose
To describe the nature and evolution of paraneoplastic cloudy vitelliform submaculopathy in patients with primary vitreoretinal lymphoma and propose a mechanism for its development and course.
Design
Retrospective, observational case series.
Methods
Three patients presenting with unilateral cloudy vitelliform submaculopathy based on clinical examination, fundus autofluorescence, fluorescein angiography, and spectral-domain optical coherence tomography (SD OCT) imaging and ultimately diagnosed with primary vitreoretinal lymphoma and/or primary central nervous system lymphoma were analyzed.
Results
In all 3 patients, cloudy vitelliform submaculopathy appeared with hazy indistinct yellow subretinal material resembling the vitelliform lesions found in acute exudative paraneoplastic polymorphous vitelliform maculopathy, although with less distinct appearance and without intense hyper-autofluorescence. In all 3 patients, cloudy vitelliform submaculopathy was transient, showed spontaneous regression within 3 months, and preceded the diagnosis of lymphoma, suggestive of a paraneoplastic process. The diagnosis of primary vitreoretinal lymphoma and/or primary central nervous system lymphoma was made within 6 months with classic features of new intraretinal or sub–retinal pigment epithelium infiltration of lymphoma in the peripheral retina (n = 2) and hyperintense lesions on brain magnetic resonance imaging (n = 2). With SD OCT imaging, the cloudy vitelliform subretinal lesions appeared as hyperreflective debris above the retinal pigment epithelium band in all 3 eyes, and were associated with an irregularly thickened and rippled retinal pigment epithelium band in 2 eyes. Resolution of the cloudy submacular lesions resulted in outer retinal atrophic changes in all 3 eyes.
Conclusion
Paraneoplastic cloudy vitelliform submaculopathy, a form of lymphoma-associated retinopathy, can precede the diagnosis of primary vitreoretinal lymphoma or primary central nervous system lymphoma and can regress spontaneously, leaving outer retinal abnormalities.
Primary vitreoretinal lymphoma, originally described as “reticulum cell sarcoma of the eye” or primary intraocular lymphoma, and recently termed “primary vitreoretinal lymphoma,” is a rare but potentially fatal non-Hodgkin lymphoma that manifests in the vitreous and/or retina. Primary vitreoretinal lymphoma is considered a subset of primary central nervous system lymphoma, since 65%–90% of patients presenting with primary vitreoretinal lymphoma develop primary central nervous system lymphoma, usually within 29 months; while approximately 15%–25% of patients with primary central nervous system lymphoma present with primary vitreoretinal lymphoma. Primary vitreoretinal lymphoma is the most common yet aggressive intraocular lymphoma, usually as diffuse large B cell lymphoma, although the T cell type can infrequently occur. The distinction between primary vitreoretinal lymphoma and uveal or choroidal lymphoma is appreciated because of their differing systemic associations and clinical implications.
Clinically, primary vitreoretinal lymphoma typically occurs in older patients with a median age of 60 years and is often fatal because of ultimate brain involvement, with a mean survival of 32 months and a 5-year survival rate of 61%. Early diagnosis of primary vitreoretinal lymphoma is imperative but often difficult because primary vitreoretinal lymphoma can masquerade as a uveitis, vitritis, or chorioretinitis. Distinctive features of primary vitreoretinal lymphoma include homogenous, large vitreous cells and irregular, multifocal, yellow-white infiltration in the retina or beneath the retinal pigment epithelium (RPE).
