Several types of benign and malignant lesions can arise from the squamous epithelium of the conjunctiva. These lesions tend to form a spectrum ranging from those that are entirely benign, to those with low malignant potential, to more aggressive, malignant neoplasms. It is often difficult to differentiate clinically between the benign and malignant lesions. The majority of epithelial lesions seen in a clinical practice are low grade proliferations with only a small chance of evolving into frank squamous cell carcinoma. Two of these are keratotic plaque and actinic keratosis (1,2,3,4). Because they may be impossible to differentiate clinically, they are considered together for this discussion. In the authors’ clinical series of 1,643 conjunctival tumors, there were four keratotic plaques and four cases of actinic keratosis each representing less than 1% of the 1,643 cases (2).

Both keratotic plaque and actinic keratosis can develop on the limbal or bulbar conjunctiva usually in the interpalpebral region. Clinically, the lesion appears as a flat, white plaque that appears gradually and shows no tendency toward aggressive growth.

Pathologically, keratotic plaque consists of acanthosis of the epithelium with keratinization of the conjunctival epithelium and parakeratosis. Actinic keratosis (senile keratosis) is a similar proliferation of epithelium with prominent keratosis, often over a chronically inflamed pingueculum or pterygium. It can have a frothy or leukoplakic appearance and may be clinically similar to a keratotic plaque.

Keratotic plaque and actinic keratosis of the conjunctiva are usually indistinguishable clinically from conjunctival intraepithelial neoplasia (CIN), which has slightly greater potential to evolve into invasive squamous cell carcinoma. Therefore, the finding of leukoplakia in the conjunctiva is a relative indication for surgical excision and supplemental cryotherapy. However, it is also acceptable to follow some such lesions until progression is documented, particularly in elderly patients, because the prognosis is generally excellent, even for CIN.

These benign lesions can simulate neoplasia because of the leukoplakia produced by the keratosis.

Squamous cell neoplasia can be a localized, minimally aggressive lesion confined to the surface epithelium or a more aggressive tumor that transgresses the basement membrane and invades the adjacent tissues. The former has no potential to metastasize and is called CIN (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28). The latter is called invasive squamous cell carcinoma and generally has a low potential for metastasis. In recent years, some authors have used the umbrella term “ocular surface squamous neoplasia” to include dysplasia, CIN, and invasive squamous cell carcinoma (10). CIN is initially confined to the epithelium but can progress to invasive squamous cell carcinoma; therefore, it is considered a “precancerous” condition, rather than a true malignancy. The main predisposing factors include sunlight and human papillomavirus (HPV). Although results are conflicting, a recent study using polymerase chain reaction established the presence of HPV 16 or 18 in cases of CIN (14).

In the authors’ clinical series of 1,643 conjunctival tumors, there were 71 cases of CIN, accounting for 39% of all premalignant and malignant epithelial lesions and for 4% of all conjunctival lesions (2).

CIN is usually unilateral in fair-skinned, middle-aged or older patients who have had considerable exposure to sunlight (1,2,3,4,11). It can develop in children (6). Both CIN and invasive squamous cell carcinoma occur more frequently in immunosuppressed patients, particularly those with acquired immunodeficiency syndrome (AIDS; 14). Clinically, CIN has several variations, but usually appears as a fleshy, sessile, or minimally elevated lesion usually at the limbus in the interpalpebral fissure and less commonly in the forniceal or palpebral conjunctiva. Secondary inflammation can lead to the misdiagnosis of atypical conjunctivitis before the neoplasm is suspected (12). Leukoplakia is usually absent or minimal; extensive leukoplakia should raise suspicion for invasive squamous cell carcinoma. Although greater thickness is believed to be a sign of malignant transformation we have seen thick tumors that remain within the epithelium. Hence, there are no consistent clinical criteria for distinguishing CIN from invasive squamous cell carcinoma. CIN can extend for a variable distance into the adjacent corneal epithelium, where it appears as a subtle advancing, gray, superficial opacity that may be relatively avascular or may have fine blood vessels (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27). When the involvement is limited to the corneal epithelium with only minimal limbal involvement, it is called “primary corneal dysplasia” (9).

Although the diagnosis of CIN is made histopathologically, it has sufficiently characteristic features that a diagnosis can be made clinically in most cases. Usually, conjunctival/corneal CIN is small and localized enough that primarily complete excision (discussed later) is the best method of establishing the diagnosis, and incisional biopsy is rarely indicated. However, some have advocated aspiration cytology (13) or impression cytology to establish the diagnosis (28).

Histopathologically, mild CIN (dysplasia) is characterized by a partial thickness replacement of the epithelium by mildly anaplastic cells that lack normal maturation. Severe CIN (carcinoma in situ) is characterized by full-thickness replacement of the epithelium by similar cells. The basement membrane is intact (1). Both variants show a characteristic abrupt demarcation between the affected epithelium and the adjacent normal epithelium (1,2). In contrast with invasive carcinoma, hyperkeratosis and dyskeratosis are relatively uncommon findings.

There are many reports that discuss management of CIN (15,16,17,18,19,20,21,22,23,24,25,26,27,28). Complete excision with adequate margins is the preferred initial treatment. For most localized lesions, we remove the growth with alcohol corneal epitheliectomy, partial lamellar sclerokeratoconjunctivectomy, and double freeze thaw cryotherapy (15). This is the same technique used for localized squamous cell carcinoma and melanoma and it is discussed and illustrated in Chapter 25. Cryotherapy is almost always used as supplemental treatment and seems to provide better control (15,16,17); low-dose irradiation with strontium-90 has been used successfully (18). Most recently, we and others have used extensively chemotherapy with topical mitomycin C for recurrent or persistent cases (19,21,22). Others used local interferon-a-2b (24) and 5-fluorouracil (25,26). A recent report described making the diagnosis of conjunctival/corneal CIN by impression cytology and treating with topical mitomycin C and interferon-a-2b in cycles (21). An antiviral drug, cidofovir, has been used with some success (23). Incomplete removal is associated with greater recurrence.