therapeutic insights
Battling Conjunctival Tumors
A new medication takes us beyond surgical management.
by Kathryn D. Nelson, O.D.

We've all frequently seen and managed pinguecula and pterygia -- especially in sunny climates. But it's important to differentiate these common conjunctival degenerative conditions from the less common, less benign conjunctival tumors, in which excision is a necessity rather than a luxury. But is excision really necessary? The use of new topical medical therapy for conjunctival tumors is on the rise as an adjunctive treatment with surgery and, sometimes, as the primary therapy for recurrent disease.

CIN runs the gamut

Corneal and conjunctival intraepithelial neoplasia (CIN) is a precancerous lesion of the ocular surface. It is reported to be the most common conjunctival malignancy in the United States and the third most common ocular tumor in the older population. Typically found in Caucasian men in their mid-60s, these lesions almost always arise near the limbus in the interpalpebral area and may spread to involve the cornea.

Figure 1: Typical raised gelatinous appearance of CIN
Figure 2: Extensive pagetoid spread onto the cornea

Know the enemy

CIN is composed of dysplastic and thickened epithelial cells, with increased cell proliferation and irregularity of the individual epithelial cells. Depending on the extent of epithelium involved and the degree of cellular atypia, we can grade histopathological changes as mild, moderate or severe. We term the lesion "carcinoma in situ" when it shows full-thickness epithelial involvement. Finally, when tumor cells invade the epithelial basement membrane and substantia propria, the lesion becomes an invasive squamous cell carcinoma (SCC) and the patient is at risk for metastatic disease.

The signs of four

CIN, carcinoma in situ and invasive SCC are difficult to distinguish on clinical examination because of the variability in their appearance. All have four common clinical presentations:

1. A raised, gelatinous mass that may appear gray or slightly red, depending on the vascularity

2. A leukoplakic or white, plaque-like lesion

3. A papilloma-like lesion

4. Pagetoid spread onto the cornea appearing as an opaque, frosted membranous-like tissue covering the corneal peripheral surface.

CIN lesions stain with Rose Bengal, which may help delineate the extent of the abnormal tissue margin. You can also use Rose Bengal to distinguish between CIN and pterygium or pannus. The CIN lesion should move freely over the underlying episcleral tissue, whereas invasive SCC has deeper involvement and is fixed to the underlying tissue. Also, invasive SCC tends to appear larger and more vascular. You can see prominent feeder vessels in both CIN and SCC.

Etiological considerations

Researchers have identified excessive ultraviolet light exposure as a major risk factor in the development of CIN. Other causative factors may include petroleum products, heavy cigarette smoking, light-colored hair and ocular pigmentation, living in an equatorial region, racial origin (especially the British Isles, Austria and Switzerland), and viral infection, including herpes simplex type I, human papillomavirus (HPV) and HIV.

In younger patients who have CIN and who have no other risk factors, suspect HIV and conduct appropriate serological tests. HPV types 16 and 18 have been associated with a similar disease of intraepithelial neoplasia of the uterine cervix. DNA from HPV types 16 and 18 has been demonstrated in both benign and malignant cervical and conjunctival lesions, providing strong evidence for an etiologic role of HPV in the development of CIN.

Surgically speaking

Traditional management of CIN is surgical excision with cryotherapy; however incomplete excision carries a significant rate of recurrence of up to 56%. Recurrence rates drop to 5% when you achieve complete excision. Repeated surgeries and the removal of considerable ocular surface tissue can result in limbal stem cell deficiency and subsequent conjunctival scarring with symblepharon formation. Also, in glaucoma patients who have filtering blebs, avoid conjunctival manipulation.

Certain other patients aren't ideal candidates for surgery either. For all of these reasons, researchers are investigating other alternatives for the treatment of CIN, including the topical chemotherapeutic agents mitomycin C (MMC) and 5-fluorouracil (5-fu), and perilesional and topical interferon alpha 2b (IFN_2b).

The wave of the future

Interferons are a family of glycoprotein molecules that act as cell surface receptors to produce antiviral and antiproliferative effects. Because CIN is a neoplasia with a possible viral etiologic component, interferon is theoretically appealing as a treatment modality. Although we don't know the exact mechanism of action of the interferons, the FDA has approved the recombinant form of IFN_2b for the treatment of chronic hepatitis B and C, condylomata acuminata, malignant melanoma, follicular lymphoma, autoimmune deficiency syndrome-related Kaposi's sarcoma and hairy cell leukemia. It's also been reported effective for the treatment of cervical intraepithelial neoplasia, as well as SCC and basal cell carcinoma of the skin.

Karp et al. were the first to report a series of combined conjunctival perilesional injections and topical IFN_2b as effective in eliminating ocular surface neoplasia with no recurrence of the lesions. However, they noted that perilesional and subconjunctival injections caused systemic side effects of transient fevers and myalgias, flu-like symptoms lasting for two or three hours following the injections. Therefore, recent studies have explored the use of topical interferon for adjunctive therapy in recurrent CIN.

Presenting some proof

Michael Boehm and Andrew Huang at the University of Minnesota treated seven patients who had recurrent corneal and conjunctival intraepithelial neoplasia with topical IFN_2b drops (1 million IU/ml) q.i.d. until they noted lesion resolution. Results indicated that six of the seven patients had successful treatment, with an average time to resolution of the recurrent CIN of 14.5 weeks. The researchers didn't report any side effects in any patient.

They concluded that topical IFN_2b is an effective treatment of recurrent corneal and conjunctival intraepithelial neoplasia, offering the benefit of topical therapy and avoiding the risks of surgical or other ocular surface toxicity, cicatricial conjunctival changes and limbal stem cell deficiency. Other researchers show similar results. Topical interferon has minimal side effects that may include a follicular conjunctivitis. This is in contrast to topical MMC and 5-fu, which can cause significant ocular surface inflammation, pain and dry eye symptoms.

Interferon has a future

Topical IFN_2b has shown itself an effective single-agent therapy for CIN and may benefit patients who have small primary or recurrent disease or lesions that are not agreeable to complete surgical excision. Interferon may also play an important role in combination therapy with other medications or as an adjunctive treatment to surgical excision. Because recurrences of CIN can occur anywhere from 33 days to 11.5 years, long-term follow up is essential. Future studies with larger populations and longer follow-up periods will likely confirm the long-term efficacy and safety of topical IFN_2b in the treatment of corneal and conjunctival intraepithelial neoplasia.

Dr. Nelson is an optometry resident at Bascom Palmer Eye Institute in Miami. Contact her at Knelson@med.miami.edu.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.