Recurrent Lisch Epithelial Corneal Dystrophy Treated with 5-Fluorouracil: A Case Report and Review of the Literature

Abstract

Purpose:

To describe a case of Lisch epithelial corneal dystrophy (LECD), review its clinical and histopathological features and diagnostic imaging, and introduce a novel treatment approach using topical 5-fluorouracil (5-FU).

Methods:

A 65-year-old female presented with a recurrent left-sided corneal lesion consistent with LECD. The lesion was evaluated clinically, with high-resolution optical coherence tomography (HR-OCT), and histologically. The lesion was successfully treated with 2 one-week cycles of topical 5-FU.

Results:

Slit lamp examination (SLE) showed an opalescent, whorl-shaped corneal lesion. HR-OCT revealed a trapezoidal area of normal thickness epithelial hyperreflectivity. Histopathology demonstrated mucosal epithelium with foamy cytoplasm and increased cell size consistent with LECD. Treatment with topical 5-FU resulted in marked clearance of the corneal lesion on SLE and HR-OCT.

Conclusion:

5-FU may be considered as a treatment option for LECD.

Introduction:

Lisch epithelial corneal dystrophy (LECD), first noted by Lisch et al in 1992, is a rare X-linked dominant dystrophy of the corneal epithelium (1, 2) that manifests clinically as a gray, band-shaped, feathery, and sometimes whorled corneal opacity. Often recurrent, LECD has been reported in limited numbers (2–8), with previously attempted treatments have been entirely procedural, including soft and hard contact lenses (3–5), photorefractive keratectomy (PRK) with mitomycin C (MMC) (7), epitheliectomy alone (2) or with cauterization of the limbal focus of origin, and keratolimbal autograft transplantation (KLAT) (8). Additionally, failure of treatment with topical medications such as artificial tears, sodium chloride, corticosteroids, and diclofenac has been reported. (2, 4). To date, no reports of topical chemotherapy treatment have been described. We therefore present a novel case of LECD that was successfully managed with topical 1% 5-fluorouracil (5-FU) chemotherapeutic eyedrops.

Case Presentation:

A 65-year-old female, a life-long sailor with no past ocular history, was referred to us following an incidental finding of a “suspicious” lesion in the left eye, and consideration for neoplasia. When presenting to our clinic, she reported a 9-month history of blurry vision in the left eye. The patient reported no known family history of corneal abnormalities or dystrophies.

Best corrected visual acuity (BCVA) was 20/25 in the right eye and 20/60 in the left eye. Slit lamp examination (SLE) of the right eye showed a pterygium. In the left eye, a whorl-shaped corneal epithelial opalescence was noted temporally at 3 o’clock extending from the peripheral cornea to the central cornea, without apparent limbal involvement. High resolution optical coherence tomography (HR-OCT) showed normal thickness epithelial hyperreflectivity assuming a trapezoidal shape with trace pigmentation in the temporal cornea at 3 o’clock, not involving the limbus. The remainder of the exam was noncontributory.

A diagnostic and therapeutic corneal scraping was performed, which revealed morphologically benign epithelium with foamy cytoplasm consistent with LECD (Figure 1A). Intracytoplasmic granules were positive with PAS stain, suggesting presence of glycogen material (Figure 1B). Mucicarmine stain was negative and Alcian blue stain was weakly positive. At one-month follow-up, patient endorsed better vision, with improvement in visual acuity to 20/20 in the left eye after incisional biopsy.

Figure 1:

Histopathological analysis of corneal lesion A. Enlarged corneal epithelial cells with foam-filled cytoplasm (arrow) are present adjacent to the well-demarcated, unremarkable epithelium (asterisk). (Hematoxylin-eosin stain, original magnification x400).

B. Granules within the cytoplasm are positive with PAS stain (arrow). (Periodic acid-Schiff stain, original magnification x400).

Seven months later, SLE of the left eye revealed a recurrent corneal lesion consisting of a feather-like opacity at 2 o’clock extending from the limbus to approximately 2 mm midperiphery. HR-OCT again showed a trapezoidal hyperreflective epithelium at 2 o’clock without thickening or abrupt transitions, consistent with recurrent LECD. The patient was observed at this time as she had no vision complaints.

Four months later (11 months from biopsy), the patient returned complaining of blurred vision in the left eye. SLE and HR-OCT showed that the previously noted recurrent corneal lesion had grown, extending from the 3 o’clock limbus to central cornea. A repeat corneal scraping with 0.02% MMC application to the area for 20 seconds was performed. Histopathology was again consistent with LECD.

