Congenital Hypertrophy of the Retinal Pigment Epithelium

Congenital Hypertrophy of the Retinal Pigment Epithelium

Congenital Hypertrophy of the Retinal Pigment Epithelium Enhanced-Depth Imaging Optical Coherence Tomography in 18 Cases Adrian T. Fung, MBBS, MMed, M...

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Congenital Hypertrophy of the Retinal Pigment Epithelium Enhanced-Depth Imaging Optical Coherence Tomography in 18 Cases Adrian T. Fung, MBBS, MMed, Marco Pellegrini, MD, Carol L. Shields, MD Objective: To describe the imaging characteristics of congenital hypertrophy of the retinal pigment epithelium (CHRPE). Design: Retrospective, observational case series. Participants: Eighteen eyes of 18 patients with CHRPE. Methods: Review of chart, fundus photography, ultrasonography, fundus autofluorescence, infrared reflectance (IR) imaging, and enhanced-depth imaging optical coherence tomography (EDI-OCT). Main Outcome Measures: Features of CHRPE as analyzed by EDI-OCT. Results: The mean age at diagnosis was 48 years (range, 13e73 years). There were 5 males and 13 females, and 17 Caucasian and 1 African American patients. The mean best-corrected visual acuity was 20/22 (range, 20/20e20/40). The CHRPE was located in the retinal periphery (n ¼ 16) with intralesional lacunae (n ¼ 14) and surrounding nonpigmented (n ¼ 4) and pigmented (n ¼ 14) halo. By ultrasonography, the mean CHRPE thickness was 1.0 mm (range, 0.9e1.4 mm). Fundus autofluorescence disclosed hypoautofluorescence (n ¼ 18) with lacunae (n ¼ 14) showing isoautofluorescence (n ¼ 10) or hypoautofluorescence (n ¼ 4). Infrared reflectance imaging displayed hyporeflectivity in the area of pigmentation (n ¼ 16) and hyperreflectivity within lacunae (n ¼ 14). On EDI-OCT, all 18 lesions were flat with a mean basal diameter of 4529 mm (median, 3707 mm; range, 697e11 617 mm). The mean central sublesional choroidal thickness (126.4 mm) was not different compared with thickness 50 mm outside the margin (126.8 mm; P ¼ 0.99). The retinal pigment epithelium (RPE) was absent (n ¼ 2), thickened (n ¼ 16), or irregular (n ¼ 15). Of 9 lesions in which lacunae were imaged, 8 showed absent RPE. The overlying retinal findings included thinning or absence of the outer retina beginning at the ganglion cell layer (n ¼ 1), outer plexiform layer (n ¼ 4), outer nuclear layer (n ¼ 12), or inner segment/outer segment junction (n ¼ 1). Additional retinal findings included hyperreflective spots (n ¼ 11), cystoid edema (n ¼ 5), and subretinal cleft (n ¼ 6). Subretinal cleft specifically occurred at the site of absent photoreceptors. Conclusions: Generally, CHRPE displays hypoautoflouorescence and hyporeflectivity with hyperreflective lacunae on IR imaging. On EDI-OCT, CHRPE seems flat with thickened, irregular RPE and absent RPE within lacunae. A prominent feature is outer retinal loss, generally involving the outer nuclear layer to photoreceptors, occasionally with a characteristic subretinal cleft. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2013;-:1e6 ª 2013 by the American Academy of Ophthalmology.

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a benign, pigmented lesion located at the level of the retinal pigment epithelium (RPE).1e3 Time domain optical coherence tomography (OCT) of CHRPE has demonstrated overlying photoreceptor loss that is thought to correlate with visual scotoma.3 In this series, we further study CHRPE in 18 patients with imaging modalities including camera-based fundus autofluorescence imaging, infrared reflectance (IR) imaging, and spectral domain (SD) enhanced depth imaging OCT (EDI-OCT). The use of SD-OCT and EDI-OCT allows for greater resolution of retinal structures and improved visualization of the choroid.4  2013 by the American Academy of Ophthalmology Published by Elsevier Inc.

