Ocular Surface Squamous Neoplasia[OSSN] - A Brief Review

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1 Ocular Surface Squamous Neoplasia[OSSN] - A Brief Review Major Review Anil Radhakrishnan MS Introduction Though conjunctivaltumours are uncommon, their early diagnosis assumes great significance due to its malignant potential in a small minority 1,4.The term Ocular Surface SquamousNeoplasia [OSSN]presently refers to the entire spectrum of dysplastic, pre-invasive and malignantsquamouslesions of the conjunctiva and cornea, indeed a wide spectrum 1,2,3,4. Classification of OSSN3 Benign OSSN - Papilloma Pseudoepitheliomatous hyperplasia Benign hereditary intraepithelial dyskeratosis Preivasive OSSN lesions confined to epithelium Conjunctival / Corneal intraepithelial neoplasia [Grade 1 3 depending on extent] Invasive OSSN Squamous carcinoma Mucoepidermoid carcinoma Demographics Though OSSN is not a common disease, it is the third most common ocular tumour after melanoma and lymphoma 3,5,6,7. Also, a lot of them may go unnoticed as they are asymptomatic and usually slow-growing. The prevalence of OSSN is more in tropical region and varies from 12 cases /million/ year in Uganda to 0.2 cases / million/ year in United Kingdom, possibly related to sunlight exposure. However Caucasian race is more predisposed to UV related skin damage,and also OSSN compared to pigmented race, especially those living at latitudes less than 30 degrees to the equator 3,8,9.Unsuspected OSSN was found incidentally in 9.8% of 538 consecutive samples of pterygia, which underwent a histopathological examination in Queensland, Australia, a geographical zone with a high incidence of UV related diseases like skin malignancy and pterygium, which suggests that true incidence of OSSN may be much higher 12. The average age of onset of OSSN is 56 years, but is seen to be younger in populations living close to equator. Also the average age of patients with carcinoma-in-situ is seen to be 5 to 9 years younger than those with invasive carcinoma, suggesting progression of neoplasia 2,6,7,8,9. Etiological factors The two main risk factors are UV- B light and Human Papilloma Virus 2,3,4,10. The other risk factors are exposure to petroleum products, heavy cigarette smoking, chemicals such as trifluridine and arsenicals, ocular surface injury, vitamin A deficiency, and European ancestry 2,3,6. Infection with HIV is emerging as a major risk factor 9,10,11. UV-B light causes DNA damage and formation of pyrimidimedimers. Failure or delay in repair can lead to somatic mutations and oncogenesis. UV radiation is known to be mutagenic for p53 [a tumour suppressor protein in the host, which regulates the cell cycle and functions as a tumour suppressor]. In patients with xerodermapigmentosa the incidence of OSSN is much higher and occurs at an early age, even in childhood. Human Papilloma Virus [ HPV] has a well proven causal relationship with cervical neoplasia. DNA of HPV -16 & 18 are found in upto 80% of cervical intraepithelial neoplasia [CIN grade 2 &3] and 90% of invasive squamous cell carcinoma. HPV-6 & 11 are associated with benign genital warts and CINgrade1. Similarly, HPV DNA has been isolated consistently from dysplastic lesions of conjunctiva and cornea. However it is likely that HPV requires another risk factor like UV-B light for oncogenesis. Pathology 1,2,3,4 Papilloma seen as papillary fibrovascular fronds covered by acanthotic epithelium. Adult papillomas show dysplastic features like nuclear enlargement and hyperchromatism, increased nuclear to cytoplasmic ratio, loss of polarity etc. Preinvasivelesions are classified as mild, moderate or severe dysplasia, depending on the degree of involvement. CIN grade 1[mild dysplasia] - dysplasia confined to basal [lower]one-third of epithelium CIN grade 2 [moderate dysplasia] extends into middle third of epithelium CIN grade 3 [severe dysplasia] extending into upper third of epithelium. The basement membrane however is intact. Full thickness dysplasia of the epithelium as in