The term “pseudovitelliform” has been used in the literature to refer to acquired pseudovitelliform macular dystrophy and is different from the vitelliform lesion in Best’s vitelliform dystrophy. More recently, acquired vitelliform lesions, defined as subretinal accretion of clinically yellow, hyper-autofluorescent material above the RPE band and within the macular region not owing to acquired vitelliform macular dystrophies, have been described in association with a variety of conditions, including cuticular drusen, reticular pseudodrusen, serous pigment epithelial detachment, pseudoxanthoma elasticum with angioid streaks, vitreomacular traction, central serous chorioretinopathy, immunogammopathies, and acute exudative paraneoplastic polymorphous vitelliform maculopathy. We present 3 patients with cloudy subretinal vitelliform maculopathy that showed features distinct from pseudovitelliform macular dystrophy and acquired vitelliform lesions, resolved spontaneously within 3 months of initial presentation, and were ultimately recognized to have underlying primary vitreoretinal lymphoma and/or primary central nervous system lymphoma. The transient nature of this retinopathy suggests a paraneoplastic process. Herein, we describe the clinical features of this paraneoplastic cloudy vitelliform submaculopathy as a possible form of lymphoma-associated retinopathy.
Methods
This retrospective study had approval from the Western Institutional Review Board and complied with the Health Insurance Portability and Accountability Act. Clinical and multimodal imaging data from 3 patients were analyzed. Patients were examined at 3 vitreoretinal referral practices located in New York, New York; San Francisco, California; and Philadelphia, Pennsylvania. All patients underwent comprehensive ophthalmic assessment with slit-lamp biomicroscopy, indirect ophthalmoscopy, color fundus photography, and camera-based fundus autofluorescence (AF) (Topcon TRC-50DX Retinal Camera; Topcon Corporation, Paramus, New Jersey, USA). When appropriate, fluorescein angiography (FA) was performed. Spectral-domain optical coherence tomography (SD OCT) was performed on all eyes with the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). The study period, taken from the first to most recent SD OCT image analyzed, was from January 2009 to February 2013 and the longest duration of retrospective follow-up was 9 months.
Results
Three white patients, aged 63–74 years, 1 female and 2 male, presented with a unilateral cloudy vitelliform submacular lesion that regressed spontaneously within 3 months (range 3–12 weeks) of initial symptoms. Within 6 months, 2 patients were diagnosed with primary central nervous system lymphoma by positive brain biopsy and manifesting with hyperintense lesions on brain magnetic resonance imaging (MRI). In the third case, diagnosis of diffuse large B cell lymphoma was suspected by features of peripheral sub-RPE infiltration found 4 months later and confirmed cytologically with sub-RPE biopsy. Resolution of the cloudy vitelliform submaculopathy resulted in outer retinal atrophic changes confirmed with SD OCT imaging in all 3 eyes. In 2 eyes there was appearance of new intraretinal or sub-RPE infiltrates in the peripheral retina after resolution of the cloudy vitelliform submaculopathy. The third case had remnant sub-RPE punctate spots above the macula. The cases are described below.
Case 1
A 63-year-old white female subject noted unilateral blurred vision in the right eye for 2 weeks. Best-corrected Snellen visual acuity was 20/100 in the right eye (OD) and 20/20 in the left eye (OS). Anterior segment examination was unremarkable. Dilated funduscopic examination OD revealed subretinal yellow, hazy material located under the fovea with gravitation inferiorly, associated with multiple, small, punctate yellow-white sub-RPE spots scattered superior to the macula. Mild vitreous cells were present. Fundus examination OS was unremarkable. SD OCT imaging OD revealed a macular detachment with hyperreflective subretinal debris resembling vitelliform deposition above the RPE band with irregular thickening of the RPE band, creating a rippled appearance. The submacular lesion was hyper-AF with fundus AF imaging and hyporeflective with near-infrared reflectance and FA imaging, although it lacked the usual intense hyper-AF seen with vitelliform lesions. Imaging studies OS were unremarkable. Systemic evaluation for infectious, inflammatory, autoimmune, and neoplastic etiologies was negative at this stage.