Methods The clinical and imaging data from 18 eyes of 18 patients diagnosed with CHRPE at the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania, between November 2010 and May 2012 were analyzed retrospectively. Institutional review board approval was obtained. All patients underwent a complete ocular examination. Demographic and clinical data recorded included age, race, sex, presenting symptoms, best-corrected visual acuity, lesion location, size of associated lacunae, halo, or subretinal fluid (SRF). Imaging performed on all patients included color fundus photography, fundus autofluorescence imaging using the Topcon TRC-50DX Retinal Camera (Topcon America, Paramus, NJ; ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.08.016

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Ophthalmology Volume -, Number -, Month 2013 Table 1. Demographics and Symptoms Patients (n [ 18)

Characteristics Age at diagnosis (yrs) Mean Median Range Sex, n (%) Male Female Race, n (%) Caucasian African American BCVA at presentation Mean Median Range Symptomatic, n (%)

48 53 13e73 5 (28) 13 (72)

CHRPE central point by performing a 2-sample t test assuming unequal variances (Microsoft Excel for Mac 2011, version 14.2.2; Microsoft Corp., Redmond, WA). The RPE thickness (thick or thin), regularity, and presence within scanned lacunae were documented. Retinal layer integrity (thickened, normal, thinned, absent) and presence of hyperreflective retinal spots, cystoid edema, or subretinal clefts were documented. Analysis of the imaging was performed by 2 independent observers (A.T.F. and M.P.) with open arbitration when there was disagreement.

Results

17 (94) 1 (6) 20/22 20/20 20/20e20/40 1 (6)

BCVA ¼ best-corrected visual acuity.

excitation light bandwidth 580 nm and barrier filter bandwidth 695 nm), IR imaging (820 nm), and EDI-OCT using the Heidelberg Spectralis HRAþOCT (Heidelberg Engineering Inc., Vista, CA). B-scan ultrasonography had been performed on 10 patients and parameters included lesion thickness and echogenicity (solid or hollow) and chorioretinal features. The area and greatest linear diameter of each lesion was measured from color fundus photographs using the digital tracing and caliper tools that come with Ophthalmic Imaging Systems, Winstation XP version 10.6.45 software (Sacramento, CA). On EDI-OCT, choroid thickness was measured by manually placing segmentation lines on Bruch’s membrane and the choroidoscleral junction for measurement of maximal difference of the thickness profile. The mean choroidal thickness 50 mm outside the margins of each lesion was compared with the thickness at the

There were 18 eyes of 18 patients identified with CHRPE. Patient demographics and clinical characteristics are summarized in Table 1. Mean follow-up was 40 months (range, 0e136 months). Only 1 patient was symptomatic (with photopsiae), but this was thought to be unrelated to the CHRPE lesion. The referring diagnosis included choroidal nevus (n ¼ 5), retinal tumor (n ¼ 3), choroidal tumor (n ¼ 2), CHRPE (n ¼ 2), or an unrelated ophthalmic condition (n ¼ 6). Clinical features and fundus imaging are presented in Table 2. All cases were located in the retinal periphery except 2 that were located within the posterior pole. Mean measurements included greatest basal linear diameter of 4529 mm (median, 3707 mm; range, 697e11 617 mm) and total lesion area of 16.1 mm2 (median, 9.7 mm2; range, 0.4e69.5 mm2). The mean distance to the optic nerve was 8.6 mm (median, 9.0 mm; range, 1.0e18.0 mm) and mean distance to the foveola was 7.8 mm (median, 8.0 mm; range, 2.0e15.0 mm). On clinical examination, lacunae were present in 14 cases, nonpigmented halo in 4, and SRF in none. On fundus autofluorescence imaging, all 18 lesions were hypoautofluorescent relative to the surrounding normal RPE. Of the 14 lesions with lacunae, isoautofluorescence was found in 10 and hypoautofluorescence in 4. On IR imaging, 17 CHRPE lesions were hyporeflective and 1 was hyperreflective. All 14 imaged lacunae were hyperreflective. B-scan ultrasonography, performed in 10 cases, documented a flat, acoustically solid mass with mean tumor thickness of 1.0 mm (range, 0.9e1.4 mm).

