Incidentally detected primary corneal squamous neoplasia in an elderly man presenting with cataract

Abstract

Primary corneal neoplasia (PCN) is a rare cancerous lesion of cornea usually encountered in elderly. The clinical symptoms are generally non-specific, with ocular irritation, redness, cosmetic disfigurement and varying degrees of visual disturbances depending on visual axis involvement. Corneal neoplasia is usually associated with surrounding conjunctival lesions and incidentally detected PCN is rarely encountered in clinical practice. Presently, we report a case of isolated unilateral PCN diagnosed incidentally in an elderly man presenting with cataract. In vivo confocal microscopy aided in its diagnosis after impression cytology was repeatedly negative. Cataract surgery was deferred and the patient was administered three cycles of mitomycin C 0.04% 4 times/day. The tumour margins receded as evident on clinical examination and on anterior segment optical coherence tomography. We discuss the role of various corneal imaging modalities in diagnosis and management of PCN besides highlighting importance of comprehensive slit-lamp examination in patients planned for cataract surgery.

Background

Primary corneal neoplasia (PCN) is a rare progressive cancerous lesion of cornea that is usually encountered in the elderly.^1–3 Although the aetiology remains unknown, PCN has been associated with excess ultraviolet exposure, infection of human papilloma virus, chemical exposure, contact lens wear and smoking. The abnormal epithelial cells in these lesions are considered to originate from the limbal stem/progenitor cell that failed to completely assume corneal type of epithelial cells differentiation and grow towards the central cornea thereby making them topographically closer to the limbal region.⁴ The clinical symptoms are generally non-specific, with ocular irritation, redness, cosmetic disfigurement and varying degrees of visual disturbances depending on the degree of visual axis involvement. The signs can vary from a distinct limbal lesion with associated neovascularisation to a grey avascular semitransparent thickened sheet of epithelium that gives cornea pearly or greyish white colour and lusterless surface. The PCN lesions tend to recur frequently after surgical excision and may require adjuvant chemotherapy for suppression of further growth of abnormal cells.

Presently, we report a case of unilateral, isolated PCN without associated limbal or conjunctival involvement that was diagnosed incidentally and managed medically in an elderly man. We also discuss the role of various corneal imaging modalities in its diagnosis and management.

Case presentation

An otherwise healthy 77-year-old man presented to us for cataract surgery in lieu of diminished vision in both eyes for 2 years. The patient did not have any risk factors for developing PCN, such as excess ultraviolet exposure, infection of human papilloma virus, exposure to chemicals, contact lens wear or smoking. Snellen’s visual acuity was 6/24 (improving to 6/6) in both eyes and could be easily attributed to grade 2 nuclear sclerosis induced myopic refraction (−1.5DS). Slit-lamp examination revealed bilateral nasal pannus formation (figure 1A) with underlying anterior stromal opacification (attributed to localised limbal stem cell deficiency). However, a more vigilant examination of right eye revealed a semitransparent 1.5 mm wide abnormal epithelium spanning the anterior corneal surface circumferentially clockwise from 1 o’clock to 5 o’clock (figure 1B, C). The lesion was located 4.7 mm from the limbus, was sharply demarcated from the adjacent nasal cornea by a serpiginous line and lacked any elevations, neovascularisation, associated limbal or conjunctival lesion or fluorescein staining. The vessels in the nasal pannus were 3 mm away from the lesion and did not seem to supply it. The entire corneal surface in right eye lacked its usual sheen but the sensations were normal. Nasally elevated conjunctival lesions (suggestive of pinguecula) could be appreciated bilaterally. Intraocular pressure and posterior segment were normal in both eyes.

Figure 1.

Slit-lamp photographs showing nasal pannus (A) and fungating vaguely opalescent localised corneal lesion with no limbal or conjunctival involvement (B, C); anterior segment opticalcoherence tomography demonstrating hyperreflective thickened epithelial layer, distinct plane between the lesion and the underlying tissue, and nasal stromal opacification (D); impression cytology depicting absence of cellular dysplasia (E).

Investigations

A clinical suspicion of PCN was made based on the characteristic fungating margins of the lesions. Findings appreciated on high-resolution anterior segment optical coherence tomography (ASOCT, Visante OCT, Zeiss, Germany) included irregularly thickened and hyperreflective epithelial layer (66 µm centrally contrary to 45 µm in other eye), a distinct plane between the lesion and the underlying tissue in the central area, and nasal anterior stromal opacification (figure 1D). The stromal hyperreflectivity corroborated with pannus area. A cytological analysis by means of impression cytology (IC) was performed immediately. However, no dysplastic epithelial cells could be appreciated on IC (figure 1E) conducted from multiple areas inclusive of both the suspicious corneal lesion and the conjunctival elevation. Repeat IC was undertaken after 1 week and the corneal lesion and the conjunctival elevation remained practically unchanged in the interim. Contrary to our expectations, repeat IC was again negative for any dysplasia. Due to high clinical suspicion and features on ASOCT, in vivo confocal microscopy (IVCM, ConfoScan4, NIDEK, Japan) of the lesion was undertaken. IVCM revealed a starry sky pattern of hyperreflective pleomorphic epithelial cells with lost polygonal shape in anterior and middle layers of epithelium and absent sub-basal plexus in the affected eye when compared with normal eye (figure 2). There was no involvement of corneal stroma, limbus or conjunctiva on IVCM.

Figure 2.

