Chapter 67 – Tumors of Conjunctiva and Cornea
JAMES J. AUGSBURGER
• Malignant and benign neoplasms, choristomas, and hamartomas arising from or within tissues of the anterior ocular walls and its coverings
• Solid mass or discrete lesion of cornea, conjunctiva, or both
• Principal categories include the following:
Tumors of stratified squamous epithelium
Miscellaneous other tumors
TUMORS OF STRATIFIED SQUAMOUS EPITHELIUM
Tumors of the stratified squamous epithelium of the conjunctiva and cornea encompass a wide spectrum of lesions, ranging from benign disturbances of epithelial maturation (actinic keratosis, pseudoepitheliomatous hyperplasia) to frankly malignant neoplasms (squamous cell carcinoma and its variants). Although advanced malignant lesions frequently exhibit clearly invasive features, less advanced malignant lesions typically resemble their benign counterparts quite closely. Consequently, lesions of the conjunctiva and cornea suspected of being neoplasms of the stratified squamous epithelium should be excised (if possible) or a biopsy done to establish their histopathological nature and provide a sound basis for subsequent management.
EPIDEMIOLOGY AND PATHOGENESIS
Tumors of the stratified squamous epithelium of the conjunctiva and cornea are almost certainly the most common type of primary ocular neoplasm encountered in clinical practice around the world. The average annual incidence of squamous cell carcinoma of the conjunctiva across all age groups has been estimated to be approximately 17 to 20 cases per million persons per year. For a population with an average life expectancy of 70 years, this average annual incidence translates to a cumulative lifetime incidence of approximately 1 case per 700 to 850 persons. By and large, they are tumors of older adults. They affect all racial groups and both sexes. Risk factors for occurrence of such tumors    include a history of repeated intense sunlight exposure, male sex, outdoor occupations, advanced age, cigarette smoking, a history of squamous cell carcinoma of the skin of the head and neck, blonde hair, light complexion, xeroderma pigmentosum, acquired immunodeficiency syndrome (AIDS), and conjunctival infection by human papilloma viruses 16 and 18.
The pathogenesis of tumors of the stratified squamous epithelium appears to be disordered maturation of the epithelium induced by various irritants. Cytogenetic studies of conjunctival squamous cell carcinomas have not revealed any consistent chromosomal or gene changes in tumor cells. Xeroderma pigmentosum, a rare autosomal recessive disorder, conveys a substantially increased risk of developing one or more neoplasms of the stratified squamous epithelium of the conjunctiva or cornea following sunlight exposure. These tumors tend to develop much earlier in life than do typical squamous cell carcinomas of the conjunctiva and their variants. Persons with AIDS also tend to develop tumors of the stratified squamous epithelium of the conjunctiva and cornea at a younger age than do individuals without this disorder. Their tumors also tend to be substantially more aggressive on average than the typical squamous cell carcinomas of the conjunctiva.
Tumors of the stratified squamous epithelium of the conjunctiva and cornea appear most frequently as focal epibulbar lesions at the corneoscleral limbus temporally or nasally. Three morphological patterns are most common. The leukoplakic lesion ( Fig. 67-1 ) appears as a focal thickening of the stratified squamous cell epithelium with a superficial plaque of opaque white hyperkeratosis. The papillomatous lesion ( Fig. 67-2 ) appears as a highly vascularized soft tissue mass. The gelatinous lesion ( Fig. 67-3 ) appears as an ill-defined translucent thickening that is not usually as prominent as the papillomatous or leukoplakic lesions. When the disordered epithelial maturation involves the corneal epithelium, it frequently appears as a zone of translucent corneal epithelial clouding ( Fig. 67-4 ) visible by slit-lamp biomicroscopy. The affected individual may or may not recognize the lesion. If symptomatic, the patient typically complains of mild foreign body sensation and visual blurring attributable to the lesion. Development of a neoplasm of the stratified squamous cell epithelium within the palpebral conjunctiva or in the superior or inferior fornix is extremely uncommon.