The patient was reexamined 3 weeks later without treatment and was noted to have spontaneous regression of the cloudy vitelliform lesion with minimal subretinal remnants noted. On SD OCT, the RPE thickening was resolved, except for a few focal areas of nodular elevation. There was partial but incomplete disappearance of the yellow-white punctate sub-RPE spots in the superior peripheral retina. Two months later, there was complete disappearance of the cloudy vitelliform submacular lesion, with resultant disruption and thinning of the outer retinal layers on SD OCT imaging. Six months later, the patient developed neurologic symptoms and a hyperintense brain lesion on MRI consistent with primary central nervous system lymphoma, with the absence of new eye findings. A brain biopsy was performed and confirmed primary central nervous system lymphoma ( Figure 1 ).
Case 2
A 62-year-old white male subject presented with blurred vision OD for 1 week. Best-corrected Snellen visual acuity was 20/40 OD and 20/20 OS. Dilated fundus examination of the right eye revealed a cloudy yellow-white submacular lesion gravitating at the inferior arcade and sparing the fovea. This was associated with multiple, small, yellow-white, punctate spots inferior to the arcade. Examination OS was unremarkable. One week later, there was progressive deterioration of visual acuity OD to 20/100. There was further accumulation of the cloudy yellow-white submacular material extending upwards from the inferior arcade, now involving the foveola. SD OCT imaging revealed hyperreflective material above the RPE band and rippled RPE thickening. An MRI brain and cerebrospinal fluid cytology and flow cytometry performed within 2 weeks of initial presentation was completely normal.
At 6 weeks, the visual acuity deteriorated to 20/125 and there was spontaneous decrease in the size of the cloudy vitelliform submacular lesion. At 8 weeks, minimal cloudy submacular debris was noted, although there was persistence of the yellow-white spots scattered throughout the macula and visual acuity remained at 20/100. SD OCT confirmed regression of the cloudy vitelliform submacular lesion, associated with less RPE thickening, although multifocal nodular, anterior protrusion of the RPE could still be appreciated. At 11 weeks, there was complete spontaneous regression of the cloudy vitelliform submacular lesion and improvement of visual acuity to 20/30. SD OCT imaging revealed complete resolution of the finding, which resulted in outer retinal thinning and disruption in that area. In the peripheral temporal retina, new yellow-white intraretinal lesions resembling acute retinitis were detected. The left eye remained unaffected. At 6 months, the patient developed right hemiparesis and the diagnosis of primary central nervous system lymphoma was made based the appearance of a hyperintense brain lesion on MRI and brain biopsy. There were new intraretinal lesions in the peripheral superior retina at this time, with resolution of the temporal lesions ( Figure 2 ).
Case 3
A 74-year-old white male subject noted sudden visual loss OS, which he described as “purple lights and floating spots.” Visual acuity was 20/30 OD and 20/200 OS. There was a cloudy yellow submacular lesion at the fovea. OCT imaging showed hyperreflective subretinal debris located above the RPE band, consistent with vitelliform deposition. Initial evaluation by the referring doctor was inconclusive and included a vitreous biopsy, which revealed predominantly histiocytic infiltration.
The patient was subsequently referred for evaluation 3 months later. At this time, visual acuity was 20/30 OD and counting fingers OS. The right eye was unremarkable. In the left eye, there was atrophic macula with pigmentary subfoveal changes and no cloudy vitelliform submacular lesion. SD OCT imaging confirmed outer retinal thinning and atrophy with abnormalities of the RPE. Fundus AF imaging showed granularity with hyper-AF and hypo-AF corresponding to RPE changes. FA imaging showed granularity and hypofluorescent changes consistent with RPE changes. On closer examination of the peripheral retina, there was large sub-RPE infiltration of presumed lymphoma, revealed on SD OCT and confirmed on fine-needle aspiration biopsy as diffuse large B cell lymphoma. The patient was treated with external beam radiotherapy and 6 months later, the infiltrates had regressed completely. Visual acuity remained at counting fingers OS. At 9 months, there was no brain involvement and lumbar puncture and MRI imaging were negative ( Figure 3 ).
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