Case 5 -

Squamous Intraepithelial Neoplasia, Severe Dysplasia / Carcinoma in Situ Arising at the Corneal Limbus and Involving the Cornea and Conjunctival Epithelium Nora V. Laver, Tufts Medical Center, Boston, MA

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Clinical History 88-year-old female referred to the eye clinic for a papillomatous growth in the right eye involving the cornea and nasal conjunctiva, progressively increasing in size. The patient denied pain or discomfort, floaters, or change in vision. Her ocular history was significant for central retinal vein occlusion in her right eye ten years ago. She also had glaucoma with suspected narrow angles, no previous surgery or laser treatment. Her medical history was significant for hypertension, pacemaker and hypothyroidism. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 Nodular lesion with prominent vascularity arising in the bulbar nasal limbus involving the cornea and adjacent conjunctival epithelium. Notice the whitish are in the center of the lesion. Case 5 - Figure 2 Higher magnification of the lesion visualized with slit-lamp microscopy highlighting the fleshy and papillomatous configuration of the lesion. Case 5 - Figure 3 (2x and 4x). Papillomatous squamous growth with mild to moderate dysplastic changes. Case 5 - Figure 4 (2x and 4x). Papillomatous squamous growth with mild to moderate dysplastic changes. Case 5 - Figure 5 (2x and 4x). Papillomatous squamous growth with mild to moderate dysplastic changes. Case 5 - Figure 6 (2x, 4x, 10x, 20x). Flat squamous intraepithelial neoplasia, severe dysplasia/carcinoma in situ. Case 5 - Figure 7 (2x, 4x, 10x, 20x). Flat squamous intraepithelial neoplasia, severe dysplasia/carcinoma in situ. Case 5 - Figure 8 (2x, 4x, 10x, 20x). Flat squamous intraepithelial neoplasia, severe dysplasia/carcinoma in situ. Case 5 - Figure 9 (2x, 4x, 10x, 20x). Flat squamous intraepithelial neoplasia, severe dysplasia/carcinoma in situ. Case 5 - Figure 10 (2x, 4x, 10x, 20x). Flat squamous intraepithelial neoplasia, severe dysplasia/carcinoma in situ. Case 5 - Figure 11 (10x). P16 immunohistochemical stain highlights the area of severe dysplasia/carcinoma in situ. Case 5 - Figure 12 (4x and 10x). Normal histopathology of the corneal limbus. Case 5 - Figure 13 (4x and 10x). Normal histopathology of the corneal limbus. Introduction: Squamous intraepithelial neoplasia includes intraepithelial dysplastic changes to full-thickness epithelial neoplasia or carcinoma in situ involving the limbus, conjunctival and corneal epithelium. Synonyms include mild, moderate, and severe dysplasia, ocular surface squamous neoplasia, intraepithelial epithelioma, corneal intraepithelial neoplasia, conjunctival intraepithelial neoplasia and bowenoid type of dyskeratosis. Rarely the involvement is limited to the corneal epithelium with only minimal limbal involvement. Clinically the lesion appears as a thickned, gray, geographic lesion with scalloped or fimbriated margins. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The lesion shows papillomatous hyperplasia of the surface epithelium with predominantly mild to moderate dysplastic changes. Focally there is a flat epithelial full thickness dysplasia. There is no evidence of stromal invasion. Immunohistochemistry for p16 highlights the area of full- thickness dysplasia and shows increased cells in cycle with Ki-67 immunostain. Differential Diagnoses: The differential diagnosis includes UV-related epithelial hyperplasias and degenerations (pterygium), intraepithelial sebaceous gland carcinoma, and rarely, intraepithelial invasion by an adenocarcinoma originating from the apocrine glands of Moll. Invasive squamous cell carcinomas tend to have a grayish white, exophitic, crater-like gross clinical appearance and are surrounded by an inflamed surface epithelium. Final Diagnosis: Squamous intraepithelial neoplasia, severe dysplasia / carcinoma in situ arising at