Diffuse Uveal Melanocytic Proliferation With Primary Vitreoretinal Lymphoma

Key Points

Question

Can diffuse uveal melanocytic proliferation occur secondary to primary vitreoretinal lymphoma?

Findings

In this case study of a patient who presented with uveal melanocytic proliferation, no systemic malignant disease was found, and the presence of primary vitreoretinal lymphoma was confirmed using chorioretinal biopsy findings.

Meaning

Primary vitreoretinal lymphoma may manifest with diffuse uveal melanocytic proliferation.

This case study describes a patient presenting with uveal melanocytic proliferation without systemic malignant disease.

Abstract

Importance

Bilateral diffuse uveal melanocytic proliferation is a rare sign of several systemic malignant neoplasms.

Observations

A patient presenting with uveal melanocytic proliferation underwent a detailed physical examination and extensive imaging. No systemic malignant neoplasm was found. Chorioretinal biopsy was performed, and its immunohistochemical results revealed the presence of primary vitreoretinal lymphoma.

Conclusions and Relevance

This patient’s results suggest that diffuse uveal melanocytic proliferation may be associated not just with systemic malignant disease, but also with primary intraocular tumors, in this case a primary vitreoretinal lymphoma.

Introduction

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular syndrome that results in profound visual loss. Ocular findings in BDUMP include scattered melanocytic tumors of the uveal tract, multiple red-orange subretinal patches with associated early hyperfluorescence on fluorescein angiography (FA), and rapid development of cataracts. BDUMP usually occurs in patients with systemic malignant disease, most commonly ovarian carcinoma in women and lung carcinoma in men. We herein report a case of diffuse uveal melanocytic proliferation occurring in a patient with primary vitreoretinal lymphoma.

A woman in her 60s presented with decreased vision in the right eye for 1 month. She had been diagnosed with uveitis and was taking systemic prednisone (60 mg/d). Her visual acuity was 20/80 OD and 20/20 OS. Intraocular pressures were 16 mm Hg OU. Results of anterior segment examination were notable only for pseudophakia in both eyes. No cells in the anterior chamber or vitreous were noted in either eye. Posterior segment examination of the right eye revealed a peripapillary scar, a gray subretinal lesion underlying most of the macula with a subretinal pseudohypopyon, and a giraffe skin–like appearance of the posterior pole, with dark spots on an orange background that extended to the midperiphery (Figure 1A). These dark spots were hypoautofluorescent (Figure 1B) and hyperfluorescent on FA (Figure 1C).

Figure 1. Findings at Initial Presentation.

A, Fundus photographs of the right and left eyes. The right eye has a giraffe skin–like appearance, with dark spots on a background of orange pigment, as well as an exudative macular detachment with a subretinal pseudohypopyon. The left eye appears unremarkable. B, Fundus autofluorescence photographs show the dark spots in the right eye to be hypoautofluorescent. Hypoautofluorescent punctate areas are also noted in the left eye. C, Fluorescein angiogram shows hyperfluorescence of the dark spots in both eyes.

Findings from clinical examination of the left fundus were unremarkable, but imaging revealed several punctate areas along the arcades that were hypoautofluorescent and hyperfluorescent on FA. Ocular coherence tomography (OCT) showed an exudative detachment of the right macula with inferiorly settled hyperreflective material and thickening of the photoreceptor layer and the underlying retinal pigment epithelium (RPE) (Figure 2A). Areas that appeared darkly pigmented on clinical examination were relatively hypoautofluorescent and hyperfluorescent on FA and corresponded to areas of RPE thinning on OCT; areas of orange pigmentation were relatively hyperautofluorescent and hypofluorescent on FA and corresponded to areas of RPE thickening on OCT. There was no subretinal fluid in the left eye. The choroid was not thickened in either eye.

Figure 2. Comparison of Findings at Initial Presentation and at 6-Week Follow-up.

A, Fundus photograph and spectral-domain optical coherence tomography (SD-OCT) of the right eye on initial presentation show subretinal fluid, pseudohypopyon with hyperreflective material, and thickening of the retinal pigment epithelium (RPE). Locations of the vertical and horizontal scans are indicated by the dotted lines on the fundus photograph. B, Fundus photograph and SD-OCT of the right eye at 6-week follow-up. The dark spots are larger and coalescent with less orange material. The SD-OCT shows interim resolution of subretinal fluid and pseudohypopyon, whereas RPE thickening persists.

The orange and black pigmentary abnormalities were consistent with the paraneoplastic syndrome of BDUMP.^1,2,3 However, the patient had no systemic symptoms apart from decreased vision. Results of a detailed physical examination, including a pelvic examination, were normal. No primary systemic malignant disease was identified on blood and cerebrospinal fluid analyses or with extensive imaging including computed tomography of the chest, abdomen, and pelvis; magnetic resonance imaging of the brain; and whole-body positron emission tomography.

