From The New York Eye Cancer Center, New York City, New York.
The authors have no financial or proprietary interest in the materials presented herein.
Supported by The Eye Cancer Foundation, Inc. ( http://eyecancerfoundation.net), and an OCT/SLO Study Grant from John and Myrna Daniels (Toronto, Ontario, and Palm Beach, FL) and Ekaterina Semenova was supported by a Fellowship Grant from the International Federation of Ophthalmological Societies–International Council of Ophthalmology.
Address correspondence to Paul T. Finger, MD, The New York Eye Cancer Center 115 East 61st Street. Suite 5B, New York City, NY 10065. E-mail: email@example.com
Fundus autofluorescence (FAF) imaging is a relatively new technology that permits topographic mapping of retinal pigment epithelium cell dysfunction without requiring injection of dye. Lipofuscin appears as hyper-autofluorescent areas. Lost or destroyed areas of retinal pigment epithelium are hypo-autofluorescent. These findings have also been found in different hereditary and acquired intraocular diseases, including age-related macular degeneration, choroidal nevi and melanomas and intraocular metastases.1–3 FAF-imaging studies have been used to understand their pathophysiology.
Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare chorioretinopathy associated with systemic cancer. Its exact pathological mechanisms are poorly understood. The pathophysiology has been described as an autoimmune reaction within the uvea that manifests as uveal thickening (proliferation of melanocytes), RPE dysfunction, secondary exudative retinal detachments and rapidly maturing cataracts.4–9 We present a case evaluated with FAF imaging.
A 55-year-old woman patient with metastatic small cell lung cancer was referred to The New York Eye Cancer Center. She had a visual acuity (VA) of 20/20 in her right eye and 20/40 in her left. Fundoscopic examination of the left eye showed a pattern of RPE thickening and diffuse lipofuscin (orange pigment) deposition, combined with RPE loss (Figs. 1A and 1B). A low-lying exudative retinal detachment was present. B-scan ultrasonography revealed choroidal thickening (Fig. 1C).
Figure 1. (A) High Resolution (11-Megapixel) Color Photography Reveals a Pattern of RPE Hyperpigmentation Surrounded by a Sea of Lipofuscin (orange Pigment). (B) A Correlation Between Scanning Laser Ophthalmoscope and Guided Optical Coherence Tomography Image Reveals RPE Layer Thickening with Shadowing of the Subjacent Choroid and Subretinal Fluid. The Most Thickened RPE Layer Corresponded with Areas of Lipofuscin Deposition. (C) 20-MHz B-Scan Ultrasonography Shows Choroidal Thickening of the Left Eye.
FAF-imaging (TopCon Medical Systems, Paramus, New Jersey, USA) of the left eye revealed a pattern of diffuse RPE hyper-autofluorescence (Fig. 2A) that was directly correlated to the pattern of diffuse orange pigment deposition seen on fundus photography. Conversely, there were islands of persistent hypo-autofluorescence corresponding to visible RPE loss. Hypo-autofluorescent spot-size varied with anterior–posterior location. Larger spots of FAF hypo-autofluorescence were found at the posterior pole, with increasingly smaller hypo-autofluorescent spots at the periphery of the affected retina.
Figure 2. (A) Initial Fundus Autofluorescence Imaging (FAF) of the Affected Eye Demonstrates a Diffuse Background of Hyper-Autofluorescence Associated with Orange Pigment Deposition and Islands of Persistent Hypo-Autofluorescence Corresponding to Loss of Retinal Pigment Epithelium. (RPE) (B) As if a Negative of the FAF Image, Fluorescein Angiography of Orange Pigment Blocks of Fluorescence and Areas of RPE Loss Are Hyperfluorescent. Below: (C) FAF Imaging 4 Months Later Demonstrates Progression of RPE Loss Seen as Enlarged Areas of Hypo-Autofluorescence. Synchronously, the Areas of Hyper-Autofluorescence (lipofuscin-related) Are Diminished. (D) Initial Fundus Autofluorescent Imaging (FAF) of the Unaffected Eye Demonstrates Lack of Orange Pigment.
FAF-images appeared like a negative of the fluorescein angiography (FA) images (Fig. 2B). While FAF revealed RPE dysfunction as hypo-autofluorescence, FA revealed similar areas of patchy hyperfluorescence. Areas of FAF hyper-autofluorescence corresponded to FA hypofluorescence due to blockage by lipofuscin-laden RPE. This pattern was also noted to include and be accentuated within the foveal and perifoveal retina.
