Man reports decreased vision, foreign body sensation

A vascularized, dysplastic-appearing pannus was found on clinical examination.

Priti Batta

Namrata Nandakumar

A 74-year-old man presented to clinic with a chief complaint of decreased vision and foreign body sensation in his right eye for the past 6 months. He denied any pain associated with these symptoms. He had previously been diagnosed and treated by an outside ophthalmologist for keratoconjunctivitis sicca, as well as a corneal dystrophy leading to recurrent erosions. He was referred to the Lahey Clinic Department of Ophthalmology due to a rapidly vascularizing cornea resistant to treatment with dexamethasone-tobramycin ointment and cyclosporine eye drops.

His ocular history included cataract extraction in both eyes, ectropion in the right eye and rosacea blepharitis in both eyes. His medical history included diet-controlled diabetes mellitus type 2, hypercholesterolemia and arthritis. Review of systems was negative. Medications at the time of presentation included aspirin, atorvastatin, amlodipine, benazepril and alfuzosin. He reported enjoying frequent outdoor activities as a retiree.

Examination

On general examination, the patient was noted to be a very fair-skinned individual. Uncorrected visual acuity was 20/300 in the right eye and 20/40 in the left eye. Pupillary exam was normal with no afferent pupillary defect, and extraocular movements were full in both eyes. External and slit lamp examination of the eyelids showed lid laxity, lid margin telangiectasias and meibomian gland inspissation in both eyes. Notably, in the patient’s right eye, slit lamp examination of the anterior segment showed 2+ conjunctival injection, thickened limbal tissue, a vascularizing pannus, as well as a central epithelial defect (Figure 1). The tarsal conjunctiva and remainder of bulbar conjunctiva were unremarkable. Anterior segment exam of the left eye was within normal limits. Dilated fundus exam was unremarkable in both eyes.

Figure 1. Right eye showing 2+ conjunctival injection, thickened dysplastic limbal tissue, vascularizing pannus, as well as central epithelial defect. Images: Cox C and Soukiasian SH

What is your diagnosis?

Vascularizing pannus, epithelial defect

The differential diagnosis for a patient with a vascularizing pannus and accompanying epithelial defect may include inflammatory, infectious or neoplastic etiologies.

Our patient had been previously diagnosed with rosacea blepharitis, an inflammatory condition of the eyelids, which in combination with keratoconjunctivitis sicca was suspected to be the underlying cause of his dystrophy-like corneal changes. Frequent corneal exposure was also suspected because the patient was noted to have significant lid laxity. A persistent and severe inflammatory state may exist when uncontrolled blepharitis is exacerbated by lack of lubrication and corneal exposure. In such cases, it is possible for corneal surface decompensation to occur, as well as for other potentially sight-threatening conditions to occur, such as limbal stem cell deficiency.

Infectious etiologies leading to a vascularizing pannus and epithelial defect may include viral agents responsible for neurotrophic corneal disease. Such viruses include those in the herpes family, most notably herpes simplex and herpes zoster virus. Persistent epithelial defects caused by frequent corneal insult may contribute to significant corneal surface disease, and in such cases, a vascularizing pannus may ultimately develop.

Our patient presented with a thickened vascularizing pannus that appeared dysplastic, thereby raising our suspicion for a neoplastic etiology. Given his close follow-up with an outside ophthalmologist, it was known that this pannus-like tissue had progressed at a rapid rate and had been resistant to aggressive lubrication plus steroids. Furthermore, the rapidly progressive and distinctly unilateral findings were not consistent with a corneal dystrophy because corneal dystrophies are hereditary and therefore typically present bilaterally. Similarly, it is unlikely that rosacea blepharitis presenting bilaterally would lead to severe vascularizing pannus in only one eye.

Corneal/conjunctival intraepithelial neoplasia (CIN) is a precursor to squamous cell carcinoma, one of the most common types of primary ocular neoplasms seen in clinical practice. Our patient presented with a number of risk factors, including age, gender, fair skin and frequent outdoor activities. Due to the lesion’s appearance and above risk factors, CIN was highest on our differential. Alternatively, sebaceous gland carcinoma was considered because the pagetoid variant can mimic CIN by presenting as flat and diffuse in appearance. Sebaceous gland carcinoma is much less common, however, and usually involves both tarsal and bulbar conjunctiva. Our patient had dysplastic tissue at the limbus and corneal surface only, making it much less characteristic in appearance for this alternative diagnosis.