cervical neoplasiais also referred to as carcinoma in situ [Fig 1]. Evidence of chronic inflammation may be seen in substantiapropria. Invasive OSSN / Squamous cell carcinoma shows nests of neoplastic cells that have penetrated the epithelial basement membrane and spread into the underlying stroma[fig 2]. Tumour cells may be well-differentiated or ill-differentiated. Two types of cells may be seen interspersed along with squamous cells-[1] spindle cells or [2] mucoepidermoid cells. The latter is notorious for intraorbital extension as well as early recurrence if left untreated. Clinical features OSSN usually presents as an elevated conjunctival lesion, Address for correspondence: Amrita Institute of Medical Sciences, Kochi 347

2 Kerala Journal of Ophthalmology Vol. XXIII, No.4, Dec seen at or near the limbus, grayish-white in colour with a characteristic tuft of blood vessels in the interpalpebral fissure area 1,2,3,4. It can become fleshy with feeder vessels. Rose Bengal or Lissamine green staining can help in delineating the extent of lesion [Fig 3 & 4]. The corneal side of the lesion may be seen as an opalesence of the epithelium, slightly raised in comparison to adjacent normal epithelium the edges of which are usually sharply defined. It is best appreciated by retroillumination. OSSN is a slow growing tumour of low-grade malignancy, which rarely metastasise. Three morphological types are described [1] Gelatinous [2] Leukoplakicand [3] Papilliformtype.In clinical practice, gelatinous type is the commonest. The gelatinous lesioncan again be circumscribed, which are most common or a nodular variety,which has a propensity for rapid growth and diffuse variety, the least common, which can masquerade as chronic conjunctivitis with no obvious tumefaction. Figure 2 Histopathology section of invasive squamous cell carcinoma showing nests of neoplastic cells in the conjunctivalstroma The lesions are usually asymptomatic and are detected by chance. A few patients may present with redness, irritation or foreign body sensation. It is nearly impossible to categorise OSSN as benign or malignant based on clinical appearance alone. Larger lesions that are fixated to the underlying tissue are usually malignant. Regional lymphadenopathy (preauricular nodes, subman dibular nodes and deep cervical) should be looked for. Diagnosis A high index of clinical suspicion is necessary. An incision / excision biopsy is considered the gold standard for diagnosis and planning further treatment. Impression cytology with Biopore membrane has reasonably good accuracy but can miss about 20% of cases. However it has a definite role in follow-up of lesions, after primary treatment, whether surgical or topical chemotherapy 3,19,20. Figure 3 OSSN seen as a limbal growth Figure 1 Carcinoma-in situ - Histopathology section demonstrating dysplastic cells involving the whole thickness of epithelium. The basement membrane is in tact. Figure 4 Lissamine green staining delineating the extent of OSSN. Note the conjunctival stippling nasally 348

3 Anil Radhakrishnan - OSSN is short duration freeze with slow thaw, repeated two or three times [freeze thaw-refreeze ]. The duration of cryotherapy depends on the location the iceball extending 2 mm for conjunctiva, 1mm for episclera and 0.5 mm for the cornea. Limbal region should not be spared, but cryo application should be limited to 3 seconds to minimize the risk of limbal stem cell damage.if cryotherapy is combined with surgical excision, the mean recurrence can be brought down to about 12% 2,3,15, 16. Figure 5 OSSN with healthy conjunctival margins sutured to absorbent paper to maintain orientation before sending for histopathological examination Treatment Because a tissue diagnosis is required before any adjunctive treatment, most surgeons resort to an excision biopsy for all cases except extensive lesions. The different treatment modalities are [1] surgical excision [2] cryotherapy [3] radiotherapy [4] topical chemotherapy and [5] topical immunotherapy. Surgical treatment A wide