the corneal limbus and involving the cornea and conjunctival epithelium. Background of squamous papilloma with mild to moderate dysplasia is also present. The lesion appears completely excised. Case Discussion: Squamous conjunctival and corneal intraepithelial neoplasia is estimated to occur in 1.9 cases/100,000 population/ year. Symptoms range from none to severe pain and visual loss. The lesion is usually unilateral in fair-skinned, middle-aged or older patients. It can develop in children less frequently. Clinically the lesions arise at the limbus where the corneal stem cells are located, with either or both conjunctival and corneal involvement. An example of the normal limbus of the cornea is included in figure Case_5D_ (4x and 10x). Clinically most lesions are well demarcated, non- keratinized, well vascularized, pink and have a raspberry- like configuration. The main predisposing factors include sunlight and human papillomavirus. HPV types 6 and 11 are found in approximately 38 percent of cases and HPV types 16 and 18 in 30 to 58 percent of cases. It occurs more frequently in immunosuppressed patients, particulary those with AIDS. Histopathologically there is usually an abrupt demarcation between the affected epithelium and the adjacent normal epithelium. A thick, hypercellular epithelium demonstrates cellular pleomorphism, abnormal maturation, mitosis and dysplastic changes. Immunohistochemistry for p16 and Ki67 can be used to aid in the diagnosis, especially of moderate to high grade dysplasia and carcinoma in situ as in the case presented. In contrast, invasive squamous cell carcinoma usually shows hyperkeratosis and dyskeratosis in the neoplastic epithelial cells. Review of the Literature/Treatment Options: Primary complete excision with adequate margins is the preferred initial treatment; incomplete removal is associated with increased recurrances. For most localized lesions, removal with alcohol corneal epitheliectomy, partial lamellar sclerokeratoconjuctivectomy and double freeze thaw cryotherapy is performed. This same technique is used for localized squamous cell carcinoma and melanoma involving the conjunctiva and cornea. Cryotherapy is used as a supplemental treatment to provide better local control. Chemotherapy and topical mitomycin C is used for recurrences. Some authors also use local interferon alpha- 2b, 5-Fluorouarcil and cidofovir, and antiviral drug with some success. Conclusion(s): Squamous intraepithelial neoplastic lesions involving the cornea and conjunctiva are not uncommon lesions occurring in sun damaged ocular surfaces, usually at the limbus in elderly men. Recurrence risk is increased with positive surgical margins. Diagnosis of these lesions should include degree of dysplasia, the presence or absence of invasion and margin status to guide patient manangement. References: Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch Ophthalmol 1992;110:525-7. Scott IU, Karp CL, Nuovo GJ. Human papillomavirus 16 and 18 expression in conjunctival intraepithelial neoplasia. Ophthalmol 2002;109;542-7. A Case of Conjunctiva-Cornea Intraepithelial Neoplasia Successfully Treated with Topical Mitomycin C and Interferon Alfa-2b in Cycles. Di Pascuale MA, Espana EM; Tseng, Scheffer C. Cornea 2004;23: 89-92. Rozenman Y, Frucht-Pery J. Treatment of conjunctival intraepithelial neoplasia with topical drops of mitomycin C. Cornea 2000;19:1-6. Yeatts RP, Engelbrecht NE, Curry CD, Ford JG, Walter KA. 5- Fluorouracil for the treatment of intraepithelial neoplasia of the conjunctiva and cornea. Ophthalmol 200;107:2190-5. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmol 2001;108:1093-8. Tumors of the eye and ocular adnexa AFIP atlas of tumor pathology, series 4, fascicle 5. Font RL, Croxatto JO, Rao NA, editors. ARP Press, 2006. Eyelid, Conjunctival and Orbital Tumors. An Atlas and Texbook. Shields JA, Shields CL, editors. Lippincott Williams & Wilkins 2008, second edition.