The larger the lesion, the greater the likelihood of its malignant histology. Other features indicative of probable malignant histology include prominent epibulbar vasculature of the lesion, corneoscleral or intraocular invasion, anterior orbital invasion, spontaneous bleeding, umbilication, and strong broad-based adhesion to the globe away from the limbus.    
DIAGNOSIS AND ANCILLARY TESTING
Clinical diagnosis of a probable or possible squamous cell carcinoma of the conjunctiva or cornea is based upon detection of a lesion having some or all of the findings mentioned in the preceding paragraph. Any discrete thickening of the conjunctiva associated with prominent conjunctival vasculature should probably be excised or sampled for biopsy without undue delay.
Patients with a suspected neoplasm of the stratified squamous epithelium of the conjunctiva or cornea require a comprehensive ophthalmologic evaluation, with mapping of the lesion at
Figure 67-1 Leukoplakic squamous cell carcinoma of conjunctiva. Discrete white hyperkeratotic limbal plaque is associated with prominent conjunctival blood vessels.
Figure 67-2 Papillomatous squamous cell carcinoma of conjunctiva. Pink limbal tumor contains multiple fine intralesional corkscrew blood vessels and is associated with dilated afferent and efferent conjunctival blood vessels.
the slit lamp and identification of invasive features, if present. Ultrasonographic biomicroscopy may be helpful if corneal or scleral invasion is suspected.
Tumors of the stratified squamous epithelium of the conjunctiva are regarded as malignant when they exhibit anaplasia, invasion of the substantia propria of the conjunctiva, or invasion of the underlying sclera, cornea, or both. The following are the most common types of tumors of the stratified squamous epithelium of the conjunctiva and cornea that appear on pathology reports:
• Hyperplasia: benign thickening of the stratified squamous epithelium with disordered transition from basal to superficial layers, but no cells with nuclear features suggestive of malignancy
• Dysplasia: abnormal epithelial maturation from basal to superficial layers of stratified squamous epithelium, accompanied by partial thickness replacement of epithelium by atypical but not frankly malignant cells ; intermediate lesion between benign hyperplasia and intraepithelial neoplasia: the more numerous and more atypical the abnormal cells, the greater the concern about neoplasia
• Intraepithelial neoplasia (carcinoma in situ): abnormal malignant-appearing (anaplastic) epithelial cells replacing the conjunctival stratified squamous epithelium ; may involve partial thickness or full thickness of epithelium
• Squamous cell carcinoma: mass composed of malignant-appearing stratified squamous epithelial cells with invasion into substantia propria ( Fig. 67-5 ) and possibly into corneal or scleral stroma
• Mucoepidermoid carcinoma: similar to squamous cell carcinoma, but with nests of cells that elaborate mucin; tends to be highly invasive
Figure 67-3 Gelatinous squamous cell carcinoma of conjunctiva. Translucent limbal mass is associated with dilated afferent and efferent conjunctival blood vessels.
Figure 67-4 Corneal intraepithelial neoplasia. Lesion appears as faint gray clouding of corneal epithelium.
Figure 67-5 Pathology of squamous cell carcinoma of conjunctiva. Tumor consists of neoplastic squamous epithelial cells thickening epithelium and extending deeply into substantia propria.
Treatment options for squamous cell carcinoma of the conjunctiva range from simple excision to exenteration. A number of factors influence the method of treatment recommended for individual patients. These factors include the size of the lesion
Figure 67-6 Excision of squamous cell carcinoma of conjunctiva with lamellar keratosclerectomy. Superficial D-shaped area of excised inner scleral and corneal lamellae straddling limbus.