surgical excision is done to maximize the chances of complete removal. Rose Bengal / Lissamine green staining is helpful to delineate the margins of the lesion. A no touch technique avoiding direct manipulation of the lesion, by holding the tissue at the healthy conjunctival borders is employed to prevent tumour seeding into new area 1,2,3,4,13,14. Shields et al recommend usage of absolute alcohol on the corneal side of the lesion to facilitate epithelial removal as one sheet alchoholepithelectomy 13. The excised conjunctival specimen is placed on an absorbent paper and air-dried to prevent loss of orientation. Rather the best method would be to spread out the specimen and apply 3 or 4 sutures, marking both the conjunctival side and corneal side. [Fig 5].The recurrence rate following surgical excision ranges from 15 52% 2,13. Erie et al 21 found that if the excised tissue margins were free of tumour, the recurrence rate was only 5% in contrast to 52% recurrence, if lesions were incompletely excised [positive surgical margins on histopathological examination]. Though a slow growing tumour with remote risk of systemic spread, if undiagnosed and untreated, it is capable of orbital and intraocular spread requiring exenteration or enucleation. Cryotherapy is done in combination with surgical excision. It acts by freezing the tissue and also obliterating the microcirculation, resulting in ischemic infarction of abnormal tissue. Cryotherapy is applied to the base and edges of the conjunctival margin to reach both superficial tumour islands and deeply infiltrated tumour cells. The cryo probe [with 2.5 or 5 mm tip] is inserted underneath the edges of resected conjunctiva to form an iceball. The recommended technique Conjunctivaldeficit is closed primarily if it is small [ < 3 clock hours]. For larger defects amniotic membrane transplantaion or conjunctivalautograft may be done. Radiotherapy is a time-testedold treatment modality whose role is now limited to extensive or diffuse lesions in conjunction with other methods. Though extremely effective, it causes significant ocular surface damage and dry eye, which is often permanent 2,3,17,18. Topical chemotherapy - Over the last decade topical agents have been used by various investigators to treat various malignant and premalignant conjunctival lesions viz primary acquired melanosis with atypia, conjunctival melanoma, OSSN and pagetoid spread of sebaceous cell carcinoma 1,3,4,7, Topical administration of chemotherapeutic agents can deliver high drug concentrations to the ocular surface with negligible systemic side effects. It is capable of treating small tumour islands on the surface, which may escape surgical excision. Also topical chemotherapy can be titrated according to clinical response. Two chemotherapeutic agents are commonly used Mitomycin-C [MMC] and 5-flurouracil. Mitomycin-C [MMC] is an alkylating agent that binds to DNA, leading to irreversible cross-linking and inhibition of nucleotide synthesis, which is not cell cycle specific. Under aerobic conditions, intermediates of MMC also react with oxygen to generate free radicals, causing cytotoxicity via lipid peroxidation. MMC is toxic to both proliferating and non-proliferating cells, but more for the former.topical use of MMC has been time-tested for glaucoma filtering surgery [to prevent fibrosis and consequent bleb failure], refractive surgery [to prevent stromal haze following surface ablation] and pterygium surgery [to prevent fibroblast cell migration and to induce apoptosis in Tenon s capsule fibroblasts]. In OSSN mitomycin C is used in concentrations of 0.02% or 0.04% 4 times a day for 1 or 2 weeks. These cycles are repeated at 4 to 6 week intervals. As MMC is relatively unstable in solution, it has to be refrigerated and a new bottle dispensed for each week of treatment. Shields et al 13,23 use a one-week on and one-week-off technique and has reported good results. 5-Fluorouracil [5FU] an anti-metabolite, which inhibits thymidylatesynthetase during S phase of the cell cycle, preventing DNA and RNA synthesis in rapidly dividing cells because of lack of thymidine. In contrast to MMC, it is cell 349

