Kerala Journal of Ophthalmology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 32  |  Issue : 2  |  Page : 143--147

Role of mitomycin C in the management of ocular surface squamous neoplasia


C Menaka1, Venkatesh Perumal1, R Shankar2,  
1 Department of Ophthalmology, Government Mohan Kumaramangalam Medical College Hospital, Salem, Tamil Nadu, India
2 Department of Community Medicine, VMKVMCH, Salem, Tamil Nadu, India

Correspondence Address:
Dr. C Menaka
Department of Ophthalmology, Government Mohan Kumaramangalam Medical College Hospital, Salem, Tamil Nadu
India

Abstract

Background: Ocular surface squamous neoplasia (OSSN) in a broader terminology recently introduced in the field of ophthalmology that includes conjunctival malignancies which ranges from mild epithelial dysplasia to invasive squamous cell carcinoma. The routinely used topical chemotherapy for OSSN is mitomycin C (MMC), 5-fluorouracil, interferon-alpha, and cidofovir, and among these, MMC is usually preferred by most of the ophthalmologists because of its cost-effectiveness and lesser side effects. Aim: The aim of study was to evaluate the role of MMC as an adjuvant therapy intraoperatively and postoperatively in the management of OSSN. Methodology: Patients in the age group of 40 years and above with a diagnosis of OSSN were included as our study subjects. The diagnosis of OSSN was made based on the clinical presentation and the cytological picture. A total of 22 patients with OSSN were taken as our study subjects. The tumor was surgically removed in toto along with 3–4 mm of uninvolved conjunctiva. Further, 0.4 mg/ml of MMC was applied over the excised site. Postoperatively, two cycles of 0.04% MMC eye drops were given for 2 weeks with a dosage of 4 times/day. It is given in two cycles, each cycle lasting for a week with an interval of 1 week in between. Results: Postoperatively, only one patient (4.5%) had recurrence which had developed after 6 months. Patients aged more than 60 years and who had the initial size of the lesion as > 8 mm were more prone to recurrence. Other postoperative complications that had occurred were one patient had allergic conjunctivitis and the other patient had punctate erosion. Conclusion: The use of MMC eye drop in the concentration of 0.04% has shown good clinical results without any serious side effects and with a very less recurrence rate during the follow-up period of 1 year when used as alternate 7-day courses.



How to cite this article:
Menaka C, Perumal V, Shankar R. Role of mitomycin C in the management of ocular surface squamous neoplasia.Kerala J Ophthalmol 2020;32:143-147


How to cite this URL:
Menaka C, Perumal V, Shankar R. Role of mitomycin C in the management of ocular surface squamous neoplasia. Kerala J Ophthalmol [serial online] 2020 [cited 2020 Nov 26 ];32:143-147
Available from: http://www.kjophthal.com/text.asp?2020/32/2/143/293288


Full Text



 Introduction



Ocular surface squamous neoplasia (OSSN) in a broader terminology recently introduced in the field of ophthalmology that includes conjunctival malignancies which ranges from mild epithelial dysplasia to invasive squamous cell carcinoma (SCC).[1],[2] Previous studies had confirmed that the most common risk factor for OSSN is the exposure to ultraviolet light which causes a mutation in the tumor suppressor gene such as p53, and other risk factors were HPV infections with subtypes 16 and 18, and HIV infection along with advanced age and smoking had shown association with OSSN.[3],[4]

The prevalence of OSSN based on certain epidemiological studies ranges between 0.13 and 1.9/100,000 population, and all these studies were from sub-Saharan African countries, whereas no such studies were available in India to project the exact prevalence of this neoplasia.[5],[6],[7] The unique clinical picture of OSSN is epithelial thickening extending onto the peripheral cornea, thereby leaving a prominent corkscrew vascular pattern with a histological appearance of hyperplasia, nuclear hyperchromasia with pleomorphism, and mitotic figures. Histologically, the lesion is graded as conjunctival intraepithelial neoplasia), when it is contained to the basement membrane, and as it invades the epithelium, it is graded between mild and severe neoplasia.[8],[9] The gold standard treatment for OSSN is surgical excision, but recurrence after excision is a major concern.[10] Recurrence rates are reported to range from 5%–33% and few studies mentioned it more than 50%, where margins were found to be positive.[11] Due to very high recurrence rate, conservative medical management is gaining popularity of late as it had shown some promising results. It is done by means of topical chemotherapy, and the routinely used agents are mitomycin C (MMC), 5-fluorouracil, interferon-alpha, and cidofovir. Among all these, MMC is usually preferred in most of the places because of its cost-effectiveness and lesser side effects.[12] It mainly acts by inhibiting the production of DNA, thereby inducing cell apoptosis and necrosis, and further, it also suppresses the cellular RNA and protein synthesis.[13],[14] The application of topical chemotherapy after surgical excision had shown a significant reduction in the recurrence rate of OSSN. As such, in India, very few studies had been done to assess the role of MMC in OSSN, and hence, the present study was conducted to evaluate the effectiveness of MMC in ocular surface neoplasia after surgical excision.