Table 2. Clinical Features, Fundus Autofluorescence, Fluorescein Angiography, and Infrared Reflectance Features Clinical Case 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Fundus Autofluorescence Imaging

Location Relative Maximum Basal Distance to Nonpigmented to Optic Disc Diameter (mm) Fovea (mm) Lacunae Halo IN ST IT S I T IT IT SN T SN IN ST ST S T ST ST

4.0 5.0 2.0 3.5 10.0 12.0 4.0 4.0 8.0 4.0 5.0 2.5 2.0 5.0 6.0 4.0 4.0 5.0

10.0 15.0 8.0 3.0 6.0 2.0 7.0 8.0 5.0 7.0 15.0 11.0 9.0 9.0 8.0 3.0 8.0 7.0

Y Y N Y Y Y Y Y N Y N Y Y Y Y Y Y N

N Y N N Y N N N N N Y N N N Y N N N

Infrared Reflectance Imaging

Main Lesion

Lacunae

Pigmented Area

Lacunae

HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF HypoAF

IsoAF IsoAF No lacunae IsoAF IsoAF IsoAF HypoAF HypoAF No lacunae HypoAF No lacunae HypoAF IsoAF IsoAF IsoAF IsoAF IsoAF No lacunae

Hypo Hypo Hypo Hypo Hypo Hypo Hypo Hypo Hypo Hypo Hypo Hypo Hyper Hypo Hypo Hypo Hypo Hypo

Hyper Hyper No lacunae Hyper Hyper Hyper Hyper Hyper No lacunae Hyper No lacunae Hyper Hyper Hyper Hyper Hyper Hyper No lacunae

hypo ¼ hyporeflectivity; hypoAF ¼ hypoautofluorescence; I ¼ inferior; IN = inferonasal; IsoAF = isoautofluorescence; IT ¼ inferotemporal; N ¼ no; S ¼ superior; SN ¼ superonasal; ST ¼ superotemporal; T ¼ temporal; Y ¼ yes.

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Table 3. Enhanced-Depth Imaging Optical Coherence Tomography Features Lesion

Case 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Choroidal Thickness (mm)

Retinal Pigment Epithelium

Contour

Central point

Mean 50 mm Outside Both Margins

Thickness*

Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat Flat

0 0 113 161 na na 140 92 130 288 na 185 148 232 155 211 41 0

0 0 97.5 285 na na 171 79.5 100 216.5 na 165.5 160.5 214.5 112 214.5 86 0

Thickened Thickened Thickened Thickened Thickened Thickened Absent Thickened Thickened Absent Thickened Thickened Thickened Thickened Thickened Thickened Thickened Thickened

Retina

Regularity

Within Lacunae

Pigment Epithelial Detachment

Drusen

Innermost Retinal Layer Thinned or Absent

Irregular Irregular Normal Irregular Irregular Irregular na Irregular Irregular na Irregular Irregular Irregular Irregular Irregular Irregular Irregular Irregular

na Normal na Absent na Absent Absenty Absent na Absenty na na na Absent na Absent Absent na

N N N N N N N N N N N N N N N N N N

N N N N N N N N N N N N N N N N N N

ONL ONL ONL ONL ONL ONL ONL GCL ONL OPL ONL OPL OPL OPL ONL IS/OS ONL ONL

Hyperreflective Retinal Spots

Cystoid Edema

Subretinal Cleft

N Y N Y Y Y N N N Y N Y Y Y Y N Y Y

N N N N N N N N N Y N Y Y Y Y N N N

N N N N N N N N N Y N Y Y Y Y Y N N

GCL ¼ ganglion cell layer; IS/OS ¼ inner segment/outer segment layer; na ¼ not applicable (scan did not cross both margins of congenital hypertrophy of the retinal pigment epithelium [RPE], RPE absent or scan line did not cross through a lacuna); N = no; ONL ¼ outer nuclear layer; OPL ¼ outer plexiform layer; Y = yes. *Compared with surrounding normal RPE thickness. y Entire lesion was a lacuna.

