At 52 years of age, Peter Jenkins* was leading a busy life. He worked hard as a tile salesman and, in his spare time, enjoyed golf and basking in the sun. Hence, the Florida native was not pleased when he first started to notice that his right eye was photophobic and increasingly felt irritated. Upon looking at the eye in the mirror, he noticed a “small white bump” located nasally on the peripheral limbal surface. Although initially he was not overly concerned, over the next six months the lesion continued to grow until it encompassed more than half of the peripheral limbus. It was at this point that we became acquainted with Mr. Jenkins.
We Get a Look
Mr. Jenkins’ medical history was significant only for insomnia and depression. Consequently, he was taking bupropion hydrochloride (Wellbutrin) and trazodone hydrochloride (Desyrel). He had no history of sexually transmitted diseases, skin cancers, papilloma or other cancers. His family history was unremarkable. He was a 25-pack-a-year smoker.
On ocular examination, visual acuity was 20/25 in the right eye and 20/20 in the left eye. Confrontation fields and motility were normal. External examination revealed rosacea. There was no afferent pupillary defect.
Biomicroscopy of the right eye revealed a normal everted lid. There was a limbal and corneal lesion extending from approximately the 11 o’clock to the 8 o’clock position (Figure 1). It involved the peripheral limbus and extended approximately 4 mm onto the corneal surface. At the limbal area, it had a papillary feature and the corneal portion was opalescent and leukoplakic (Figure 2). The central cornea was clear. Dilated fundus examination revealed normal optic disc, macula, vessels and periphery.
The left eye was normal.
His intraocular pressure was 21 mmHg in the right eye and 19 mmHg in the left. No enlarged preauricular or submandibular lymph nodes were appreciable on palpation bilaterally.
Many etiologies needed to be included in the differential diagnosis. Conjunctival and corneal intraepithelial neoplasia and squamous cell carcinoma were certainly possible offenders.
In addition, etiologies such as an inflamed pinguecula or pterygium and inflammatory pannus were considered. Nodular conjunctivitis, phlyctenulosis and keratoacanthoma also seemed like plausible causes (although the latter of the three usually progresses more rapidly).
In order to reach a firm conclusion, we took a biopsy of the lesion.
What’s Your Diagnosis?
AT THE BIOMICROSCOPE. (Figure 1) We observe a limbal and corneal lesion from approximately the 11 o’clock to the 8 o’clock position. It extends 4 mm onto the corneal surface. (Figure 2) Note the papillary features at the limbus. The corneal portion of the lesion is opalescent and leukoplakic. The central cornea is clear.
Biopsy. (Figure 3) H & E staining with 20x magnification discloses faulty epithelial maturational sequencing extending to full thickness (carcinoma in situ). No invasion into the substantia propria is present. (Figure 4) He showed successful response after six treatments of weekly intralesional interferon injections.
Pathologic examination of the specimen revealed the presence of a carcinoma in situ conjunctival and corneal intraepithelial neoplasia (CIN) (Figure 3).
The epithelium contained faulty epithelial maturational sequencing that extended to full thickness. Foci of cellular and nuclear atypia, including dyskeratosis, were identified. No invasion was identifiable. He was negative for HIV Ab.
CIN is most prevalent in elderly individuals. In the United States it is the most frequent tumor of the conjunctiva.1 Coined in 1978 by Pizzarello and Jakobiec, the term CIN is synonymous with Bowen’s disease, intraepithelial epithelioma and carcinoma in situ.1 (The acronym, incidentally, also can refer to cervical intraepithelial neoplasia.)
Risk factors. The condition’s potential risk factors include ultraviolet light exposure, human papillomavirus infection, human immunodeficiency virus infection, petroleum product exposure and cigarette smoking.1,2
Symptoms. Clinically, CIN presents with a foreign body sensation, redness and irritation that is accompanied by an ocular surface mass. The growth traditionally can include elevated papillary and gelatinous features, as well as leukoplakic lesions due to keratinization.1 Most CIN lesions arise in the interpalpebral conjunctiva at the limbus and are mobile over the sclera. The corneal surface can take on a grayish, frosted, opaque epithelial appearance in either a geographic distribution or a discontinuous pattern. Rose Bengal dye can help determine a lesion’s surface boundaries.
Disease course. CIN lies on the same spectrum of dysplastic disease as squamous cell carcinoma (SCC) , which is now often referred to as ocular surface squamous neoplasia (OSSN). Although the disease usually has a slow progression, it should be dealt with swiftly when found, as it can lead to pain, vision loss, tumor extension and, rarely, metastasis, and may warrant enucleation. The rate of metastases to the parotid gland and cervical lymph nodes is less than 5 percent and, thankfully, more distant metastasis is even rarer.1
Notably, since it is difficult to differentiate CIN from SCC on clinical evaluation alone, a biopsy is necessary.
Treatment options. Conventionally, surgical excision with cryotherapy has been used to treat CIN. This is associated with a 56 percent rate of recurrence, in cases of incomplete excision, and between a 5 and 33 percent recurrence in cases of complete excision.3 There are drawbacks to extensive and recurrent ocular surgery, such as the loss of limbal stem cells and the obliteration of normal conjunctiva. As a result, in recent years, alternative modalities for primary treatment have been developed. These include radiation, mitomycin-C, 5-fluorouracil and interferon alfa-2b (IFNa2b).
Because of the significant degree of limbal involvement and past experience and successes with this agent, we treated Mr. Jenkins with IFNa2b.
Use of Interferon Alfa-2b
Interferons have antiviral properties and inhibit tumor growth by increasing cell cycle length, diminishing necessary metabolites and catalyzing cell lysis.1
INFa2b is a recombinant form that has been approved by the FDA for condylomata acuminatum, hepatitis B and C, hairy cell leukemia, AIDS-associated Kaposi’s sarcoma, follicular lymphoma and malignant melanoma.1,2
Since CIN is a tumor that is potentially virally mediated, use of interferon has shown promise. In over 20 reported cases of its use, every patient has achieved clinical resolution without recurrence at one year follow-up.1 It has been used in the form of subconjunctival injections alone, subconjunctival injections combined with topical IFNa2b, and topical drops alone.
Karp et. al found in a series of five patients that the average time to clinical resolution using topical IFNa2b was 11.6 weeks,2 which they report is longer than the 4.5-week period noted for resolution with a combination of topical eyedrops (1 million IU/ml four times a day) and intralesional injections (3 million IU in 0.5 ml).2
Subconjunctival/ intralesional injections of interferon can induce systemic side effects, most frequently transient fevers and myalgias, while topical interferon has resulted in follicular conjunctivitis.
Mr. Jenkins’ Case
For Mr. Jenkins, we used subconjunctival injections alone. He received weekly injections of 3 million IU in 0.5 ml. After six weeks, his CIN had clinically resolved (Figure 4) and he returned to playing the game he loves: golf. * Patient name is fictitious.
1 Vann, R. R. and C. L. Karp. Ophthalmology
2 Karp, C. L. et al. Ophthalmology
3 Tabin, G. et al. Ophthalmology
Dr. Karp is professor of clinical ophthalmology at the University of Miami.
Dr. Bhui is a resident at the University of British Columbia at Vancouver.