4 Kerala Journal of Ophthalmology cycle specific.though the experience with 5FU is less in comparison with MMC, it is equally efficacious and better tolerated. Also it is stable in aqeous solution for at least three weeks, does not require refrigeration and is inexpensive. With the existing scientific literature, it is clear that both mitomycin and 5-FU are effective for complete eradication of preinvasive OSSN in majority of patients when used as a primary treatment 1,2,3,4, The success rates for topical chemotherapeutic agents [24%] are comparable to other treatment modalitiesin preinvasive disease 3, 21,22,24. Vol. XXIII, No.4, Dec are involved, topical chemotherapy should be added with monthly follow-up and quarterly Biopore impression cytology for a year to evaluate recurrence. If disease free for one year, 6 monthly follow-up is suggested. Figure 6 Treatment plan for OSSN < 3 clock hours For invasive OSSN, these agents achieve chemoreduction or decrease in tumour size. Shields et al 23 reported that chemoreduction was effective in reducing the tumour base a mean of 57% using an average of 4 cycles of topical MMC. Postoperative MMC application, have also been used by several authors as adjunctive therapy following primary excision of OSSN with good success. Chen et al 25 reported no tumour recurrence in 27 cases with a mean follow-up of 27 months. Special care is required while handling these chemotherapeutic agents and punctual plugs are recommended to protect the nasopharyngeal tissue 3,22,24,26,27. Pregnant women should avoid contact with these agents. Ocular side effects of topical chemotherapeutic agents are ocular surface toxicity and epithelial defect formation, progression of cataract and punctual stenosis 3,22,24,26,27. No cases of corneal or scleral melting have been reported. An intact epithelium prevents deeper penetration, topical MMC or 5FU should not be given to any patient with a conjunctival or corneal epithelial defect. [2] Suspected OSSN 3 6 clock hours As there is a risk of producing limbal stem cell deficiency, excision biopsy + cryotherapy is better avoided. A diagnostic biopsy is required [Fig 7]. In pre-invasive lesions topical chemotherapy is likely to achieve tumour resolution. If invasive, surgery + cryotherapy is done after chemoreduction with 4 to 6 cycles of topical chemotherapy. Figure 7- Treatment plan for OSSN 3-6 clock hours Immunotherapy- Interferons are naturally occurring glycoproteins with antiviral and antitumour properties with clinical application in cutaneous malignancies 3,22,28. Successful outcome was reported in all the 6 cases of biopsy proven OSSN treated with a combination of intralesional and topical interferon 2b 28. Larger studies with longer follow-up are required to cement its place as a treatment modality. Management Though topical chemotherapy has opened new vistas in the approach towards OSSN, with a proliferation of advocates of non-surgical management, there is a definite risk of undertreating islands of tumour cells in invasive neoplasias 22. Though there are no standard protocols, following has been suggested as a treatment guideline by Basti and Mascai 22. [1] Suspected OSSN < 3 clock hours Excision biopsy + base/ edge cryotherapy + alchoholepitheliectomy is done. [Fig 6].If the margins are free of tumour cells, quarterly follow-up for a year is recommended to confirm absence of recurrence. Thereafter 6 monthly follow-up should suffice. If margins [3] OSSN > 6 clock hours A diagnostic biopsy is required. In pre-invasive lesions topical chemotherapy is quite likely to achieve tumour resolution. If invasive, surgery + cryotherapy is done after chemoreduction with 4 to 6 cycles of topical chemotherapy. If there is no response to chemotherapy palliative radiotherapy or extensive surgery like enucleation / exenteration may be required. 350