Five months later, the corneal lesion was noted to have recurred inferotemporally at 5 o’clock, extending from paracentral to central cornea, without limbal involvement (Figure 2A). Clustered intraepithelial microcysts were seen on high magnification with retroillumination (Figure 2B). HR-OCT again showed trapezoidal epithelial hyperreflectivity at 2 o’clock (Figure 3A). After discussion, the patient elected to try topical chemotherapy with 1% 5-FU eyedrops, used in cycles. Each cycle was one-month long and consisted of one week of treatment four times a day, followed by a 3-week treatment break.

Figure 2:

Slit lamp images before and after treatment with 5-FU A. Feathery, whorled paracentral corneal epithelial opacification (white arrow). Inset shows clustered, intraepithelial microcysts on retroillumination.

B. Clinical resolution of LECD lesion after 2 cycles (ie, 2 months) of 5-FU. Each cycle consisted of one week of treatment with four times daily application, followed by three weeks off.

Figure 3:

Anterior segment HR-OCT images before and after treatment with 5-FU. A. Non-thickened, trapezoidal shaped, hyperreflective epithelium (white arrow) of corneal lesion before 5-FU treatment initiation. Inset shows location of raster scan.

B. Normalized thin dark epithelium (white arrow) of corneal lesion after treatment with 2 cycles (ie, 2 months) of 5-FU. Each cycle consisted of one week of treatment with four times daily application, followed by three weeks off. Inset shows location of raster scan.

After 2 treatment cycles (ie, 2 months), the patient endorsed significant improvement in vision and BCVA in the left eye was 20/20. SLE showed resolution of the paracentral corneal epithelial opacity. (Figure 2C). HR-OCT showed normalized dark epithelium of normal thickness (Figure 3B). Based on the encouraging findings, the patient was advised to continue 5-FU treatment for 2 additional cycles.

Two months following the lesion resolution and after the patient had completed her fourth cycle of 5-FU, the SLE and HR-OCT findings reflected sustained resolution of the opacity, with normalized epithelial findings.

Discussion/Conclusions:

LECD is a rare condition that presents with characteristic corneal epithelial findings of a band-shaped, whorled opacity. On retroillumination, clear densely huddled intraepithelial microcysts are noted (1, 2, 9). Although pathogenesis remains unclear (6), the abnormal epithelial cells are thought to originate from pathologic limbal stem cells (7). Symptoms include reduced vision and monocular diplopia (2). Electron microscopy demonstrates widespread epithelial vacuolization (1) and in vivo confocal microscopy reveals highly hyperreflective epithelial cytoplasm with hyporeflective nuclei (7).

HR-OCT in LECD displays homogenous epithelial hyperreflectivity in a trapezoidal shape, with an angled transition to normal epithelium. It lacks epithelial thickening, a hallmark of ocular surface squamous neoplasia.

Diagnosis is confirmed upon histopathologic examination, which shows bubbly vacuolization of epithelial cytoplasm. These vacuoles are optically empty and contain a weakly osmophilic, partly homogenous and partly lamellar substance. They fuse to create structureless clear cytoplasm (2).

Treatment of LECD lesions consists mainly of observation unless there is an associated change in vision or comfort. In review of the literature, corneal epithelial debridement, also referred to as epitheliectomy or superficial keratectomy, has been the traditional management approach for LECD (2–4, 6–8, 10, 11). Unfortunately, recurrence was common, noted in 7 out of 9 eyes of 9 patients. In contrast, no recurrences were noted over a 2-year period in 2 eyes of 2 patients who underwent KLAT and keratectomy with cauterization of the limbal focus of origin (8, 11). Contact lenses have also been examined for their therapeutic value with mixed results. In one study, hard contact lens use did not impact the LECD (4). However, in another study, corneal opacities in 2 eyes from 2 patients improved with use of soft hydroxyethlmethacrylate and silicone hydrogel contact lens for 3 months and 1 month, respectively. However, the corneal lesions progressed 2 and 12 months, respectively, after discontinuation of contact lens wear (5).

Our case is the first to report the use of topical 5-FU eyedrops in the treatment of recurrent LECD. As an anti-metabolite, 5-FU has been used in the treatment of ocular surface tumors and works by inhibiting biosynthetic processes. The lesion clinically resolved on slit lamp and HR-OCT photographs after only two one-week cycles of the drug. Generally, 5-FU is well tolerated with known side effects including mild pain and redness, eyelid swelling, and conjunctival congestion. Our patient tolerated treatment well with application of petroleum jelly on the eyelids. Further studies are needed to reproduce our results and evaluate the long-term prognosis of this treatment. We believe 5-FU should be explored as a potential noninvasive treatment approach in LECD.

Abbreviations:

BCVA

Best corrected visual acuity

5-FU

5-fluorouracil

HR_OCT

High-resolution optical coherence tomography

KLAT

Keratolimbal autograft transplantation

LECD

Lisch epithelial corneal dystrophy

MMC

Mitomycin C

PRK

Photorefractive keratectomy

SLE

Slit lamp examination