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Man presents with chronic red eye and worsening vision
Examination demonstrated a temporal conjunctival lesion with adjacent perilimbal corneal epithelial lesions in the right eye.
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A 63-year-old man was referred to the New England Eye Center cornea department with a 4-month history of worsening vision in the right eye. The patient reported a 3-year history of right eye injection, which was associated with intermittent surface irritation and itch. He was treated by his local optometrist for presumed dry eye and used artificial tears as needed for symptomatic relief. Over the past few months, however, he noticed a gradual decrease in the vision of the right eye, which prompted a referral to an outside ophthalmologist.
On initial examination with the outside provider, the patient was thought to have a dendrite in the right eye and was started on systemic valacyclovir and topical ganciclovir for treatment of presumed herpes simplex virus keratitis. Unfortunately, the patient’s vision did not improve with treatment and he was therefore referred to NEEC for further management. He had a medical history of hypertension and hyperlipidemia, for which he took simvastatin and chlorthalidone. He was a nonsmoker.
Examination
Source: Aubrey R. Tirpack, MD, and Michael Goldstein, MD
Initial examination at NEEC revealed a best corrected visual acuity of 20/50 in the right eye and 20/25 in the left eye. Confrontational visual fields and extraocular movements were full bilaterally. Both pupils were briskly reactive without evidence of an afferent pupillary defect. IOPs were normal bilaterally. Slit lamp examination showed diffuse injection of the right temporal conjunctiva that extended to the limbus. The right cornea demonstrated multiple, discrete elevated white epithelial lesions with scalloped borders that stained diffusely with rose bengal (Figure 1). The left eye anterior segment examination was normal, without conjunctival or corneal lesions. Corneal sensation was mildly decreased in both eyes. No dendritic or pseudodendritic lesions were appreciated. The anterior chamber was quiet in both eyes. The patient had mild nuclear sclerotic cataracts. The posterior segment examination was normal.
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Unilateral corneal epithelial lesions
The differential diagnosis of the unilateral corneal epithelial lesions seen in our patient includes neoplastic, inflammatory, degenerative and infectious etiologies. Our patient’s chronic presentation with a multiple year history of red eye was concerning for neoplastic etiology, specifically ocular surface squamous neoplasia (OSSN) given the “frosted”-appearing epithelial lesions with scalloped borders, occurring adjacent to the interpalpebral limbus.
Other inflammatory causes of conjunctival injection and corneal opacification can be considered, including an inflamed pterygium, chronic blepharoconjunctivitis, limbal stem cell deficiency, or previous inflammation with anterior corneal stromal scarring. Degenerative conditions such as Salzmann nodular dystrophy and band keratopathy can present with anterior corneal opacification but are not typically associated with adjacent conjunctival injection. Infectious causes of corneal opacification, such as HSV infection, Acanthamoeba infection, and bacterial or fungal keratitis must be considered. Our patient did not demonstrate dendritic lesions or geographic ulceration classically seen in cases of HSV keratitis. Additionally, he did not have an epithelial defect or discrete infiltrates typically seen in cases of infectious keratitis. Thygeson’s superficial punctate keratopathy can demonstrate corneal intraepithelial opacities but would not have the conjunctival inflammation or lesion seen in our patient.
Diagnosis and management
Our patient’s clinical presentation was most concerning for OSSN, and therefore an excisional biopsy was recommended. Before the biopsy, the patient underwent anterior segment OCT imaging to better evaluate his corneal and conjunctival lesions (Figure 2). AS-OCT showed a thickened, hyperreflective corneal epithelial layer in the region of the corneal lesion. This further raised clinical suspicion for OSSN.
After informed consent, the patient underwent excisional biopsy of the temporal conjunctival lesion with double freeze-thaw cryotherapy and placement of an amniotic membrane graft with fibrin glue. He also underwent removal of his multiple corneal epithelial lesions with application of 20% alcohol and superficial keratectomy.
Pathology showed increased epithelial thickness with full-thickness dysplasia (Figure 3a). There was no evidence of penetration of Bowman’s layer. Staining with both Ki-67, a marker of cellular proliferation, and p63, a marker of squamous differentiation, showed diffuse uptake (Figures 3b and 3c). A diagnosis of conjunctival intraepithelial neoplasia was made based on the pathologic findings. Corneal biopsy also showed full-thickness dysplasia, confirming corneal involvement with no penetration of Bowman’s layer.
After biopsy, the patient was managed with a bandage contact lens and topical antibiotic and steroid drops. Once the corneal epithelial defect had healed, the antibiotic drops were discontinued. The patient was monitored closely and did require tapering of the steroid drops and initiation of topical glaucoma medications secondary to an elevation in IOP. Within 2 weeks of surgery, the patient was also started on interferon alfa-2b 1 million IU/mL four times a day given the diffuse corneal findings.
