Neoplasia

Squamous Lesions

Squamous papillomas

The most common ocular surface neoplasms are those of the squamous family. Squamous papillomas may be divided clinically into pedunculated and sessile subtypes.

Pedunculated papillomas are exophytic, pink-red, strawberry-like papillary growths (Fig 5-15A) that occur more commonly in children, in whom multiple lesions often exist. They are associated with human papillomavirus (HPV) subtypes 6 and 11. The histologic examination of a pedunculated papilloma demonstrates papillary fibrovascular fronds covered by hyperplastic squamous epithelium (Fig 5-15B). Goblet cells may be present as in normal conjunctival epithelium. If there is overlying tear-film disruption resulting in exposure, the number of goblet cells may be reduced and the surface keratinized. Neutrophils may be seen within the epithelium, and a chronic inflammatory infiltrate may occupy the stroma, to varying degrees, which may be indicative of eye rubbing. Pedunculated papillomas exhibit benign behavior. They may spontaneously involute over months or years, and a small, nonirritating papilloma may be observed. Excisional biopsy may be performed for an irritating or cosmetically objectionable papilloma or if the diagnosis is in doubt.

Sessile papillomas occur more commonly in adults, arising on the bulbar conjunctiva, especially adjacent to the limbus. They may be difficult to distinguish clinically from ocular surface squamous neoplasia (see the following discussion). In sessile papillomas, the distinction between truly “benign” and “premalignant” is often not clear-cut. Sessile papillomas are associated with HPV subtypes 16 and 18, the same subtypes associated with squamous neoplasia. Worrisome clinical features suggestive of transformation into neoplasia would include leukoplakia (white surface) and inflammation. Sessile papillomas may be observed closely if there are no suspicious features, but biopsy is often required for histologic diagnosis. Histologically, a sessile papilloma exhibits a broad base (as opposed to the more narrow base seen in a pedunculated papilloma) and lacks the fingerlike projections seen in a pedunculated papilloma. The epithelium exhibits hyperplasia, but the individual cells should appear normal. If there are features such as nuclear hyperchromasia and pleomorphism, altered cell polarity, and abundant mitotic figures, then a diagnosis of ocular surface squamous neoplasia should be made.

Figure 5-15 Squamous papilloma. A, Clinical appearance at the caruncle. B, The epithelium is hyperplastic, draped over

fibrovascular cores. (Part A courtesy of Robert H. Rosa, Jr, MD.)

Ocular surface squamous neoplasia

Ocular surface squamous neoplasia (OSSN) typically arises adjacent to the limbus, over a preexisting pinguecula, that is, over an area of solar elastosis, similar to actinic keratoses of the skin. Ultraviolet light (UV) exposure, especially in individuals with light skin pigmentation, is a known risk factor for OSSN, and the prevalence of OSSN is higher in equatorial regions of the world. UV-associated mutations in tumor suppressor genes such as p53 have been demonstrated in OSSN, and hereditary deficiency of DNA repair such as in xeroderma pigmentosum increases the risk of OSSN formation. OSSN is also associated with HPV infection, subtypes 16 and 18, as well as with human immunodeficiency virus (HIV) infection. HIV-associated OSSN is especially common in sub-Saharan Africa, and HIV should be suspected in any patient with OSSN younger than 50 years. Non–HIV- related immunosuppression is also a risk factor for OSSN. Other risk factors include older age and smoking.

The clinical appearance of OSSN is characterized by epithelial thickening, and the lesion may extend onto the peripheral cornea. There may be a prominent “corkscrew” vascular pattern, or the surface may appear gelatinous or leukoplakic, indicative of surface keratinization (Fig 5-16). Surface keratinization is not pathognomonic for OSSN and may be seen over any elevated lesion not covered adequately by the tear film; however, it is very commonly seen in OSSN and must therefore arouse suspicion. The adjacent conjunctiva may appear injected, with prominent “feeder” vessels leading to the lesion.

Histologically, the epithelium exhibits hyperplasia, loss of goblet cells, loss of normal cell polarity, nuclear hyperchromasia and pleomorphism, and mitotic figures. There is often surface keratinization, correlating with the leukoplakia observed clinically. Dyskeratosis (non-surface cells producing keratin) may also be seen. A chronic inflammatory response is often present in the substantia propria.

The most important assessment to be made histologically in OSSN is whether the neoplasia is contained by the basement membrane (ie, intraepithelial or in situ) or whether neoplastic cells have traversed the epithelial basement membrane and invaded the stroma. For lesions contained by the basement membrane, the term conjunctival intraepithelial neoplasia (CIN) may be used. The neoplasia may be graded as mild, moderate, or severe, according to the degree of cellular atypia (although this grading does not necessarily have clinical utility in terms of prognosis). In cases with the most severe atypia, full-thickness involvement of the epithelium is seen, often with squamous eddies or keratin whorls/pearls. For these more advanced lesions, the term squamous carcinoma in situ may be used. If, however, the neoplastic cells have invaded the stroma, then the diagnosis is invasive squamous cell carcinoma (Fig 5-17; see Fig 5-16). Clinically, the term CIN has fallen out of favor in preference to the more general term OSSN, because it is not possible to determine on clinical examination whether stromal invasion has occurred. CIN should be regarded as a histologic term, reserved for noninvasive lesions. Invasion through the sclera or cornea and intraocular spread are uncommon complications of invasive squamous carcinoma. When there is intraocular spread, it often occurs at the site of a previous surgical procedure, such as cataract surgery. However, intraocular invasion may also occur through previously nonviolated sclera, especially in immunosuppressionrelated cases and cases occurring in ozone-depleted areas, as these cases tend to be more aggressive. Although regional lymph node metastasis is not as common as it is with squamous carcinomas of the skin or other sites, dissemination and death can occur.

Figure 5-16 Ocular surface squamous neoplasia (OSSN). A, Clinical appearance: note the “corkscrew” vascular pattern of the conjunctival portion and leukoplakia of the corneal portion. Also note feeder vessels. B, Note the sharp demarcation (arrow) between normal and abnormal epithelium in OSSN. The epithelium is hyperplastic, with surface keratinization (K). With the basement membrane intact, a diagnosis of conjunctival intraepithelial neoplasia (CIN) is made. There is a chronic inflammatory response in the substantia propria (CI). Also note areas of elastotic degeneration in the substantia propria (arrowheads), indicating that the lesion arose over a pinguecula. C, High magnification (different patient) shows transition zone where neoplasia begins (arrow). To the right of the arrow, the epithelium exhibits mild keratinization, hyperplasia, nuclear hyperchromasia, loss of goblet cells, altered cellular polarity, significant pleomorphism, full-thickness involvement, and mitotic figures (M). The basement membrane is intact (arrowheads), with an underlying chronic inflammatory response. D, In invasive squamous carcinoma, tongues of epithelium violate the basement membrane and invade the stroma (arrows), with squamous eddies (arrowheads). E, Gross photograph of squamous carcinoma invading the limbus and anterior chamber

angle through a previous surgical incision (arrow). (Part A courtesy of Vahid Feiz, MD; parts B–E courtesy of George J. Harocopos, MD.)