5 Anil Radhakrishnan - OSSN Figure 8- Treatment plan for OSSN more than 6 clock hours Conclusion Ocular Surface SquamousNeoplasia [OSSN] though an uncommon entity needs to be picked up early, as prompt treatment in early stages is usually curative. Though slow growing in nature,advanced invasive lesions may end up in mutilating surgery like exenteration. The advent of topical chemotherapy has indeed augmented the treatment armamentarium and has made a paradigm shift in the management of this condition in the last decade. References 1] Pe'er J. Ocular surface squamousneoplasia.ophthalmol Clin North Am. 2005;18(1): ] Lee GA, Hirst LW. Ocular surface squamous neoplasia. SurvOphthalmol 1995; 39: ] Basti S, Mascai MS. Ocular surface squamous neoplasia. Cornea 2003;22(7): ] Kiire CA, Srinivasan S, Karp CL. Ocular surface squamous neoplasia. IntOphthalmolClin. 2010;50(3): ] Rudkin AK, Dodd T, Muecke JS. The differential diagnosis of localized amelanoticlimbal lesions: a review of 162 consecutive excisions. Br J Ophthalmol 2011;95: ] Alves LF, Fernandes BF, Burnier JV, Zoroquiain P, Eskenazi DT, BurnierJr MN. Incidence of epithelial lesions of the conjunctiva in a review of 12,102 specimens in Canada (Quebec). Arq Bras Oftalmol. 2011;74(1): ]Spraul CW, Grossniklaus HE. Tumors of the cornea and conjunctiva. CurrOpinOphthalmol. 1996;7(4): ] Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane- a 10 year survey. Arch Ophthalmol.1992;110(4): ] Templeton AC.Tumours of the eye and adnexa. Recent Results Cancer Res. 1973; 41: ] Coroneo M. Eye Contact Lens. Ultraviolet radiation and the anterior eye.2011;37(4): ] Nagaiah G, Stotler C, Orem J, Mwanda WO, Remick SC.Ocular surface squamousneoplasia in patients with HIV infection in sub- Saharan Africa. CurrOpinOncol Sep;22(5): ]Hirst LW, Axelsen RA, Schwab I. Pterygium and associated ocular surface squamous neoplasia. Arch Ophthalmol. 2009;127(1): ] Shields JA, Shields CL, DePotter P. Surgical management of conjunctivaltumours. Arch Ophthalmol.1997;115: ] Char DH, Crawford JB, Howes EL, et al. Resection of intraocular squamous cell carcinomas. Br J Ophthalmol. 1992;76: ] Peksayar G, Soyurtuk MK, Demiryont M. Long term results of cryotherapy on malignant epithelial tumours of the conjunctiva. Am J Ophthalmol. 1989; 107: ]Fraunfelder FT, Wingfield D. Management of intraepithelial conjunctivaltumours and squamous cell carcinomas. Am J Ophthalmol. 1983;95: ] Goldberg JR, Becker SC, Rosenbaum HD.Gamma radiation in the treatment of squamous cell carcinoma of the limbus. Am J Ophthalmol.1976;55: ]Cerezo L, Otero J, Aragon G et al. Conjunctival intraepithelial and invasive squamous cell carcinoma treated with strontium 90. RadiotherOncol. 1990;17: ] Tole DM, McKelvie PA, Daniell M. Reliability of impression cytology for the diagnosis of ocular surface squamous neoplasia employing the Biopore membrane. Br J Ophthalmol.2001;85: ] McKelvie PA, Daniell M. Impression cytology following mitomycin therapy for ocular surface squamous neoplasia. Br J Ophthalmol.2001;85: ] Erie JC, Campbell RJ, Liesegang TJ.Conjunctival and Corneal intraepithelial and invasive neoplasia. Ophthalmology 1986;93: ] Kim JW, Abramson DH. Topical treatment options for conjunctival neoplasms.clinical Ophthalmology 2008:2(3) ] Shields CL, Demicri H, Marr BP et al. Chemoreduction with topical mitomycin prior to resection of extensive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol 2005;123: ] Sepulveda R, Pe'er J, Midena E, Seregard S, Dua HS, Singh AD. Topical chemotherapy for ocular surface squamousneoplasia: current status.br J Ophthalmol. 2010;94(5): ] Chen C, Louis D, Dodd T et al. Mitomycin C as an adjunct in the treatment of localized ocular surface squamous neoplasia. Br J Ophthalmol 2004;88: ] Gupta A, Muecke J. Treatment of ocular surface squamous neoplasia with Mitomycin C. Br J Ophthalmol. 2010;94(5): ] Abraham LM, Selva D, Casson R, Leibovitch I. The clinical applications of fluorouracil in ophthalmic practice.drugs. 2007;67(2): ] Vann RR, Karp CL. Perilesional and topical interferon alfa2b for conjunctival and corneal neoplasia. Ophthalmology 1999;106: