Loss of Retinal Pigment Epithelium Associated with Bilateral Diffuse Uveal Melanocytic Proliferation

Introduction

Bilateral diffuse uveal melanocytic proliferation is a rare paraneoplastic disease characterized by painless visual loss without any evidence of systemic cancer at presentation in the majority of patients.^1,2 The primary carcinoma, often discovered later, can most commonly arise from the ovaries, cervix, and uterus in women and the lung in men.^1,2 Bilateral diffuse uveal melanocytic proliferation in association with esophageal, colon, breast, vesica fellea, thyroid, and pancreatic adenocarcinomas have also been reported.² There seems to be a slight female predilection and patients typically present between 50 and 80 years of age.^1,2 Fundus lesions, serous retinal detachments, and cataracts are the most frequent ocular manifestations of bilateral diffuse uveal melanocytic proliferation, in decreasing order.²

We describe a patient in whom the diagnosis of bilateral diffuse uveal melanocytic proliferation led to the discovery of disseminated bronchogenic carcinoma. The eyes had patchy areas of retinal pigment epithelial loss and elevated melanocytic lesions without detectable diffuse uveal thickening.

Case Report

A 69-year-old otherwise healthy woman was referred to us because of poor visual acuity in both eyes despite successful cataract extractions 3 months earlier. She reported that cataracts developed rapidly and simultaneously in both eyes.

Her visual acuity was hand motions in each eye. The pupillary reflexes were intact. There were in-the-bag posterior chamber intraocular lenses with clear posterior capsules in both eyes. Occasional non-pigmented cells were observed in the anterior chamber and anterior vitreous. Fundus examination revealed a solitary, mildly pigmented uveal melanocytic lesion measuring 9 × 8 × 2.5 mm with accompanying shallow serous retinal detachment and orange pigment in the right eye (Fig. 1A). There was a similar lesion measuring 5 × 5 × 1.5 mm in the inferotemporal quadrant of the left eye (Fig. 2A).

Figure 1. (A) Right Fundus View Showing the Choroidal Melanocytic Lesion with Large Amounts of Orange Pigment. (B) Late Phase Fluorescein Angiography Demonstrates Small, Confluent Areas of Hyperfluorescence Corresponding to Transmission Defects. (C) Optical Coherence Tomography Reveals Local Retinal Pigment Epithelial Loss over the Melanocytic Lesion and Collections of Material with Subretinal Fluid.

Figure 2. (A) Left Fundus View Shows a Solitary Melanocytic Lesion Below the Inferior Vascular Arcade. (B) On Late Phase Fluorescein Angiography, There Are Multiple Pinpoint Foci of Hyperfluorescence. (C) Fluorescein Angiography Depicts an ill-Defined Area of Small Confluent Islands of Hypofluorescence and Hyperfluorescence. (D) Optical Coherence Tomography of the Same Area Shows Hyperreflective Elements over a Local Area of Retinal Pigment Epithelial Loss.

Fluorescein angiography showed that the melanocytic lesions had hypofluorescent and hyperfluorecent areas in early phases and mottled hyperfluorescence in late phases (Figs. 1B and 2B). There were clinically unidentifiable, flat, small irregular nummular areas of hypofluorescence and hyperfluorescence superior to the optic disc in the left eye (Fig. 2C). Optical coherence tomography demonstrated retinal pigment epithelial atrophy over the elevated uveal lesions (Fig. 1C) and the fluorescein angiographically detected zones of retinal pigment epithelial alterations in the left fundus (Fig. 2D). Electroretinography showed decreased amplitudes of a and b waves in photopic and scotopic recordings. A- and B-scan ultrasonography did not demonstrate diffuse uveal thickening.

The diagnosis of bilateral diffuse uveal melanocytic proliferation was made and the patient was immediately sent for a systemic work-up. Thoraco-abdominal computed tomography scans revealed a large mass in the left superior pulmonary lobe (Fig. 3) with multiple bone and hepatic metastases. The systemic status of the patient deteriorated rapidly and she died 10 days after the ocular diagnosis.

Figure 3. Thoracal Computed Tomography of the Patient Showing a Bilobular Mass (arrows) Measuring 4.5 × 2 cm at the Anterior Segment of the Superior Lobe of the Left Lung.

Discussion

Bilateral diffuse uveal melanocytic proliferation is a highly unusual but well-documented paraneoplastic disease based on the experience gained from 30 cases reported in the literature during the past 43 years.^1–6 Initial observations allowed Gass et al.¹ to establish the now classic diagnostic criteria, which included multiple elevated red round patches at the level of retinal pigment epithelium and early hyperfluorescence corresponding to these areas on fluorescein angiography, pigmented or amelanotic uveal melanocytic tumors with diffuse thickening of the uvea, exudative retinal detachment, and rapid development of cataract.

As more cases are recorded, new features of the disease begin to emerge. Saito et al.³ reported a case of bilateral diffuse uveal melanocytic proliferation with non-recordable electroretinography and autoantibodies against recoverin and heat shock cognate protein 70 in serum and aqueous humor, suggesting an accompanying cancer-associated retinopathy. The profound visual loss despite normal-appearing foveas and electroretinography abnormalities in our patient may also represent cancer-associated retinopathy components. However, we were unable to test autoantibodies.

Three recent reports expanded the clinical spectrum of bilateral diffuse uveal melanocytic proliferation by focusing on retinal pigment epithelium changes and highlighting nummular loss of retinal pigment epithelium as a distinct feature.^4–6 Wu et al.⁴ observed only round confluent red-gray patches at the retinal pigment epithelium level without uveal thickening or choroidal lesions. Optical coherence tomography demonstrated zones of complete retinal pigment epithelium loss and thickened areas of retinal pigment epithelium without any debris.⁴ These findings led the authors to speculate that apoptosis driven by a paraneoplastic process was the cause for selective retinal pigment epithelium loss.⁴ Others also observed extensive nummular areas of retinal pigment epithelium atrophy without underlying uveal melanocytic proliferation.^5,6 In these cases, optical coherence tomography showed focal collections of debris overlying atrophic retinal pigment epithelium that was interpreted in favor of a degenerative process rather than apoptosis.^5,6 Our similar optical coherence tomography finding of islands of focal accumulations of material over the affected areas of retinal pigment epithelium and the presence of large amounts of lipofuscin may support the degeneration hypothesis.

In our patient, the differential diagnosis could have included metastatic melanoma, multiple bilateral nevi, bilateral multicentric or diffuse uveal melanomas, and metastatic carcinoma.^7,8 However, bilateral profound loss of vision, depressed a and b waves in photopic and scotopic electroretinography recordings, and fluorescein angiography findings are all in favor of bilateral diffuse uveal melanocytic proliferation.

Our patient demonstrated that identical retinal pigment epithelium alterations and losses occur over zones of uveal melanocytic proliferations and over areas with apparently normal uveal thickness. This finding may favor the possibility of two distinct simultaneous paraneoplastic stimuli acting over the uveal melanocytes and the retinal pigment epithelium.