Diagnosis and management

To rule out possible viral infection, ocular herpes simplex culture was obtained and was found to be negative. A biopsy was performed within 2 weeks of initial examination in order to assess for neoplastic disease. During this procedure, blunt subepithelial lamellar dissection of the cornea was performed, with care not to disrupt Bowman’s layer. Four tissue samples were removed, including two conjunctival biopsies to assess for subclinical disease and two 3-mm sections of pannus-like tissue extending from the limbus to the central corneal epithelium. Samples were sent both in fresh solution, to assess for sebaceous gland carcinoma, and in formalin, to assess for CIN/squamous cell carcinoma. A bandage contact lens and pressure patch were applied to facilitate healing.

As was initially suspected, each 3-mm section of pannus-like tissue taken from the corneal epithelium indicated the presence of in situ CIN. No invasive tumor was seen. Conjunctival biopsies showed fibrosis and low-grade actinic atypia only.

Given the patient’s confirmed diagnosis and relatively diffuse disease, he was started on topical interferon alpha-2b (1 million international units, four times per day). At 2-week follow-up, his epithelial defect had completely healed and his eye appeared much less inflamed. After 3 months of topical interferon treatment, all evidence of dysplastic limbal tissue had regressed except for mild peripheral and central corneal haze. His uncorrected vision had improved to 20/60 in the right eye, and he reported complete resolution of symptoms (Figure 2).

Figure 2. Regression of tumor over 3 months of treatment with interferon alpha-2b.

The most common symptoms in CIN — also referred to as ocular surface squamous neoplasia — include foreign body sensation, tearing, redness and decreased vision. Risk factors for CIN include age older than 60 years, male gender, fair hair and/or skin, frequent ultraviolet light exposure, cigarette smoking and, in some reports, viral infection with HPV 16 or 18.

On histopathological analysis, CIN is graded as mild (CIN 1), moderate (CIN 2) or severe (CIN 3), depending on extension of dysplastic tissue into the corneal or conjunctival epithelium. Mild CIN includes the lower third, moderate CIN includes the middle third and severe CIN includes the upper third of epithelial layers. Full-thickness CIN, or carcinoma in situ, implies involvement of all epithelial layers, with basement membrane remaining intact. CIN is considered invasive when this basement membrane is violated and dysplastic tissue extends into corneal stroma. Invasive CIN is also referred to as squamous cell carcinoma and has the potential for malignant spread. During our patient’s biopsy procedure, extra care was taken not to disrupt Bowman’s layer in order to prevent seeding and spread of dysplastic cells. Malignant squamous cell carcinoma can spread to the eyelid, globe, orbit, adjacent paranasal sinus structures and/or brain, thereby requiring enucleation in some of the most severe cases. Dissemination and death by lymph node metastasis is extremely rare, but has been reported.

Management of CIN can include both topical and surgical treatments. Surgery involves local excision with the addition of cryotherapy because high recurrence rates, 30% to 50%, have been noted using excision alone. Topical treatment without excision is minimally invasive and therefore the treatment of choice in cases of more diffuse tumor growth. Topical agents include 5-fluorouracil, mitomycin C and interferon alpha-2b. Multiple side effects have been reported with the use of 5-fluorouracil and mitomycin C, including limbal stem cell deficiency. Interferon alpha-2b, on the other hand, is well-tolerated and has become the preferred agent for diffuse, microscopic disease. In cases of CIN tumor growth involving greater than four limbal clock hours, or in cases of tumor recurrence following local excision, interferon alpha-2b is an excellent treatment choice. Mean clinical regression has been reported to range from 4 to 22 weeks, although confocal microscopy has shown microscopic disease persisting for up to 1 to 2 months after complete resolution by slit lamp examination. Importantly, because recurrences have been reported up to 11.5 years after termination of treatment, close follow-up of CIN patients is essential.

References:

• Gabison EE, Labbé A, Brignole-Baudouin F, et al. Confocal biomicroscopy of corneal intraepithelial neoplasia regression following interferon alpha 2b treatment. Br J Ophthalmol. 2010;94(1):134-135.
• Galor A, Karp CL, Chhabra S, Barnes S, Alfonso EC. Topical interferon alpha-2b eye-drops for treatment of ocular surface squamous neoplasia: a dose comparison study. Br J Ophthalmol. 2010;94(5):551-554.
• Hirst LW, Axelsen RA, Schwab I. Pterygium and associated ocular surface squamous neoplasia. Arch Ophthalmol. 2009;127(1):31-32.
• Karp CL, Moor JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmology. 2001;108(6):1093-1098.
• Yanoff M, Duker JS. Ophthalmology. Elsevier; 2009:241-243.

• Catherine Cox, MD, and Sarkis H. Soukiasian, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; website: www.neec.com.

• Edited by Priti Batta, MD, and Namrata Nandakumar, MD. Drs. Batta and Nandakumar can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; website: www.neec.com.