Topical interferon alpha 2 beta therapy in the management of conjunctival papilloma

Falco, Laura A.; Gruosso, Paul J.; Skolnick, Keith; Bejar, Lorena

doi:10.1016/j.optm.2006.10.017

« Previous Next »Optometry - Journal of the American Optometric Association
Volume 78, Issue 4 , Pages 162-166, April 2007

Topical interferon alpha 2 beta therapy in the management of conjunctival papilloma

Article Outline

Abstract
Case
Discussion
Conclusion
References
Copyright

Abstract

Background

This article describes the differential diagnosis of conjunctival papillomas and reviews the treatment options with a focus on the new topical interferon alpha 2 beta therapy.

Case

A 45-year-old white man presented with a red right eye of approximately 6 months’ duration. The lesion was suspicious and suggestive of malignancy; therefore, the patient was referred for consultation. The lesion was diagnosed as a conjunctival papilloma. The patient was placed on topical interferon alpha 2 beta eye drops, and within 2 weeks he experienced complete lesion regression.

Conclusion

Interferons, in particular interferon alpha-2b (IFN-α2β), have recently been shown to be successful in treating conjunctival papillomas and conjunctival intraepithelial neoplasia (CIN). Previously, treatment was limited to observation for asymptomatic patients. Larger lesions in symptomatic patients were treated by surgical excision and cryotherapy. Additional treatment modalities included topical antimetabolite treatment with mitomycin-C and 5-fluorouracil. These treatments, although effective, had significant attendant postsurgical complications and toxic ocular adverse reactions. Interferons represent a new successful treatment modality.

Keywords: Conjunctival papilloma, Interferon alpha 2 beta therapy, Conjunctival lesions, Conjunctival intraepithelial neoplasia, Pyogenic granuloma, Squamous cell carcinoma

Primary eye care practitioners encounter numerous growths on the ocular surface and adnexa. Most are benign, although cosmetic concerns or structural compromise may necessitate their removal. However, some lesions require extra vigilance and care because of malignant potential. This article focuses on topical interferon therapy for conjunctival papillomas.

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Case

A 45-year-old white man presented with a red right eye. He reported that 6 months previously he accidentally got paint in his eye, with subsequent redness and irritation. The patient reported that the condition became progressively worse. He reported using Visine (Johnson and Johnson, New Brunswick, New Jersey) in the affected eye in the mornings for redness with little relief. The patient’s medical history was negative for any type of cancer or new skin growths. He reported that he was not taking any systemic medications at the time, and there was no history of any surgical procedures.

Best-corrected visual acuities were 20 /20 in the right eye (O.D.) and the left eye (O.S.). Pupil testing, confrontation visual fields, and extraocular motilities were unremarkable. Biomicroscopy of the anterior segment of the right eye found a large, heavily vascularized growth that appeared to be consistent with a conjunctival papilloma. However, what made this presentation atypical was that the borders were not clearly delineated, and it did not have a uniform evenly spaced vasculature. In addition, there was a small pustule in the center of the lesion that may have been indicative of a concurrent bacterial infection overlying the papilloma. Intraocular pressures measured via Goldmann applanation tonometry were 17 mmHg both O.D. and O.S. There were no other biomicroscopic abnormalities in either eye (see Figure 1).

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Figure 1.
Appearance of the lesion before treatment in different gazes.

Dilated fundus examination showed pink and distinct optic nerve heads, flat maculae, and unremarkable peripheral retinal views in each eye. A 1-disc diameter flat choroidal nevus was located in the posterior pole of the right eye with distinct borders and no lipofuscin deposits or other findings suggestive of malignancy.

Because of the patient’s chronic, unremitting symptoms, as well as mild concern about the lesion’s ill-defined borders and atypical vascularity, it was recommended that he have the papilloma removed. Initially for management, he was prescribed topical interferon alpha 2 beta (IFN-α2β) eye drops at a concentration of 1 million units per cubic centimeter (cc) 4 times a day O.D. He was concurrently placed on a 10-day, 4 times a day course of Polytrim (polymyxin B sulfate and trimethoprim; Allergan, Irvine, California) ophthalmic solution. Per the discretion of the treating ophthalmologist, the patient was advised if the lesion did not respond to topical management, an excisional biopsy would be necessary. Because of the success rate of interferon therapy and the less invasive treatment modality, an excisional biopsy was not ordered by the treating ophthalmologist.

After 2 weeks of using the topical interferon, the entire conjunctival papilloma showed impressive regression. In that location, all that remained was a small pinguecula with slight epithelial haze (see Figure 2). The patient is currently scheduled for appropriate periodic evaluation.