The EDI-OCT features of the lesions are presented in Table 3. On EDI-OCT, all lesions were flat (Figs 1e3). The mean choroidal thickness 50 mm outside the margin of each lesion (126.8 mm) was not different from that at its central point (126.4 mm;, P ¼ 0.99, t test). The mean subfoveal choroidal thickness was 260.4 mm (median, 261.5 mm; range, 52.0e522.5 mm). The RPE was fully absent in 2 lesions that were considered entirely lacunae (cases 7 and 10). Of the 16 remaining cases, the RPE was thickened in all 16 (100%) and irregular in 15. Of 9 lesions in which the raster line included lacunae, 8 showed absent RPE in the area of the lacunae. Thickened RPE was associated with increased optical shadowing, whereas absent RPE allowed increased optical transmission. No cases had RPE detachment, drusen, or SRF. The overlying retinal findings included absence or thinning of the outer retina external to and including the ganglion cell layer (n ¼ 1), outer plexiform layer (n ¼ 4), outer nuclear layer (n ¼ 12), or inner segment/outer segment junction (n ¼ 1). Additional findings included hyperreflective spots in the retina (n ¼ 11), cystoid edema (n ¼ 5), and subretinal cleft (n ¼ 6).

Discussion In recent years, CHRPE has been studied using various retinal imaging modalities. In a study of 13 consecutive cases, CHRPE was found to be uniformly darkly hypoautofluorescent, with lacunae exhibiting slightly greater autofluorescence.5 This is consistent with our current series, where all lesions were hypoautofluorescent and lacunae were isoautofluorescent (n ¼ 10 of 14) or

hyperautofluorescent (n ¼ 4 of 14). The hypoautofluorescence of CHRPE has been explained by the histopathologic absence of lipofuscin within the enlarged heavily and uniformly pigmented RPE cells.5,6 Segmental absence of RPE in lacunae with resultant unmasking of background scleral autofluorescence has been proposed as the reason why lacunae exhibit trace hyperautofluorescence.5 The variation from iso- to hyperautofluorescent lacunae could depend on the thickness of the intervening choroid, particularly in heavily pigmented individuals with a darker choroid. This hypothesis is further supported by IR imaging showing hyperreflective lacunae likely from bare sclera7 and SD-OCT colocalizing RPE absence with lacunae. Hyporeflectance of pigmented portions of the CHRPE lesions is caused by absorption of this wavelength by the pigmented RPE cells. A previous report of 10 patients with CHRPE studied with time-domain OCT revealed the overlying retina to be thinned with photoreceptor loss in all cases.3 Both EDI-OCT and SD-OCT in our current larger study allow for improved resolution of the choroid and retina. In our study, the retina overlying CHRPE showed absence or thinning of the outer retina (n ¼ 12; 67%) beginning at the outer nuclear layer, and all cases (n ¼ 18) displayed complete absence of the photoreceptor layer on SD-OCT. This finding is consistent with previous case reports of CHRPE imaged with SD-OCT8,9 and supports the belief that photoreceptor loss is complete, a feature that was previously suggested by time-domain OCT.3

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Figure 1. Case 8. A, Pigmented congenital hypertrophy of the retinal pigment epithelium (CHRPE) with lacunae. B, Fundus autofluorescence imaging demonstrates marked hypoautofluorescence of the mass and mild hypoautofluorescence of lacunae. C, Infrared reflectance imaging shows hyporeflectivity of pigmented portion with hyperreflectivity of lacunae. D, Enhanced-depth imaging optical coherence tomography shows a flat tumor with thickened, irregular retinal pigment epithelium absent at sites of lacunae (dotted lines). Arrows point to the margins of the lesion. The mean choroidal thickness 50 mm outside the margins of the lesion measured 80 mm and were 92 mm at the center point. The outer retina is notably absent overlying the CHRPE.

