Corneal Epithelial Disorder Associated With The Antineoplatic Drug S-1

Abstract

Purpose: : S-1 is an oral antineoplastic drug that contains tegafur and has been shown to induce corneal disorders. To characterize the cellular changes in the corneal epithelium associated with S-1-induced keratopathy, we examined affected corneal epithelial cells by in vivo confocal microscopy and histopathologic analysis.

Methods: : Three men and three women treated with S-1 participated in the study. The 12 eyes of the six subjects were evaluated with a confocal laser-scanning microscope, consisting of a Heidelberg Retina Tomograph II® attached to a Rostock Cornea Module ®(HRTII-RCM). Corneal epithelial debridement and histopathologic analysis of the specimens were performed for the five eyes of three subjects that were affected in the pupillary zone of the cornea.

Results: : Slitlamp examination revealed a local limbal abnormality characterized by abnormal epithelial invasion toward the central cornea in all 12 eyes. HRTII-RCM examination revealed an altered structure of the corneal epithelium with abnormal epithelial cells. Hematoxylin-eosin staining showed that each abnormal epithelial sheet lacked the stratified structure of the normal corneal epithelium. Immunofluorescence analysis of cytokeratins 12 and 4 revealed the presence of four types of cells-those positive for one, both, or neither of these proteins-in each lesion.

Conclusions: : Four different phenotypes of cells were found in the corneal epithelium affected by S-1 administration. Cells lacking both cytokeratins 12 and 4 are likely undifferentiated cells, whereas those expressing cytokeratin 4 alone are likely conjunctival epithelial cells that entered the cornea through the limbus.

Keywords: cornea: clinical science • drug toxicity/drug effects • imaging/image analysis: clinical