Ocular surface squamous neoplasia (OSSN) is the most common non-pigmented malignancy of the ocular surface and comprises a spectrum of epithelial squamous conditions ranging from dysplasia to carcinoma. Prominent risk factors for OSSN development include a history of OSSN, ultraviolet light exposure, prior skin cancer, older age, male gender, smoking and HIV or HPV infection.^1,2

Presentation Characteristics

OSSN can have varied clinical presentations. Common presentations include conjunctival papillomatous, gelatinous or leukoplakic lesions that extend onto the cornea. Infrequently, lesions may be pigmented. Vital dye staining with rose bengal or lissamine green can be helpful in identifying these lesions, especially those that are smaller or more subtle, and it is always important to evert the upper eyelid and examine the palpebral conjunctiva and fornices for lesions as well.^1,2

Diagnosis

Anterior segment optical coherence tomography (AS-OCT) is a highly sensitive and specific modality to diagnose OSSN lesions. Work by Dr. Carol Karp has shown that OSSN has a characteristic appearance on AS-OCT of abnormally thickened and hyperreflective epithelium, abutting an abrupt transition from normal epithelium.³ These findings can be used to distinguish OSSN lesions from other epithelial and subepithelial lesions of the ocular surface.⁴ AS-OCT can also be used to detect subclinical disease after patients have undergone treatment for OSSN, and studies have shown that AS-OCT can help clinicians extend therapy past the point of clinical resolution, which can be beneficial to reduce risk of lesion recurrence.⁵ Histopathology from incisional or excisional tissue biopsies is the gold standard for diagnosing OSSN when physicians are uncertain about making a diagnosis.⁶

Management

Surgical management of OSSN traditionally involves wide-margin (~4mm margins) surgical excision with no-touch technique, followed by cryotherapy via a double or triple-freeze slow-thaw technique, application of absolute alcohol to remove corneal components or both. Primary wound closure can be performed for smaller excisions, but larger lesion excisions are typically closed with amniotic membranes. Partial lamellar sclerectomies may be needed for lesions with scleral invasion and, in cases with intraocular or orbital invasion, enucleation or exenteration may be required. Surgical excision can be diagnostic and therapeutic but can be associated with conjunctival scarring, symblepharon formation or even limbal stem cell deficiency.⁷

Medical management of OSSN has gained increasing popularity due to its advantages of treating the entire ocular surface and addressing areas of multifocal or subclinical disease. Medical treatments can also be used to debulk OSSN lesions, reduce the area of surgical excision and treat subclinical or recurrent disease after surgical excision. Common topical chemotherapeutic agents used for OSSN treatment are 5-fluorouracil (5-FU), mitomycin-C (MMC) and interferon-alpha (IFN).^7,8 Unfortunately, IFN has been hard to obtain recently due to manufacturing changes, so 5-FU and MMC are being employed more commonly and show effective resolution of lesions. Side effects of topical therapy can include ocular irritation, keratitis, conjunctivitis or punctal stenosis, depending on the agent. Typically, one cycle of IFN treatment includes daily doses for 4 weeks, while 5-FU and MMC are often cycled, with 1 to 2 weeks of daily therapy and 2 to 3 weeks of drug holiday. Treatment length, duration and cycle can vary among clinicians. 

Conclusion

Timely diagnosis and treatment of OSSN are critical to prevent unwanted sequelae such as intraocular extension, metastasis or recurrent lesions. Imaging tools such as AS-OCT are powerful adjuncts for diagnosis, and customizing patient treatment with medical and surgical options can help address patient preference and compliance.

For a more in-depth review of OSSN diagnosis and management, see my article “Tackling Ocular Surface Tumors” in the November 2023 issue of Corneal Physician. 

References

1. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol. 1995 May-Jun;39(6):429-450. doi:10.1016/s0039-6257(05)80054-2
2. Sayed-Ahmed IO, Palioura S, Galor A, Karp CL. Diagnosis and medical management of ocular surface squamous neoplasia. Expert Rev Ophthalmol. 2017;12(1):11-19. doi:10.1080/17469899.2017.1263567
3. Kieval JZ, Karp CL, Shousha MA, et al. Ultra-high resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia and pterygia. Ophthalmology. 2012 Mar;119(3):481-486. doi:10.1016/j.ophtha.2011.08.028
4. Venkateswaran N, Mercado C, Wall SC, Galor A, Wang J, Karp CL. High resolution anterior segment optical coherence tomography of ocular surface lesions: a review and handbook. Expert Rev Ophthalmol. 2021;16(2):81-95. doi:10.1080/17469899.2021.1851598
5. Tran AQ, Venkateswaran N, Galor A, Karp CL. Utility of high-resolution anterior segment optical coherence tomography in the diagnosis and management of sub-clinical ocular surface squamous neoplasia. Eye Vis (Lond). 2019 Aug;6:27. doi:10.1186/s40662-019-0152-3
6. Kao AA, Galor A, Karp CL, Abdelaziz A, Feuer WJ, Dubovy SR. Clinicopathologic correlation of ocular surface squamous neoplasms at Bascom Palmer Eye Institute: 2001 to 2010. Ophthalmology. 2012 Sep;119(9):1773-1776. doi:10.1016/j.ophtha.2012.02.049
7. Nanji AA, Moon CS, Galor A, Sein J, Oellers P, Karp CL. Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications. Ophthalmology. 2014 May;121(5):994-1000. doi:10.1016/j.ophtha.2013.11.017
8. Venkateswaran N, Mercado C, Galor A, Karp CL. Comparison of topical 5-fluorouracil and interferon alfa-2b as primary treatment modalities for ocular surface squamous neoplasia. Am J Ophthalmol. 2019 Mar;199:216-222. doi:10.1016/j.ajo.2018.11.007 

Nandini Venkateswaran, MD practices at Massachusetts Eye and Ear Harvard Medical School Department of Ophthalmology, where she is also an instructor. Her specialties are complex and premium cataract surgery, cornea and external diseases, corneal crosslinking, and refractive surgery. She is a consultant for CorneaGen.