Aim

The aim of the study was to evaluate the role of MMC used as an adjuvant therapy during intraoperatively and postoperatively in the management of OSSN.

 Methodology



A prospective study was conducted for a period of 1 year at a tertiary care hospital in Chennai. The study was started after getting clearance from the institutional ethical committee and the informed consent was obtained from all the study subjects involved in the study. Patients in the age group of 40 years and above with a diagnosis of OSSN were included as our study subjects. The diagnosis of OSSN was made based on the clinical presentation and the cytological picture which includes limbal involvement, with lesions either in the form of gelatinous, leukoplakic, or papillary form and the presence of feeder vessels and cork screw vascular pattern. Patients who had lesions with scleral involvement, intraocular and orbital involvement, and with any other ocular diseases such as limbal stem cell deficiency, ocular surface disorders, and intraocular tumors; patients with any other systemic illness such as HIV or any other immunocompromised conditions; and pregnant women were excluded from the study. Satisfying the above-mentioned inclusion and exclusion criteria, a total of 22 patients with OSSN were considered as our study sample.

A semi-structured questionnaire was prepared to collect the demographic details and clinical history. A comprehensive ophthalmological examination was done on all patients that include visual acuity, slit-lamp examination, fundus examination, gonioscopy, ultrasound biomicrosopy, and B-scan to rule out other comorbidities.

After the routine basic investigations, all the patients were taken up for the surgery, following strict aseptic precautions, and the surgery was done under the peribulbar block. The tumor was surgically removed in toto along with 3–4 mm of uninvolved conjunctiva. Further, 0.4 mg/ml of MMC was applied over the excised site for 3–4 min and a saline wash was given. The surgical site is then closed by the primary suturing of the conjunctiva or by applying graft.

MMC was started 2 weeks after the procedure and it is given in two cycles of 0.04% eye drops for 2 weeks with a dosage of 4 times/day. The duration of one cycle is 1 week with an interval 1 week between two cycles. Along with MMC, patients were also given topical steroids and lubricants throughout the entire postoperative period. Patients were followed up for a period of 1 year at an interval of 3 months to assess for complications and recurrence.

All data were entered and analyzed using SPSS Version 22.0. Armonk, NY: IBM Corp. Mean and standard deviation were calculated for parametric variables and percentages were calculated for nonparametric variables, and Chi-square test was used to derive the statistical inference, considering P < 0.05 as statistically significant.

 Results



Age- and gender-wise distribution of the study subjects shows that majority of them were in the age group between 50 and 60 years and males were comparatively more than females with a male-to-female ratio of 1.4:1, and the mean age was 56.1 years [Table 1]. The most common type of OSSN presentation among our patients was either gelatinous or papillomatous lesion and the least common was leukaplakic, and right eye involvement is found to be more common than the left eye [Table 2]. In our study, more than 85% of the patients lesion were primary in nature and recurrence type of lesion was observed in less than 15% with an average size of lesion ranging between 5 mm and 7 mm and it was more than 10 mm for only two patients [Table 3]. The most common indication for surgery among the patients was ocular irritation followed by visual impairment and one patient had cosmetic disfigurement as a predominant complaint about surgery. Corneal involvement was seen only in three patients [Table 4]. Postoperatively, after 2 weeks, all patients were given MMC eye drops as described in the methodology. Among the postoperative complications, one patient had developed allergic conjunctivitis and the other patient had punctate erosion and all the patients were followed up for a period of 1 year, particularly to assess for recurrence, and only one patient was reported with recurrence which was developed after 6 months postoperatively [Table 5]. Further analysis was done to assess for the factors influencing the recurrence, and we found that patients aged more than 60 years and the initial lesion size of more than 8 mm were more prone to develop recurrence compared to patients aged <60 and lesion size of <8 mm and it was found to be statistically significant (P < 0.05) [Table 6]. Pre-operative and post-operative images of few of our patients are shown below [Figure 1]and [Figure 2] {Table 1}{Table 2}{Table 3}{Table 4}{Table 5}{Table 6}{Figure 1}{Figure 2}

