Kim and Abramson approach, and whether a single topical agent can achieve long-term cures of conjunctival neoplasms. The goal of this review is to summarize the essential published literature on the use of topical agents for both melanocytic and squamous conjunctival neoplasms. Further- more, our aim is to offer speciﬁc therapeutic guidelines for clinicians using the available data that has been published by various investigators, augmented by our own clinical experience at the Memorial Sloan-Kettering Cancer Center in New York, NY. To accomplish these goals, we reviewed the relevant medical literature by searching MEDLINE (1970–2006) for articles describing the use of topical che- motherapy agents for conjunctival neoplastic processes. In performing this search, the following keywords were used both singly and in combination: chemotherapy, topical, mitomycin, 5-ﬂuorouracil, interferon, conjunctival neoplasm, conjunctival tumor, primary acquired melanosis (PAM), conjunctival melanoma, squamous cell carcinoma, ocular surface squamous neoplasia, conjunctival papilloma, and sebaceous cell carcinoma. Additional articles were identiﬁed by reviewing the bibliographies of publications found in the MEDLINE search. Topical agents for conjunctival neoplasms Mitomycin-C Mitomycin C (MMC) is an alkylating agent that binds to DNA during all phases of the cell cycle, leading to irrevers- ible cross-linking and inhibition of nucleotide synthesis. Isolated from Strepmyces caespitosus, enzymatic reduction of its quinine ring and methoxy group permits MMC to cross link DNA between adenine and guanine at three different sites (McKelvie and Daniell 2001). Under aerobic conditions, intermediates of MMC also react with molecular oxygen to generate free radicals, causing cytotoxicity via lipid peroxida- tion. Hence, MMC appears to be toxic to both proliferating and nonproliferating cells. In clinical oncology, MMC has been used extensively to treat superﬁcial transitional cell carcinoma of the bladder epithelium (Murphy, Soloway et al 1981). In its ophthalmic use, MMC has an established track record for safety and efﬁcacy in pterygium and glau- coma surgery (Palmer 1991; Donnenfeld et al 2003). When applied to conjunctival surfaces as a surgical adjunct, MMC has been shown to inhibit ﬁbroblast cell migration, decrease extracellular matrix production, and to induce apoptosis in Tenon’s capsule ﬁbroblasts. It is well known that chronic tissue effects from topical MMC administration can persist 504 for many years after the cessation of treatment, similar to the effects of ionizing radiation (Demirci et al 2000; McKelvie and Daniell 2001). Topical MMC has been reported to cause various histo- pathologic changes to the conjunctival epithelium. Folberg and associates (1999) reported an analysis of 18 conjunctival biopsy specimens taken from ten patients treated with MMC for PAM with atypia (Salomao et al 1999). The patients in this study were treated with topical 0.02% MMC for 14–21 consecutive days, with biopsies being performed 3–6 weeks following the last day of therapy. In these conjunctival specimens, epithelial cells consistently demonstrated dys- plastic changes, such as nuclear enlargement and chromatin hyperchromasia, but only in the superﬁcial layers of the conjunctival epithelium. The authors also emphasized that an enlargement of the nucleus and the cell appeared to occur proportionately (ie, cytomegaly), resulting in a preserved nucleus-cytoplasmic ratio. Other histopathologic features included cytoplasmic condensation and eosinophilia, focal epithelial sloughing, and single cell necrosis, all suggestive of apoptosis. The authors commented that the distinction between chemotherapy effect and recurrent neoplasm was less problematic in patients with PAM since the atypical cells following topical MMC were superﬁcially located, while the melanocytes of PAM were in the basal layers of the epithelium. Conversely, degenerative changes in the normal conjunctival epithelium induced by topical MMC may be dif- ﬁcult to distinguish from recurrent or persistent conjunctival squamous neoplasia (Nadjari et al 1999). In a report by Nad- jari and colleagues (1999), cytology samples were taken 2 weeks following the completion of topical MMC therapy for conjunctival intraepithelial neoplasia (CIN). Not only were there cellular changes such as chromatin clumping, nuclear pyknosis, and cytoplasmic vacuolization, DNA cytometric analysis revealed aneuploidy in nonneoplastic squamous cells (Nadjari et al 1999). Despite the cellular changes induced by topical MMC treatment, the nucleus to cytoplasmic ratio remained constant in nonneoplastic cells, whereas this ratio increased markedly with recurrent CIN (Nadjari et al 1999; McKelvie and Daniell 2001). McKelvie and Daniell (2001) reported the long-term results of impression cytology follow- ing topical MMC therapy for ocular surface squamous neo- plasia. Samples from four patients with primary or recurrent ocular surface squamous neoplasia (OSSN) were analyzed between 4 and 17 weeks after topical MMC therapy. The predominant form of cell death in dysplastic cells appeared to be apoptosis, although areas of necrosis were also seen. Apoptotic bodies were identiﬁed up to 12 weeks after starting Clinical Ophthalmology 2008:2(3)