A new observation with SD-OCT, not visible with time-domain OCT, was the presence of a subretinal cleft. This was seen in 6 lesions (33%), always overlying the pigmented portion of CHRPE and with retinal thinning and

absent photoreceptors in each case. Similar to another RPE congenital abnormality, torpedo maculopathy,10 we prefer the term subretinal cleft over SRF because the tissue is retracted in a shallow lenticular fashion without elevation

Figure 2. Case 16. A, Lightly pigmented congenital hypertrophy of the retinal pigment epithelium (RPE) with 1 visible lacunae. B, Fundus autofluorescence imaging shows marked hypoautofluorescence of the lesion and relative isoautofluorescence of lacunae. The pigmented marginal halo is hyperautofluorescent. C, Infrared reflectance imaging shows hyporeflectivity of the lesion with slight hyperreflectivity of lacuna and margin. D, Enhanceddepth imaging optical coherence tomography depicts a flat lesion with irregularly thickened RPE. Arrows point to the margins of the lesion. The lacuna is demarcated by parallel dotted lines, demonstrating increased optical transmission from overlying RPE absence. A subretinal cleft with retracted outer retinal tissue is noted (asterisk). The mean choroidal thickness 50 mm outside the margins of the lesion measured 215 mm and was 211 mm at its center point. The outer retina, including the inner segment/outer segment junction, is absent over the lesion.

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Figure 3. Case 17. A, Lightly pigmented congenital hypertrophy of the retinal pigment epithelium (RPE) with several lacunae. B, Fundus autofluorescence imaging shows hypoautofluorescent pigmented areas and isoautofluorescent lacunae. C, Infrared reflectance imaging shows hyporeflectivity of the lesion and hyperreflective lacunae. An arrow points to a lacuna that the raster line passes through. D, Enhanced-depth imaging optical coherence tomography of flat congenital hypertrophy of the RPE (CHRPE) with thickened, irregular RPE. Arrows point to the margins of the lesion. At the site of the lacuna (dotted lines), absent RPE allows light transmission. The mean choroidal thickness 50 mm outside the margins of the lesion measured 86 mm and was 41 mm at its bisection. The outer retina from the outer nuclear layer is absent. Hyperreflective spots are visible within the remaining inner retina.

of the inner retina, as if the outer retinal absence led to this defect. The photoreceptor loss overlying CHRPE is likely a consequence of an inability of dysfunctional RPE to phagocytose photoreceptor outer segments.3,6,11 The absence of drusen is consistent with previous observations.12 Another new feature identified in this report using EDI-OCT technology was the finding of normal choroid underlying CHRPE. The choroid was identical in thickness and vascular appearance under the CHRPE center compared with the tissue immediately outside the CHRPE margin. Based on the normal choroidal findings underlying CHRPE, we suspect that this RPE lesion is unrelated to the choroid. Enhanced-depth imaging OCT is an ideal method for studying the choroid underneath these lesions, even though there is slight optical shadowing from densely pigmented lesions. Other imaging methods are likewise inhibited from the dense hyperpigmentation of CHRPE that render these lesions hypofluorescent on fluorescein angiography and indocyanine green angiography.13 Our study is limited by its retrospective nature, small cohort size, and EDI-OCT raster lines that were not standardized and often limited to a single scan through each lesion. Nevertheless, our findings of CHRPE imaged by EDI-OCT are consistent with prior histopathologic reports of this lesion.6,11,14 In particular, there is an abrupt thickening of the RPE within CHRPE with overlying complete photoreceptor cell loss and preservation of inner retina.6,11 On histopathology, the RPE cells are approximately twice