(basal area and thickness), location of the lesion, clinical invasiveness of the lesion, the status of the fellow eye, and the age and general health of the patient. If the lesion in question is a discrete nodular limbal mass, it frequently can be removed completely by simple excision. To maximize the likelihood of complete lesion excision, the margins of the lesion can be marked with a sterile methylene blue pen prior to making the first conjunctival incision. The bulbar conjunctiva is incised around the lesion about 2?mm from its marked margins. The incision is carried down to bare sclera. The conjunctiva containing the limbal lesion is separated from the underlying sclera up to the limbus using blunt or sharp dissection, and the conjunctival specimen is excised as a single piece. Depending on the size of the conjunctival defect created by the excision, the defect can either be left to granulate in or closed surgically with or without a conjunctival transposition flap or mucous membrane graft.
If the lesion is strongly adherent to the sclera at the limbus, superficial lamellar keratosclerectomy can be performed to increase the chance of complete removal of the tumor ( Fig. 67-6 ). A surgical blade is used to create a partial thickness scleral incision around the area of strong adhesion. A thin lamellar scleral flap is dissected under the lesion and into the peripheral clear cornea. The conjunctiva and adherent limbal corneoscleral flap are then excised as a single piece with Westcott or Vannas scissors. Immediately following excision of the specimen, a cotton-tipped applicator stick soaked in absolute alcohol is applied briefly to the peripheral cornea adjacent to the now bare bulbar sclera to loosen the epithelium. Using a surgical blade, the loosened peripheral corneal epithelium is then removed. Some authors have also suggested a microscopically controlled excision approach similar to the Mohs’ micrographic technique used for skin cancers to increase the likelihood of complete tumor excision.  This method of excision is not used widely.
A word about handling the excised specimen to maximize the likelihood of satisfactory histopathological assessment of completeness of lesion excision is appropriate. The ophthalmic surgeon who excises a conjunctival specimen should flatten the specimen on either a segment of a sterile tongue blade or a heavyweight paper (e.g., the paper in suture packets), unrolling all of the edges as he or she does so, allowing it to air dry momentarily, and then immersing it in formaldehyde or paraformaldehyde for delivery to and processing by the ophthalmic pathologist. If the specimen is allowed to roll up, it will be virtually impossible for the pathologist to determine completeness of excision reliably.
Cryotherapy to the bulbar conjunctiva adjacent to the incision around the lesion and to the sclera underlying the site of the excised limbal lesion frequently is performed immediately following excision to reduce the likelihood of local tumor recurrence. It can also be performed as a separate procedure following early postoperative healing if histopathological study reveals tumor extension to the margins of the resected specimen. To avoid performing inadvertent cyclocryotherapy, the surgeon should inject anesthetic into the substantia propria of the conjunctiva to elevate the stratified squamous epithelium from the sclera before freezing the conjunctiva. The elevated epithelium typically is frozen for about 10–30 seconds, allowed to thaw, and then refrozen for another 10–30 seconds. Cryotherapy typically causes pronounced local tissue swelling that may take several weeks to subside. It can also cause symblepharon, restricted ocular motility, and scleral melting.
During the past decade, quite a few patients with extensive conjunctival or corneal intraepithelial neoplasia (CIN), incompletely excised intraepithelial neoplasia of the bulbar conjunctiva by histopathological criteria, and recurrent intraepithelial neoplasia following prior excision have been treated by topical chemotherapy using mitomycin C (0.02–0.04% solution) or 5-fluorouracil (1% solution) drops.     Such usage of mitomycin C and 5-fluorouracil is not approved by the U.S. Food and Drug Administration. Treatment with topical chemotherapeutic drops is most often considered for eyes with extensive CIN of the cornea, diffuse or multifocal residual or recurrent intraepithelial neoplasia of the bulbar conjunctiva after prior excision, or both. Because application of mitomycin C and 5-fluorouracil to bare sclera and de-epithelialized cornea following pterygium surgery has been associated with occasional corneoscleral melting, the bulbar conjunctiva and corneal epithelium should be allowed to heal prior to initiation of such therapy. Typical regimens call for administration of one drop to the surface of the affected eye 4 times daily for 2 weeks, a 2-week period during which the drops are not given, and a second 2-week course of treatment if there appears to be any clinically apparent residual intraepithelial disease. Most intraepithelial tumors of the stratified squamous epithelium respond favorably to this therapy. Topical chemotherapy is not considered appropriate for deeply invasive epithelial neoplasms of the stratified squamous epithelium of the conjunctiva and cornea.
