Bustillo AL, Rosa MEA, Erazo RMB (2021) Effectiveness of Topical Chemotherapy in Pigmented and Squamous Lesions of the Ocular Surface: Literature Review. Int J Ophthalmol Clin Res 8:128.

Review Article | OPEN ACCESS DOI: 10.23937/2378-346X/1410128

Effectiveness of Topical Chemotherapy in Pigmented and Squamous Lesions of the Ocular Surface: Literature Review

Alejandra Lozano Bustillo1*, Mariel Eunice Amador-Rosa2 and Rocío Mitchell Banegas Erazo3

1Ophthalmology Specialist, National Autonomous University of Honduras (UNAH), Honduras

2Ophthalmology Specialist 'Alliance Diagnostic Center', Honduras

3Ophthalmology Resident, San Felipe General Hospital (UNAH), Honduras



The standard of care for the treatment of ocular surface lesions seems to have changed from surgery to topical chemotherapeutic agents as supplements to it or even as sole therapy, despite the scarcity of long-term studies in the published literature.


A search in the academic search engines of PubMed, Google academic and Cochrene, of articles published in English language from the years 1997 to 2020 on chemotherapeutic management of ocular surface diseases.


Topical or perilesional chemotherapy as a single therapeutic agent has proven to be an effective treatment avoiding the risks of repeated surgical interventions. Larger controlled studies with longer follow-up periods are recommended to confirm the long-term efficacy and safety of these treatments.


Chemotherapy, Topical, Mitomycin C, 5-fluorouracil, Interferon, Squamous neoplasia, Melanocytic lesions, Ocular surface


Topical chemotherapy is becoming the preferred approach in treating ocular surface lesions, especially for diffuse, annular, or multifocal lesions which are difficult to manage surgically. Ocular surface neoplasms can present as a pigmented or non-pigmented lesion of the conjunctiva or cornea, usually near the limbus. Ocular surface squamous neoplasms (OSSN) can be diagnosed clinically by their gelatinous, papillary, or leukoplastic appearance. They often spread as a cell growth on the cornea. Pigmented or melanocytic lesions of the conjunctiva and cornea include nevi, primary acquired melanosis (PAM) with or without atypia and conjunctival melanoma.

Inadequate initial therapy is a major risk factor for recurrence. Treatment strategies are affected by tumor staging according to the American Joint Cancer Committee (AJCC) T-stage at presentation [1,2], so any suspicious lesion requires a histopathological diagnosis currently assisted by imaging studies such as anterior segment optical coherence tomography (AS-OCT) [3-5].

Current chemotherapeutic treatments in ophthalmology include Interferon alfa 2b (IFNa2b), 5-fluorouracil (5FU) and Mitomycin C (MMC) mainly. Many studies in other entities that have taken interest in recent years, such as the use of nucleases in dry eye or previous uveitic diseases, have been very popular with good and bad results [6-11]. The purpose of this review is to familiarize general ophthalmologists with ocular surface chemotherapy treatments, as well as to summarize the essential published literature on the use of agents for corneal and conjunctival neoplasms.


We review different articles in the relevant medical literature that describe the use of topical chemotherapy agents as a treatment for neoplastic melanocytic and non-melanocytic entities and OSSN.

A search was carried out in the academic search engines of PubMed, Academic Google and Cochrene, for articles published in English language from the years 1997 to 2020 on the diagnosis and management of ocular surface diseases. Only original articles, case reports, case series and scientific comments were included. Review articles, letters to the editor, and articles in a language other than English were excluded.

Search included the following keywords individually and in combination: chemotherapy, topical, mitomycin C, 5-fluorouracil, interferon, conjunctival neoplasia, conjunctival tumor, conjunctival nevi, primary acquired melanosis, conjunctival melanoma, squamous cell carcinoma, squamous surface ocular neoplasm and conjunctival papilloma.

Interferon in ocular surface lesions

Interferons (IFNs) are a group of glycoproteins that form a network of complex interactions with other cytokines and connect innate and adaptive immunity. They exhibit a variety of biological functions, including antiviral, anti-proliferative, immunomodulatory, and cytotoxic activities. It is currently the most studied molecule since it has been shown to be effective and safe as a treatment for primary or recurrent ocular surface lesions with minimal adverse effects, providing a less invasive approach [12,13].

Currently, it is Interferon alpha 2b (IFNa2b) that is frequently used in ophthalmology, and it appears to be as successful as cryotherapy and surgical excision, which are the traditional forms of treatment for suspicious ocular surface lesions [14,15]. It is used topically, subconjunctival and/or perilesional injection or in conjunction with surgery.