Initially, the volume of subretinal fluid in the right eye decreased and prednisone therapy was tapered, but new subfoveal fluid accumulated in the left eye, with visual acuity decreasing to 20/25. The vitreous remained clear. In the right eye, the subretinal pseudohypopyon resolved, but the dark lesions enlarged and became confluent while the orange pigmentary abnormalities decreased in size (Figure 2B). New, small, deep, cream-colored lesions were noted to be scattered in both eyes, consistent with vitreoretinal lymphoma (Figure 3A). Diagnostic chorioretinal biopsy of the right eye revealed numerous atypical lymphocytes with large nuclei in the choroid and retina (Figure 3B-C). Their immunohistochemical profile (CD3⁻, CD19⁺, CD79a⁺, PAX5⁺, and >95% Ki67⁺) indicated a diagnosis of primary vitreoretinal diffuse large B-cell lymphoma. The patient received systemic high-dose methotrexate sodium and intravitreal methotrexate in both eyes, and the cream-colored lesions resolved bilaterally. At 8 months, the visual acuity was 20/400 OD with resolved subretinal fluid, persistent macular RPE thickening, and midperipheral orange and black pigmentary abnormalities. Visual acuity improved to 20/20 OS and remained stable with no subretinal fluid.

Figure 3. Diagnosis of Primary Vitreoretinal Lymphoma.

A, Composite fundus photograph of the right eye at 6-week follow-up shows new deep lesions (arrowheads) suggestive of vitreoretinal lymphoma. Similar lesions were also noted in the left eye. B, Hematoxylin-eosin–stained sections of chorioretinal tissue show numerous atypical lymphocytes with large nuclei (original magnification ×20). C, Detail of part B outlined in red (original magnification ×60).

Discussion

Gass et al¹ described the characteristic findings in BDUMP as multifocal red-orange subretinal patches with associated early angiographic hyperfluorescence, scattered melanocytic tumors of the uveal tract, exudative retinal detachment, and rapid cataract progression. All these features were present in the present case except cataract progression because the patient had pseudophakia. The most common malignant neoplasms associated with BDUMP are ovarian carcinoma in women and lung carcinoma in men; other associated diseases include carcinomas of the breast, colon, urinary bladder, gallbladder, pancreas, esophagus, and liver.⁴ The appearance of BDUMP has been described in a patient with lymphoma of the central nervous system,⁵ but to our knowledge, this report is the first to describe the development of diffuse uveal melanocytic proliferation associated with primary vitreoretinal lymphoma (PVRL) in a patient with no identifiable systemic disease at the time of presentation.

Several OCT findings have been found to be associated with PVRL, including intraretinal, subretinal, and sub-RPE hyperreflective infiltrates, as well as RPE irregularities, thickening, and detachments.⁶ Deák et al⁷ also described vertical hyperreflective lesions extending from inner retinal layers to the RPE in 7 patients with primary and secondary vitreoretinal lymphoma. Recently, Barry et al⁸ identified OCT findings that were particularly suggestive of early PVRL, including scattered hyperreflective foci in the posterior vitreous; intraretinal, subretinal, and pre-RPE nodules; and, most importantly, a subretinal infiltrate that appeared as a confluent band. In the present case, hyperreflective intraretinal infiltrates and a confluent band of subretinal material suggestive of PVRL were prominent on the initial OCT. However, the concurrent presence of diffuse uveal melanocytic proliferation complicated the diagnosis, which was ultimately made using results of a chorioretinal biopsy.

The pathogenesis of BDUMP remains unclear, although an IgG factor isolated from serum from patients with BDUMP has been previously found to stimulate melanocytic proliferation.⁹ Diffuse uveal melanocytic proliferation is usually bilateral, although it can be asymmetric; only 1 unilateral case has been reported to date.³ In our case, diffuse uveal melanocytic proliferation was more prominent in the right eye, which had a substantially higher tumor load. In the left eye, punctate areas of hypoautofluorescence and hyperfluorescence on FA resembled the pattern in the right eye; however, we do not know whether these findings were manifestations of early PVRL or simply asymmetric diffuse uveal melanocytic proliferation.⁸ The association of melanocytic proliferation with lymphoma in this patient supports the possible existence of a diffusible factor produced by tumors that stimulates such proliferation. Further research is needed to elucidate the nature of such a factor and its potential role in early tumor diagnosis and treatment, a task complicated by the relative rarity of patients presenting with BDUMP.

Conclusions

In this patient, diffuse uveal melanocytic proliferation may be associated not just with systemic malignant disease but also with primary intraocular tumors, in this case PVRL. The association of tumor load with melanocytic proliferation in this patient supports a role for a diffusible factor produced by the tumor or in response to the tumor that results in melanocytic proliferation.