An alternative to topical chemotherapy that has been used in selected patients with CIN and residual intraepithelial conjunctival neoplasia of the bulbar conjunctiva is topical immunotherapy with interferon alfa-2b. This therapy appears to provide results similar to topical chemotherapy but may be less toxic to the normal epithelium or the cornea and conjunctiva.
Contact radiation therapy with high–dose rate strontium-90 applicators or moderate-to-low–dose rate temporary ruthenium-106 or iodine-125 plaques is used occasionally to treat both incompletely excised and recurrent invasive carcinomas of the stratified squamous epithelium of the conjunctiva.  It is an effective therapy when tumor extends deeply into the lamellar cornea or sclera at the limbus and is incompletely excised. Treatment generally targets the eye wall to receive approximately 60?Gy at 1?mm depth. The selected applicator or plaque must cover the entire area to be treated. Consequently, contact radiation therapy is not usually employed to treat diffuse or multifocal conjunctival intraepithelial disease. One potential complication of contact radiation therapy is corneoscleral breakdown at the treatment site due to disintegration of an extensive tumor infiltrate that has replaced the eye wall tissue, tissue necrosis induced by the radiation, tissue breakdown attributable to collagenases and other factors acting on the bare sclera following loss of conjunctiva, or some combination of these factors.
Enucleation usually is advised when a malignant neoplasm of the stratified squamous epithelium of the conjunctiva and cornea has invaded through the cornea or sclera into the eye. Although a few patients with intraocular invasion have undergone successful eye wall resection with placement of a scleral or
corneoscleral patch graft, most such procedures have not been successful long term. Exenteration usually is recommended when an epibulbar neoplasm of the conjunctival stratified squamous epithelium has invaded the anterior orbit. Such surgery can eliminate residual or recurrent tumor, but local failures frequently occur even following this aggressive intervention.
COURSE AND OUTCOMES
Patients whose tumors of the stratified squamous epithelium of the conjunctiva and cornea are excised completely by histopathological criteria are usually cured.    In contrast, patients whose tumors are excised incompletely have a substantial risk of local tumor recurrence. Because of this, virtually all patients with incompletely excised malignant neoplasms of the stratified squamous epithelium of the conjunctiva and cornea are advised to undergo supplemental treatment (e.g., wider excision, cryotherapy, contact radiation therapy, topical chemotherapy). Patients who experience a local relapse of their epibulbar neoplasia of stratified squamous epithelium are much less likely to be cured by local treatment than are patients who do not.
As mentioned above, aggressive malignant neoplasms of the conjunctiva and cornea occasionally invade the eye or the orbit. These advanced forms of the disease typically require enucleation or exenteration for cancer eradication. Mucoepidermoid carcinoma is a form of neoplasia of the stratified squamous epithelium of the conjunctiva that is particularly aggressive and most frequently requires enucleation or exenteration. 
Although metastasis of malignant neoplasms of the conjunctiva and cornea occurs infrequently, it is observed in occasional advanced cases due to patient neglect and in persons with extremely aggressive tumors. Patients with concurrent AIDS are particularly likely to exhibit rapidly progressive malignant neoplasms of the conjunctival and corneal stratified squamous epithelium and metastasis of those neoplasms. Tumors arising from the temporal limbal area most frequently metastasize initially to preauricular lymph nodes, while those arising from the medial limbal area most frequently metastasize initially to the anterior cervical lymph nodes.