Discussion
Ocular surface squamous neoplasia is a term first used in 1995 to describe mild dysplasia to invasive squamous cell carcinoma of the cornea and/or conjunctiva. Given its broad terminology, many clinicians have favored a more specific description based on histopathologic findings. There are many known risk factors for the development of OSSN, including Caucasian race, pale skin or irides, a history of smoking or ultraviolet light exposure, increasing age and male gender. Certain systemic diseases are also known to predispose to the development of OSSN, including HIV infection, xeroderma pigmentosum and HPV infection.
Clinically, OSSN typically presents as a perilimbal lesion involving the conjunctiva, cornea or both. It commonly presents as an interpalpebral lesion adjacent to the limbus; however, its appearance can vary, thus requiring a high index of suspicion. Various forms have been described, including gelatinous, leukoplakic, papilliform, nodular and diffuse. Rose bengal, which stains devitalized epithelial cells, can be used to delineate the margins of the involved tissue. Classically, suspicious lesions are managed surgically with excisional biopsy using the “no-touch” technique, which allows for both diagnosis and treatment. A superficial keratectomy is required should the cornea be involved, and a partial sclerectomy can be performed if there is evidence of scleral involvement. Double freeze-thaw cryotherapy is used at the margins of the excised lesion to obliterate the microcirculation, leading to ischemic infarction and thus rendering potential residual tumor cells nonviable.
While traditional treatment of OSSN included excision alone, recurrence rates of up to 33% were reported in the literature by Tabin and colleagues despite clear margins on histopathology. This supported the theory of residual microscopic neoplastic cells that extended beyond the clinically identifiable margins. Adjuvant use of topical medical treatments for OSSN have shown significantly reduced rates of recurrence. Currently utilized therapies include interferon alfa-2b, 5-fluorouracil and mitomycin C. Interferon alfa-2b, a commonly used adjuvant therapy that was given in our patient’s case, is typically dosed at 1 million IU/mL four times a day for several months. It is generally well tolerated with a potential for follicular conjunctivitis, which may limit its use in certain patients. 5-fluorouracil 1% is dosed four times a day for 30-day cycles with the potential side effects of superficial punctate keratitis and conjunctivitis. MMC can also be used but is limited by its side effects, which include scleral melt, limbal stem cell deficiency, punctal stenosis and corneal erosions. In addition to these medications, there has been recent interest in topical anti-VEGF agents, which have shown promise in cases of recalcitrant OSSN. Additionally, current studies have investigated the use of topical chemotherapy for OSSN without surgical excision. Proponents cite the risks of surgical intervention, including limbal stem cell deficiency and symblepharon formation, and data that show comparable recurrence rates with the use of topical chemotherapy alone (Sturges and colleagues).
There has also been recent interest in the use of noninvasive technology in the diagnosis of OSSN. OCT, which has been revolutionary in the diagnosis and management of posterior segment diseases, has shown promise in anterior segment disease as well. OSSN demonstrates a characteristic appearance on AS-OCT, which can aid in diagnosis (Thomas and colleagues). OSSN typically shows a thickened, hyperreflective epithelial layer with an abrupt transition zone at the border of normal and abnormal tissue. This appearance on OCT can help differentiate OSSN from other similarly appearing clinical entities, such as pterygia, which show normal epithelial thickness with an underlying thickened hyperreflective subepithelium. While new technologies and treatments have shown promise in aiding in the management and diagnosis of OSSN, a high index of suspicion is still required to accurately diagnose this neoplasia.
Clinical course
Our patient continues to do well. He is currently continuing his interferon alfa-2b therapy. His topical steroids have been tapered off. He continues on glaucoma medications for management of IOP. His vision has improved to 20/30 in the operative eye, and he has noted resolution of his subjective blur and irritation. Repeat AS-OCT showed resolution of the thickened, hyperreflective epithelial layer seen preoperatively (Figure 4). He will continue to follow closely with our cornea department to monitor for signs of recurrent disease.
- References:
- Besley J, et al. Am J Ophthalmol. 2014;doi:10.1016/j.ajo.2013.10.012.
- Dandala PP, et al. J Clin Diagn Res. 2015;doi:10.7860/JCDR/2015/16207.6791.
- Kiire CA, et al. Int Ophthalmol Clin. 2010;doi:10.1097/IIO.0b013e3181e246e5.
- Margo CE, et al. Eye (Lond). 2014;doi:10.1038/eye.2014.62.
- Nanji AA, et al. Curr Opin Ophthalmol. 2013;doi:10.1097/ICU.0b013e3283622a13.
- Sturges A, et al. Ophthalmology. 2008;doi:10.1016/j.ophtha.2008.01.006.
- Tabin G, et al. Ophthalmology. 1997;doi:10.1016/S0161-6420(97)30287-5.
- Thomas BJ, et al. Ocul Surf. 2014;doi:10.1016/j.jtos.2013.11.001.
- For more information:
- Aubrey R. Tirpack, MD, and Michael Goldstein, MD, can be reached at New England Eye Center, Tufts University School of Medicine. 800 Washington Street, Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Aubrey R. Tirpack, MD, and Astrid C. Werner, MD. They can be reached at the New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.