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Figure 2.
Appearance of the lesion after treatment in different gazes.

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Discussion

Conjunctival tumors are generally categorized as either acquired or congenital. They can then be further categorized based on the origin of the mass. They can span the spectrum from benign to malignant and life threatening. Patients will present with a wide spectrum of symptoms secondary to these lesions, ranging from being asymptomatic to a foreign body sensation with dry eye complaints, depending on the size and location of the lesion. Dry eye symptoms and irritation are more likely if normal lid structure and function are compromised. Patients may also complain of the cosmetic appearance of the lesion.

Epithelial and stromal cells comprise the conjunctiva, and tumors can develop from either cell layer. Unique to the conjuctiva is that it is visible and exposed to ultraviolet rays, which can affect the development of certain types of tumors. Because these tumors can be inspected closely during slit lamp biomicroscopy, often a diagnosis can be reached by clinical observation when the clinician is familiar with hallmark signs of certain tumors.¹ When evaluating a conjunctival papilloma, it is important to include pertinent differential diagnoses including conjunctival intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), phlyctenular keratoconjunctivitis, and pyogenic granuloma (see Table 1).

Table 1. Differential diagnoses of conjunctival papillomas

Type of growth	Gross appearance	Adhesion to sclera	Linked to human papilloma virus	Standard treatment	Recurrence rate
CIN	Leukoplakic gelatinous lesion with a translucent leading edge¹	Loose, will move freely upon palpation¹	Yes, types 16 and 18¹⁵^,16	Complete surgical excision followed by supplemental cryotherapy¹, ¹³, ¹⁴	Up to 56% if not completely excised; however, it is a precancerous lesion¹³, ¹⁴
SCC	Develops in the interpalpebral space usually from prolonged sun exposure, fleshy and elevated appearance with leukoplakic plaques on the surface. Heavily vascularized and asymmetrical with irregular borders, large feeder vessel common.¹	Because of the invasion of the lesion into the deeper stromal tissue, it will not move freely upon palpation¹	Yes, types 16 and 18¹⁵^,16	Surgical excision with supplemental cryotherapy, large area of tissue needs to be removed to ensure the removal of the entire lesion¹, ¹³, ¹⁴	Locally destructive and can metastasize to distant sites if left untreated¹³, ¹⁴
Pyogenic granuloma	Elevated, red mass with extensive vascularization¹	Usually loose	No	Corticosteroids, if necessary surgical intervention¹	Usually not a problem because it is a benign proliferative fibrovascular response to a previous chemical injury, burn or trauma¹
Phlyctenular keratoconjunctivitis	Single or multiple pinkish conjunctival or limbal nodules surrounded by discreet conjunctival hyperemia, commonly develops ulcerative necrotic center, usually occurring as an allergic hypersensitivity response of the cornea. Ropelike mucopurulent discharge may be present.		No	Mild cases require lid hygiene, moderate cases require an antibiotic or antibiotic steroid combination. Cycloplegia may be necessary if there is significant inflammation present. Treatment is continued for 2 to 4 weeks, and the steroid tapered.	Can be frequent depending on causative antigen (ex. staphylococcus blepharitis)

Conjunctival papilloma is a benign tumor arising from the squamous epithelium and does not typically have a propensity to convert to a malignant growth. It commonly appears as pink fibrovascular fronds that can be either sessile (broad-based attachment) or pedunculated (stalklike). These lesions are typically symmetric with evenly spaced vasculature and defined borders. The epithelial surface is typically a transparent covering that has a glistening appearance. The most common location for this growth is in the inferior fornix.¹

Pedunculated papillomas are commonly described as resembling a cauliflower, whereas the sessile version has a more spongy or fleshy appearance. Most papillomas will show loose adhesion to the underlying sclera on palpation, indicating that the lesion has not spread into or through that tissue. The development of conjunctival papillomas is strongly associated with the human papilloma virus (types 6 and 11), which is spread by direct contact.¹, ², ³, ⁴ In addition, the loss of the P53 protein function has recently been correlated to tumor development.⁵ These growths can be found in both children and adults. The adult papillomas have more of a tendency to exhibit features that mimic a squamous cell carcinoma by invading the corneal tissue, appearing like an advancing hazy edge. These lesions will possess an extensive blood supply containing multiple vascularized papillary fronds.¹