Topical IFNa2b avoids the risks of further destruction of limbal stem cells and damage from surgical excision and could even be cost-effective for patients [16]. If invasive disease is diagnosed at any stage, topical therapy is contraindicated and surgical excision is required [18,19]. An important mechanism of action of IFNa2b is the reduction of the viral load of human papillomavirus (HPV) in infected cells of the conjunctiva in the squamous epithelium (Kostkowski and Herman 2004). Patients with primary or recurrent OSSN or large papillomas treated topically or with subconjunctival injections of IFNa2b until tumor resolution have had excellent results with low recurrence rates and a median resolution of up to 1.4 months [20,21]. IFNa2b, when properly combined with surgical excision in OSSN, provides proliferative control of up to 95% of cases, reaching rates of 90% in tumors in situ, in 100% of T1, 100% of T2, 94% of T3 and in 100% of T4 tumors according to the AJCC classification [22].

Whether via subconjunctival/perilesional or topical, IFNa2b in giant OSSN above 20 mm treated with subconjunctival injection achieved almost complete tumor control (immunotherapy) in most of the patients reported in Kim, et al. study and a partial tumor control with reduction in size (immunoreduction) which allows subsequent surgical excision. A combination of topical and injectable IFN 2b completely resolved tumors larger than 30 mm during a period of up to 6 months in follow-up [23,24].

Many forms of synergistic treatment combinations to enhance the effectiveness of IFNa2b in those patients with associated systemic conditions have been made [25,26]. An example in ocular surface is the use of topical interferon alpha 1 million IU/ml drops 4 times a day in combination with retinoic acid 0.01% once every two days, which seems to be effective in the treatment of CIN lesions with minimal side effects, with faster resolution and longer tumor-free period compared to other studies using interferon alfa-2b alone [27].

In a large study conducted at the Bascon Palmer Eye Institute from 2001 to 2010, the recurrence rate in patients treated with IFNa2b at 1 year was 10% and 21% at 5 years. In those patients with positive margins of lesions, the use of postoperative topical therapy reduced the recurrence rate to a level similar to patients with negative margins [28]. Other comparative studies report recurrence rates between surgery and topical therapy at 1 year of 5% in surgery groups versus 3% in the IFNa2b groups. This leads us to conclude that both topical IFNa2b and surgical excision appear to be effective for the primary OSSN [29,30].

The efficiency of interferon in pigmented lesions has been documented in some studies, but its use has not been as well studied as with MMC, but even in some patients with recurrences to other treatments it has shown to be effective [31]. In both precursor lesions as PAM with atypia or conjunctival melanoma, Garip, et al. demonstrated a mean decrease in tumor size of 66% after a first treatment cycle, 55% after a second and up to 74% after a third cycle showing promising results with minimal side effects [32].

Use of interferon in other disease

IFN-a, IFN-b and IFN-g type interferons exist in recombinant form and are used in a clinical setting for the treatment of various immunosuppressive diseases such as Kaposi's sarcoma in HIV / AIDS, hepatitis type B and C, condylomata acuminata, multiple sclerosis, gliomas and herpes virus or HPV infections (IFN-b) [33-35]. In addition, IFN-a2b has been tested in patients with Behcet uveitis relapsed to corticosterides and patients with multiple sclerosis (MS), as well as systemically recombinant human interferon alfa-2a (rhIFNa-2a) at doses of 6 million units subcutaneously per day has had positive results, improving vision and in some cases a complete remission of ocular vasculitis in ocular Behcet and multiple sclerosis [36-39]. Some findings suggest that IFN plays a key role in promoting conjunctival squamous metaplasia and apoptosis in dry eye and provide information on the immune response of keratoconjunctivitis sicca [40,41].

Mitomycin C

The uses of MMC on ocular surface have been widely studied. Topical MMC application is an effective treatment for squamous intraepithelial lesions and even conjunctival squamous cell carcinoma with excellent long-term results [42-45]. MMC is an antineoplastic antibiotic (alkylating agent) isolated from Streptomyces caespitosus that acts inhibiting DNA synthesis [46].

Combination therapies with mitomycin seem promising. Its use with topical cyclosporin A (0.05%) combined with mitomycin C (0.01%) as adjunctive treatment after surgical excision in cornea and conjunctival intraepithelial neoplasia and squamous cell carcinoma prevents tumor recurrence especially in extensive lesions, when surgical excision cannot guarantee a tumor-free margin or even in failed IFNa2b treatment [47-49].

In pigmented lesions, variable responses have been reported. Side effects of local chemotherapy generally resolve after treatment interruption, being a good alternative to surgical excision and cryotherapy in treatment of nevi with atypia, PAM with atypia and even melanoma [50-52]. Treatment with topical MMC not only reduces the size and degree of clinical pigmentation lesions, in conjunctiva and lesions involving corneal epithelium, but also eradicates residual atypical conjunctival melanocytes [53,54].