as tall as normal cells, with intense, uniformly distributed round pigment granules that do not autofluoresce with ultraviolet fluorescent microscopy.6 Lacunae are associated with RPE atrophy and loss.6,11,14 Bruch’s membrane can be normal or thickened, and the choriocapillaris is normal.11,14 Generally, CHRPE displays hypoautoflouorescence with isofluorescent or hyperautofluorescent lacunae and hyporeflectivity with hyperreflective lacunae on IR imaging. On EDI-OCT, CHRPE is flat with thickened, irregular RPE in the pigmented portion and absent RPE in the lacunae. There is often increased optical shadowing deep to the thickened RPE and increased optical transmission through lacunae. Outer retinal loss most commonly begins at the outer nuclear layer, with photoreceptor loss in every case and occasional subretinal cleft. The choroid seems unaffected with normal thickness and appearance.

References 1. Shields CL, Mashayekhi A, Ho T, et al. Solitary congenital hypertrophy of the retinal pigment epithelium: clinical features and frequency of enlargement in 330 patients. Ophthalmology 2003;110:1968–76. 2. Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2008432–9. 3. Shields CL, Materin MA, Walker C, et al. Photoreceptor loss overlying congenital hypertrophy of the retinal pigment

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epithelium by optical coherence tomography. Ophthalmology 2006;113:661–5. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. Shields CL, Pirondini C, Bianciotto C, et al. Autofluorescence of congenital hypertrophy of the retinal pigment epithelium. Retina 2007;27:1097–100. Lloyd WC III, Eagle RC Jr, Shields JA, et al. Congenital hypertrophy of the retinal pigment epithelium. Electron microscopic and morphometric observations. Ophthalmology 1990;97:1052–60. Theelen T, Hoyng CB, Klevering BJ. Near-infrared subretinal imaging in choroidal neovascularization. In: Holz FG, Spaide RF, eds; Krieglstein GK, Weinreb RN, series eds. Medial Retina: Focus on Imaging. Essentials in Ophthalmology. New York: Springer; 2010:79e80. Klein A, Barak A, Habot-Wilner Z, et al. The appearance of congenital hypertrophy of retinal pigment epithelium by

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high-resolution optical coherence tomography. Retina 2011;31:1740–1. De Salvo G, Krebs I, Binder S. High-definition optical coherence tomography in a case of congenital hypertrophy of the retinal pigment epithelium. Ophthalmic Surg Lasers Imaging 2010;41(suppl):S93–5. Golchet PR, Jampol LM, Mathura JR Jr, Daily MJ. Torpedo maculopathy. Br J Ophthalmol 2010;94:302–6. Buettner H. Congenital hypertrophy of the retinal pigment epithelium. Am J Ophthalmol 1975;79:177–89. Arroyo JG, Bula D. Congenital hypertrophy of the retinal pigment epithelium inhibits drusen formation. Retina 2005;25: 669–71. Giuffre G. Indocyanine green angiography in congenital hypertrophy of the retinal pigment epithelium. Eur J Ophthalmol 2005;15:162–4. Parsons MA, Rennie IG, Rundle PA, et al. Congenital hypertrophy of retinal pigment epithelium: a clinico-pathological case report [letter]. Br J Ophthalmol 2005;89:920–1.

Footnotes and Financial Disclosures Originally received: May 19, 2013. Final revision: August 12, 2013. Accepted: August 13, 2013. Available online: ---.

Support provided by the Eye Tumor Research Foundation, Philadelphia, PA (C.L.S.). Manuscript no. 2013-794.

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. Dr. Fung is currently in practice at Sydney Eye Hospital, Sydney, NSW, Australia. Financial Disclosures: The authors have no proprietary or commercial interest in any of the materials discussed in this article.

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The funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript. Carol L. Shields, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: carol. [email protected]