 Discussion



Initially, treatment for OSSN was considered to be only excision, but later in 1994, Maskin had introduced the usage of interferon both intraoperatively and postoperatively, and based on his results, few other authors had also followed the similar method and found very good postoperative results.[15] Few other operative methods have also tried in the management of OSSN, as the one performed by Shields et al., he did excision biopsy by resecting 4 mm of safety margin from unaffected conjunctiva, but it led to the occurrence of anterior staphyloma which is considered as a severe ocular surface problem.[16] Few other studies have tried cryotherapy as a procedure for OSSN, but all these studies reported with a high recurrence rate. Photodynamic therapy which is considered as one of the newer modalities of treatment is currently under investigation.

The common chemotherapy agent used for OSSN intra- and postoperatively was 5-flurouracil, MMC, or interferon. Considering the cost factor and minimal adverse events, we selected MMC as an adjuvant therapy along with surgical excision for assessing its efficacy in the treatment of OSSN.[17],[18]

In the present study, the mean age of the patients with OSSN was 56 years and males were more commonly affected than the females, and a similar type of results was also observed by the studies done earlier on OSSN.[19],[20] Few of the studies done earlier on OSSN had mentioned that chronic sun exposure and smoking were the risk factor for OSSN, but in our study, we did not find any such association.[21],[22]

In the current study because of ethical issues and the number of cases being limited, we have not done a randomized controlled trial for assessing the efficacy of MMC, but we have taken only a single group in which the drug MMC was used both intra and postoperatively and assessed its efficacy in terms of incidence of recurrence and adverse events. As mentioned in previous studies, the trend of recurrence of OSSN after surgery is on an average 1 year, and hence, we followed our patients for a period of 1 year. The usage of topical MMC is a well-known drug that has been used for the treatment of OSSN, and different types of results were mentioned in different studies based on different drug concentrations and varied follow-up periods. In our study, we used the drug concentration as 0.04% for 7 days in alternate weeks for two cycles, as mentioned in a study done by Wilson et al.[18] The results of our study showed a good clinical response with a very minimal recurrence rate at the end of 1 year of follow-up. Studies which had used MMC systemically had mentioned bone marrow suppression, leukemia, thrombocytopenia, alopecia, gastrointestinal toxicity, fever, and dermatitis as the various adverse events that had occurred in the patients, but in our study, we used MMC at a very low concentration and it was used topically, and still, to prevent even minimal absorption, punctual occlusion was done by applying pressure through the fingers, and so none of our patients were reported with any of those above-mentioned adverse events.[23] The only adverse event reported in the present study was one patient developed punctuate corneal erosion and another had developed allergic conjunctivitis, whereas none of the patient had reported with severe adverse events such as scleral thickening, cataract, or iritis. The recurrence rate reported in our study was 4.5% at the end of 1 year, whereas the study done by Shields et al. on ten patients with extensive conjunctival and corneal SCC found 0% recurrence rate at the end of 60 months and few other studies had mentioned the recurrence rate was <5% among the patients who were given MMC and all these studies had a follow-up period ranging between 1 and 5 years.[14],[24],[25],[26],[27]

