Signs and Symptoms
Ocular surface squamous neoplasia (OSSN) refers to a spectrum of cancerous and precancerous lesions of the conjunctiva; the term encompasses several conditions, including conjunctival intraepithelial neoplasia (CIN), carcinoma-in-situ and invasive squamous cell carcinoma.1 In industrialized nations such as the United States, the typical patient with OSSN tends to be over 50 years of age, Caucasian and male (by a ratio of about 3:1).2 However, in the equatorial regions of Africa, younger individuals may display this condition, particularly those who are immunocompromised secondary to HIV infection.2,3
The earliest stages of OSSN (CIN, carcinoma-in-situ) appear as a fleshy or gelatinous, slightly elevated mass of pink tissue, usually at the limbus in the interpalprebal space. At this stage, the lesion may be mistaken for a variety of benign conditions, including pinguecula, pterygium or conjunctival papilloma. As the lesion grows larger and more elevated, it may begin to take on an irregular shape. Characteristic “feeder vessels” may be seen within and surrounding the mass; these vessels represent a rich intrinsic blood supply, emanating from the adjacent conjunctiva and/or episclera. Significant extension onto the corneal surface should be viewed as highly suspicious for malignancy. Another pathognomonic sign of invasive squamous cell carcinoma is the presence of leukoplakia—overlying, placoid, white areas on the tumor surface, secondary to hyperkeratosis.4
Patients with OSSN may present in early stages with cosmetic concerns, or may be entirely asymptomatic. Larger lesions may interfere with lid function, causing dry eye complaints and possibly dellen formation on the adjacent cornea. Advanced, invasive lesions may compromise the episclera, sclera, cornea or angle structures. Pain may be a significant factor in later stages due to associated keratitis, uveitis or secondary glaucoma.5
Ocular surface squamous neoplasia, as the name implies, represents abnormal, excessive growth of the conjunctival tissue. Histologically, atypical squamous cells replace the normal epithelium, resulting in a loss of normal cell maturation. Depending upon the severity of the dysplasia, clinicians may use the term CIN or carcinoma-in-situ. After the dysplastic squamous cells encroach beyond the borders of the basement membrane, the lesion is referred to as invasive squamous cell carcinoma.1
The pathophysiology of OSSN is believed to be multifactorial.2 While a variety of potential etiologic factors have been linked to the development of squamous cell carcinoma, solar ultraviolet radiation remains the most significant.6-8 HIV seropositivity also appears to significantly increase the risk of developing OSSN.2,3,9,10 In Africa, rates of HIV infection as high as 79% have been found in patients diagnosed with these lesions.9 Other factors which have been associated with the development of OSSN include the human papilloma virus (HPV-16 and -18, specifically), chronic inflammatory diseases (e.g., atopic keratoconjunctivitis) and exposure to arsenic or immunosuppressive drugs.1,2,11-13
Management of OSSN begins with identification of clinically suspicious conjunctival lesions. Any elevated mass of the ocular surface that is not easily identifiable as a benign entity should warrant further evaluation, particularly in at-risk individuals; this includes older patients with a history of chronic sun exposure as well as any individual with known HIV infection. Several non-invasive techniques can be performed, such as impression cytology or exfoliative cytology, in conjunction with Papanicolaou and Giemsa staining.14 In vivo confocal microscopy can also help differentiate OSSN from other benign and malignant lesions.15 However, only histopathologic evaluation of tissue biopsy can conclusively differentiate the three lesions in the spectrum of OSSN.1
Management of biopsy-proven lesions usually consists of surgical excision, with wide margins (4-5mm) to increase the chance of complete removal. Advanced lesions in which there is involvement of the cornea or sclera may warrant deep lamellar keratectomy or sclerectomy. In all cases, a ‘‘no touch’’ technique is used to avoid direct manipulation of the mass and prevent tumor cell seeding.5 Still, surgical excision alone appears to yield an unacceptably high recurrence rate.16
Adjunctive cryotherapy applied to the surrounding conjunctival tissue helps to destroy the tumor’s microcirculation, and further improves the surgical outcome.1,5,16 Likewise, the adjunctive use of topical antimetabolites, including 5-fluorouracil (5-FU) or mitomycin-C (MMC) appears to be beneficial toward diminishing recurrence rates.2,17,18 The topical immunomodulatory agent interferon -2b has proven to be equally effective in the adjunctive management of non-invasive OSSN as 5-FU and MMC.18,19 Topical cyclosporine 0.05% (Restasis, Allergan) in conjunction with MMC following surgical excision seems to further prevent tumor recurrence while improving visual outcome.16
In those rare cases where intraocular extension has occurred, surgical removal of the globe (enucleation) or even the entire orbital contents (exenteration) may be required to preserve life.20
• Clinicians must be suspicious of any rapidly growing mass on the conjunctival surface that fails to respond to antibiotic or anti-inflammatory therapies. Realize that two or more feeder vessels, leukoplakia, changes or variations in color or a predilection toward bleeding all constitute “red flags” for malignancy.
• Those patients who undergo non-surgical forms of treatment (e.g., chemotherapy or radiation therapy alone) tend to have higher rates of recurrence and greater complications. Chemotherapeutic agents typically induce a toxic keratoconjunctivitis, while irradiation of OSSN lesions poses a substantial risk for corneal burns and radiation retinopathy.
• Photodynamic therapy with systemically injected verteporfin has been investigated as a potential management option for those with invasive squamous cell carcinoma of the conjunctiva.21,22 Preliminary reports are positive; however, additional research is required to determine if this treatment modality has long-term benefits.
• While most forms of OSSN carry a good prognosis, metastasis is always a possibility. Once a diagnosis has been made, patients should be comanaged with an experienced oncologist to be certain that the cancer has not spread to other organ systems. Since the liver is the single most common site of metastasis from ocular malignancies, it is important to consider testing liver enzymes in any patient with cancer of the eye.
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