Its use as an adjuvant agent after completed surgical resection [55,56] has been corroborated in many studies. Birkholz, et al. complementary used of MMC with a significantly reduced prevalence of recurrence of 5.9% vs. 66.7% when it was not used. In invasive melanomas and adjuvant brachytherapy achieves high rates of local tumor control with little ocular morbidity, except in nodular tumors where they appear to be resistant to topical chemotherapy with MMC. Without caruncular involvement, disease-specific mortality is rare [57,58] and when surgical margins are positive in extensive lesions, the use of MMC is associated with a lower prevalence of tumor recurrence [59,60]. Long-term studies have evaluated the recurrence and effectiveness of MMC in neoplastic pigmented lesions, such as the study by Kurly and Finger, which followed a 12-year follow-up in patients with PAM with atypia and conjunctival melanoma. Both entities responded to topical chemotherapy with 0.04% MMC; Subepithelial nests were resistant to treatment, and they concluded that as primary or adjunctive therapy, topical MMC produced an overall recurrence rate of 50% [61].


5-Fluorouracil (5-FU) is an effective and well tolerated agent as primary treatment for OSSN, with up to an 82% favorable response rate [62]. Despite being a treatment sparsely used nowadays due to the rise of new therapies such as IFNa2b [67], topical 5-FU, as single or combined therapy, can be considered a safe and effective long-term treatment for OSSN as corneal toxicity is minimal [63].

Several comparative studies have been conducted of measure the efficacy of topical treatment with 5-FU and IFNa2b (1 MIU/ml) as primary treatment modalities for OSSN. Both modalities have yielded similar results with a high rate of lesion resolution and low recurrence. Usually, doses used topically are 4 times a day for 1 week followed by a 3-week drug break [64,65].

Subconjunctival/perilesional 5-FU injections are also an effective and safe treatment for OSSN. In a study carried out by Sun & Hua in China they used 10 to 25 injection doses, with an average duration of treatment between 6 to 20 weeks, resulting in the disappearance of both intratumoral and conjunctival feeding vessels in OSSN demonstrated by OCT-AS [66].

Side Effects of Topical Therapies


The adverse effects of topical use of interferon have been widely studied and described. Even the systemic use has repercussion in different presentations, from effects at the anterior segment to secondary retinopathies including retinal ischemia, choroidal neovascularization and ischemic optic neuropathy [68-72]. Retinal changes are usually reversible with discontinuation of therapy. Local adverse effects include conjunctival hyperemia, follicular hypertrophy, giant papillary conjunctivitis, irritation, epithelial corneal defects, and flu-like symptoms. All these effects usually resolve on average one month after discontinuation the medication [73].

Galor, et al, concluded that there were no significant differences between patients who used doses of 1 million IU/ml versus 3 million IU/ml for the treatment of conjunctival intraepithelial neoplasms (CIN) topically with results and similar side effects. The average duration of treatment is variable and in most of the studies it has been used until lesions are resolved, all side effects generally disappear when the treatment is suspended. For melanocytic lesions, topical doses of 1 drop 5 times a day for 6 weeks are suggested with few or no side effects [16,75].

Mitomycin C

In the largest study of topical MMC complications in ocular surface neoplasia by Khong & Muecke (2006), allergic reaction and point stenosis were the most common complications with no medium-term complications [76].

Histologically, nuclear enlargement, cellular hyperchromasia in the superficial layers of the epithelium were the main secondary effects observed. Cytoplasmic eosinophilia, unicellular necrosis, and occasionally chronic subepithelial inflammation were also observed [77,78]. Ditta, et al. evaluated the long-term complications (6 months) of MMC therapy in patients with conjunctival melanoma. The most common complications included injection, tearing, irritation, pain, and limbal stem cell deficiency [46]. Other complications reported have been keratopathy, cataract [79] or even metastasis [80], according to the same authors could be associated with treatment delay.


Some of the adverse effects reported are conjunctival inflammation, epithelial defects, skin and epiphora erythema. The use of subconjunctival injections of 5-FU after glaucoma surgery can lead to squamous metaplastic changes and nuclear atypia and apoptotic cell death in the conjunctival epithelium in a short period. Adverse effects are generally transient and mild [62,81].


Topical or perilesional chemotherapy on the ocular surface as a single therapeutic agent has proven to be an effective treatment avoiding the risks of repeated surgical interventions and their effects such as scar conjunctival changes. The three drugs revised in this study seems to be effective and safe, but larger controlled studies with longer follow-up periods are recommended to confirm long-term efficacy and safety of these treatments. Its use for residual or recurrent lesions should be carefully considered and closely monitored to avoid metastasis, especially in melanocytic lesions. The main results and recommended doses of the larger studies included in this review are summarize in Table 1.

Table 1: Summary of effectiveness of the different topical therapies per study. View Table 1


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Bustillo AL, Rosa MEA, Erazo RMB (2021) Effectiveness of Topical Chemotherapy in Pigmented and Squamous Lesions of the Ocular Surface: Literature Review. Int J Ophthalmol Clin Res 8:128.