 Conclusion



OSSN is relatively common and a serious neoplastic disorder reported in the ophthalmology department. The standard method of treatment is wide excision, which commonly results in a high recurrence rate. The use of MMC eye drop in the concentration of 0.04% has shown good clinical results without any serious side effects and with a very less recurrence rate at the end of 1-year follow-up when used as alternate 7-day courses. More number of large sample multicentric studies with a longer follow-up period is warranted to substantiate our findings.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39:429-50.
2Shields CL, Chien JL, Surakiatchanukul T, Sioufi K, Lally SE, Shields JA. Conjunctival tumors: Review of clinical features, risks, biomarkers, and outcomes: The 2017 J. Donald M. Gass Lecture. Asia Pac J Ophthalmol (Phila) 2017;6:109-20.
3Shields CL, Demirci H, Karatza E, Shields JA. Clinical survey of 1643 melanocytic and nonmelanocytic conjunctival tumors. Ophthalmology 2004;111:1747-54.
4Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch Ophthalmol 1992;110:525-7.
5Sun EC, Fears TR, Goedert JJ. Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiol Biomarkers Prev 1997;6:73-7.
6Furahini G, Lewallen S. Epidemiology and management of ocular surface squamous neoplasia in Tanzania. Ophthalmic Epidemiol 2010;17:171-6.
7Emmanuel B, Ruder E, Lin SW, Abnet C, Hollenbeck A, Mbulaiteye S. Incidence of squamous-cell carcinoma of the conjunctiva and other eye cancers in the NIH-AARP diet and health study. Ecancermedicalscience 2012;6:254.
8Gichuhi S, Irlam JH. Interventions for squamous cell carcinoma of the conjunctiva in HIVinfected individuals. Cochrane Database Syst Rev 2013:CD005643. doi: 10.1002/14651858.
9Kim RY, Seiff SR, Howes EL Jr, O'Donnell JJ. Necrotizing scleritis secondary to conjunctival squamous cell carcinoma in acquired immunodeficiency syndrome. Am J Ophthalmol 1990;109:231-3.
10Ip MH, Coroneo MT. Treatment of previously refractory ocular surface squamous neoplasia with topical cidofovir. JAMA Ophthalmol 2017;135:500-2.
11Kabra RC, Khaitan IA. Comparative analysis of clinical factors associated with ocular surface squamous neoplasia in HIV infected and non HIV patients. J Clin Diagn Res 2015;9:NC01-3.
12Ip MH, Robert George CR, Naing Z, Perlman EM, Rawlinson W, Coroneo MT. Topical cidofovir for treatment-refractory ocular surface squamous neoplasia. Ophthalmology 2018;125:617-9.
13Chen C, Louis D, Dodd T, Muecke J. Mitomycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia. Br J Ophthalmol 2004;88:17-8.
14Rahimi F, Alipour F, Ghazizadeh Hashemi H, Hashemian MN, Mehrdad R. Topical mitomycin-C for treatment of partially-excised ocular surface squamous neoplasia. Arch Iran Med 2009;12:55-9.
15Maskin SL. Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol 1994;112:1145-6.
16Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol 1997;115:808-15.
17Frucht-Pery J, Sugar J, Baum J, Sutphin JE, Pe'er J, Savir H, et al. Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: A multicenter experience. Ophthalmology 1997;104:2085-93.
18Wilson MW, Hungerford JL, George SM, Madreperla SA. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol 1997;124:303-11.
19Tunc M, Char DH, Crawford B, Miller T. Intraepithelial and invasive squamous cell carcinoma of the conjunctiva: Analysis of 60 cases. Br J Ophthalmol 1999;83:98-103.
20Tabin G, Levin S, Snibson G, Loughnan M, Taylor H. Late recurrences and the necessity for long-term follow-up in corneal and conjunctival intraepithelial neoplasia. Ophthalmology 1997;104:485-92.
21McKelvie PA, Daniell M, McNab A, Loughnan M, Santamaria JD. Squamous cell carcinoma of the conjunctiva: A series of 26 cases. Br J Ophthalmol 2002;86:168-73.
22Napora C, Cohen EJ, Genvert GI, Presson AC, Arentsen JJ, Eagle RC, et al. Factors associated with conjunctival intraepithelial neoplasia: A case control study. Ophthalmic Surg 1990;21:27-30.
23Sweetman SC. Martindale: The Complete Drug Reference. 34th ed. London: Pharmaceutical Press; 2005. p. 573-5.
24Shields CL, Naseripour M, Shields JA. Topical mitomycin C for extensive, recurrent conjunctival-corneal squamous cell carcinoma. Am J Ophthalmol 2002;133:601-6.
25Vann RR, Karp CL. Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia. Ophthalmology 1999;106:91-7.
26Siganos CS, Kozobolis VP, Christodoulakis EV. The intraoperative use of mitomycin-C in excision of ocular surface neoplasia with or without limbal autograft transplantation. Cornea 2002;21:12-6.
27Barbazetto IA, Lee TC, Abramson DH. Treatment of conjunctival squamous cell carcinoma with photodynamic therapy. Am J Ophthalmol 2004;138:183-9.