Optical coherence tomography imaging (OCT [OPKO, Miami, FL]) revealed a pattern of increased and decreased thickness of the RPE layer (Fig. 1B). Thickened RPE was hyper-autofluorescent on FAF-imaging and corresponded to areas of lipofuscin (orange pigment) on fundus photography. Conversely, where FAF was hypo-autofluorescent there was thinned or missing RPE on OCT. These areas were darkened on fundus photography and hyperfluorescent on FA.
The patient returned for re-evaluation 4 months later. Visual acuity in her left eye decreased to 20/50. There were no signs of cataract formation in either eye. Dilated fundus examination revealed increasing areas of RPE loss. This was evidenced by enlargement of the previously noted hypo-autofluorescent patches with synchronous diminution of the hyper-autofluorescent areas on FAF-imaging (Fig. 2C). The retinal detachment appeared unchanged. The right eye was unaffected at the time of initial diagnosis and during follow-up. Three months later, the patient died due to complications from lung cancer.
This case demonstrates that metastatic cancer can induce progressive destruction of the RPE that can be monitored by FAF-imaging. By evaluating FAF over consecutive visits, we noted an increase in lipofuscin or increase in dying RPE. This confirms what is believed about the pathophysiology of this disease. In review of the literature, we found that several eyes with BDUMP have undergone histopathologic examination.7–9 They revealed patchy infiltration of the choroid, ciliary body and iris by small spindle-shaped melanocytes. Few mitoses have been found. The overlying RPE was described as depigmented, necrotic or thickened. There were numerous drusen and a decrease in ganglion cells and photoreceptors. Both submacular and supramacular gliosis have been noted.
In this case, FAF, FA, OCT and ultrasound imaging are consistent with the findings. FAF and FA clearly demonstrated RPE loss and dysfunction. OCT revealed both thickening and thinning of the RPE with disorganization of the normal overlying retinal layers. Ultrasound revealed thickening of the subjacent uvea.
Like Wu et al.,4 we have found that FAF is useful for the diagnosis of diffuse uveal melanocytic proliferation, also termed as “nummular loss of the retinal pigment epithelium”.4 In this case, FAF, FA and OCT imaging complement each other and correspond to the clinical findings. In addition, we present unique images documenting the progression of this disease by fundus autofluorescence imaging.
- Bindewald A, Bird AC, Dandekar SS, Dolar-Szczasny J, et al. Classification of fundus autofluorescence patterns in early age-related macular disease. Invest Ophthalmol Vis Sci. 2005;46:3309–3314. doi:10.1167/iovs.04-0430 [CrossRef]
- Hopkins J, Walsh A, Chakravarthy U. Fundus autofluorescence in age-related macular degeneration: an epiphenomenon?Invest Ophthalmol Vis Sci. 2006;47:2269–2271. doi:10.1167/iovs.05-1482 [CrossRef]
- Schmitz-Valckenberg S, Holz FG, Bird AC, et al. Fundus autofluorescence imaging: review and perspectives. Retina. 2008;28:385–409. doi:10.1097/IAE.0b013e318164a907 [CrossRef]
- Wu S, Slakter JS, Shields JA, et al. Cancer-associated nummular loss of the pigment epithelium. Am J Ophthalmol. 2005;139:933–935. doi:10.1016/j.ajo.2004.11.005 [CrossRef]
- Lee JM, Seong JK, Nam WH, et al. Cancer-associated nummular loss of the retinal pigment epithelium. Korean J Ophthalmol. 2007;21:261. doi:10.3341/kjo.2007.21.4.261 [CrossRef]
- Gass JDM, Gieser RG, Wilkinson CP. Bilateral diffuse uveal melanocytic proliferation in patients with occult carcinoma. Arch Ophthalmol. 1990;108:527–533.
- Borruat FX, Othenin-Girard P, Uffer S, et al. Natural history of diffuse uveal melanocytic proliferation. Case report. Ophthalmology. 1992;99:1698–1704.
- Rohrbach JM, Roggendorf W, Thanos S, et al. Simultaneous bilateral diffuse melanocytic uveal hyperplasia. Am J Ophthalmol. 1990;110:49–56.
- Margo CE, Pavan PR, Gendelman D, et al. Bilateral melanocytic uveal tumor associated with systemic non-ocular malignancy. Retina. 1987;7:137–141. doi:10.1097/00006982-198700730-00001 [CrossRef]