In the past, treatment for conjunctival papilloma was limited to observation for asymptomatic patients because of the high rate of spontaneous resolution and reoccurrence. Patients with larger lesions and symptoms were treated by surgical excision and cryotherapy. Recurrence, or regrowth, is a high probability if the entire lesion is not removed. With unclear margins, removing the entire lesion is difficult, especially in CIN and SCC. Subsequent surgery would increase the chance of corneal and conjunctival cicatricial changes and infection. Fixation difficulties, such as nystagmus, previous surgical procedures, including laser in situ keratomileusis or filtering blebs, are contraindications to surgical excision.¹ A sect of patients always exists that are just uncomfortable with surgical intervention. Additional treatment modalities for conjunctival lesions include topical antimetabolite treatment with mitomycin-C or 5-fluorouracil.¹, ⁶, ⁷, ⁸ Mitomycin-C and 5-fluorouracil have been shown to be effective, especially when used in conjunction with surgery. However, antimetabolite therapy is toxic to the eye and can cause pain, conjunctivitis, corneal erosions, hyperemia, punctate keratopathy, allergic reactions, punctal stenosis, and possibly scleral melts.¹, ⁶, ⁷, ⁸

A relatively new addition to the treatment armamentarium for conjunctival lesions is a topical solution of IFN-α2β.¹, ⁹, ¹⁰, ¹¹, ¹² Interferons, in particular IFN-α2β, have recently been shown to be successful in treating conjunctival papillomas and CIN.⁹, ¹⁰, ¹¹, ¹² Interferons are produced naturally by the body in response to viral infections and tumors. They are also responsible for regulating immunity. The body makes three different kinds of interferon; alpha, beta, and gamma. They are a family of glycoprotein molecules that act as cell surface receptors to produce antiviral and antiproliferative effects, although the exact mechanism of action of the interferons is unknown.

Systemic treatments with interferons have caused minor side effects including flulike symptoms and myalgias. Interestingly, nonproliferative retinopathy can develop in some patients from these medicines (personal experience). No adverse reactions have been noted with the topical use of interferons.⁹, ¹⁰, ¹¹ Another advantage of effective topical therapy is that the entire ocular surface is treated. This is especially important in multiple lesions or spreading multifocal lesions. Topical interferon therapy is being utilized as a single therapeutic agent for CIN and recurrent corneal neoplasia as well.⁹, ¹⁰ Interferon therapy does not carry the adverse topical reactions as seen in antimetabolite therapy and does not pose the risks associated with ocular surgery. Interferon therapy does not have to be used as sole treatment; it can be used as adjunctive therapy when surgical excision cannot ensure a tumor-free margin.

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Conclusion

The patient in this case was treated empirically with IFN-α2b. The working diagnosis was conjunctival papilloma (with possible concurrent bacterial infection) versus CIN. If the lesion had not shown improvement with the interferon therapy, then a biopsy was planned. Fortunately, within the first 2 weeks of treatment, the lesion completely resolved (see Figure 2). IFN-α2b was well tolerated, and the patient did not complain of any side effects. Interferons are not widely available, and we were fortunate to obtain the medication. This case shows that topical interferon therapy can be an efficacious and safe treatment option before surgical intervention. Hopefully, in the future, these drops will be more widely available.

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References

Shields J, Shields C. Tumors of conjunctiva and cornea. Surv Ophthalmol. 2004;49:3–24

Sjo NC, Heegaard S, Prause JU, et al. Human papillomavirus in conjunctival papilloma. Br J Ophthalmol. 2001;85:785–787

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Khong JJ, Muecke J. Complication of mitomycin C therapy in 100 eyes with ocular surface neoplasia. Br J Ophthalmol. 2006;90(7):819–822

Prabhasawat P, Tarinvorakukp P, Tesavibul N, et al. Topical 0.002% mitomycin C for the treatment of conjunctival-corneal intraepithelial neoplasia and squamous cell carcinoma. Cornea. 2005;24(4):443–448

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Karp C, Moore J, Rosa R. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon ά 2 β. Ophthalmology. 2001;108(6):1093–1098

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Schechter B, Rand W, Velazquez G, et al. Treatment of conjunctival papillomata with topical interferon ά 2 β. Am J Ophthalmol. 2002;134(2):268–270

Chen HC, Chang SW, Huang SF. Adjunctive treatment with interferon alpha–2b may decrease the risk of papilloma-associated conjunctival intraepithelial neoplasm recurrence. Cornea. 2004;23(7):726–729

Digital Reference of Ophthalmology. Cornea and external diseases, infectious. Available at: http://dro.hs.columbia.edu/phlyctenular/htm. Last accessed October 12, 2006.
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