Clinical photographs and confocal microscopy images at 17 µm, 31 µm and 42 µm of right (A–D) and left eye (E–H), respectively. Note the presence of hyperreflective epithelial cells (B, C) and the absence of sub-basal plexus in the affected eye (C, D) when compared with unaffected eye.

Differential diagnosis

Other differentials such as pterygium, corneal pannus, viral keratitis, corneal dystrophy and fatty degeneration were ruled out by lack of vascularisation, normal sensations, its non-elevated nature and unilateral presentation.

Treatment

After confirming a diagnosis of PCN, the patient and his family were explained about the risk of intraocular seeding and the need to defer the cataract surgery. Considering the large size of the lesion, we started our patient on topical mitomycin C (MMC) 0.04% 4 times/day for a week, followed by 1 week off after obtaining written informed consent.

Outcome and follow-up

The patient was followed up after each cycle and at the end of three cycles, significant recession of both horizontal and vertical margins was noted clinically. The blood vessels in the nasal pannus seemed unchanged with treatment (figure 3). ASOCT also demonstrated receding margins, blunting of demarcation line between involved and uninvolved areas and decreasing nasal haze (due to effect of MMC) at each follow-up (figure 4). Following this, the patient was shifted to interferon α-2b (IFN α-2b) 1 million international units (MIU) 4 times/ per day and presently is being followed-up bimonthly.

Figure 3.

Clinical photographs at presentation (A) and after second (B) and third (C) cycles of topical mitomycin C showing receding margins of lesion (arrowheads) and unchanged nasal blood vessels (arrows).

Figure 4.

Anterior segment optical coherence tomography images obtained at presentation (A) and after second (B) and third (C) cycles of topical mitomycin C showing receding margins of tumour (arrows), and decreased nasal haze (arrowheads).

Discussion

The typical presentation of PCN occurs as a symptomatic localised, slightly elevated, minimally invasive lesion around the limbal region that gradually invades into corneal and/or conjunctival epithelium and is often accompanied by neovascularisation.^{3 4} In our case, it is possible that the lesion remained less clinically evident and asymptomatic due to its flat, less obvious appearance and non-neovascular nature.

Clinical examination, IC analysis and histopathologic examination of excised tissue are commonly employed techniques for the diagnosis and follow-up of corneal dysplastic and neoplastic lesions.^{5 6} As seen in our case, clinical examination is subjective and may sometimes miss subclinical microscopic disease unless performed meticulously. IC or exfoliative cytologic analysis which is a useful tool for its screening and diagnosis may sometimes miss hyperkeratotic lesions. Besides, IC does not yield any details on potential invasiveness of neoplastic lesions. Excisional biopsy, the present gold-standard for diagnosing PCN, carries a risk of inducing conjunctival scarring, limbal stem cell deficiency and tumour recurrence in large lesions and missing small lesions if not included in the excised tissue. Therefore, to overcome these shortcomings, recently, newer, more objective and non-invasive techniques such as ASOCT and IVCM are being used for the diagnosis and management of corneal neoplastic lesions.⁷ IVCM can discern a cellular level resolution of corneal architecture almost comparable to conventional histology, although without any added shrinkage from tissue fixation. However, similar to IC, IVCM cannot differentiate intraepithelial lesions from invasive squamous cell carcinoma as both provide only en face images of corneal layers and their cells.⁸ ASOCT is particularly helpful in assessing small superficial non-pigmented lesions but suffers from poor resolution and shadowing in large, thick or pigmented lesions and unpredictability in perceiving deep or micro-invasion of the tumour or intracellular features for histologic grading.^{9 10} Considering the benefits and limitations of each modality, multi-modal imaging may be desirable for accurate diagnosis and management of corneal neoplastic lesions, only limited by their inflated cost and restricted availability. This may, therefore, sometimes, mandate referral of similar cases to higher centres. However, it is important to remember that all these investigations are complementary and not supplementary to clinical examination. In our case, ASOCT demonstrated grossly abnormal epithelium and IVCM facilitated detailed objective evaluation of cells in this abnormal epithelium only because of a proficient slit lamp examination. Also, multimodal imaging aided in ruling out primary conjunctival involvement in our case due to the following reasons; suspicious elevated and vascularised nasal conjunctival lesions were present bilaterally (hence suggestive of pinguecula) whereas the corneal lesions were present only in one eye, clear separation between the PCN and the adjacent nasal pannus, absence of neoplastic cells on IC and cellular infiltration of the conjunctiva on confocal microscopy and lack of change of size, shape and vascularisation of the conjunctival lesion with treatment. While all these suggest a primary corneal neoplasia and not an extension of conjunctival neoplasia in our case, a conjunctival biopsy would be the best modality to confirm its involvement. Similarly, a biopsy can also be used to ascertain Bowman’s membrane involvement in corneal neoplasia.

The management of PCN can be either surgical or medical.^{1 11} Surgical excision is an effective way of eradicating the lesion, but mandates large macroscopic tumour-free margins and carries risk of seeding, deeper invasion and recurrences. Due to its undeniable complications, parasurgical treatment options including topical chemotherapy (MMC, 5-fluorouracil), topical/local immunomodulation with IFN α-2b and topical antiviral medications (cidofovir) are presently being explored for managing these lesions. MMC is a potent alkylating agent and can be used as a primary or adjunctive topical chemoreductant for corneal neoplasia.¹² Both MMC 0.02% 3 times/day or MMC 0.04% 4 times/day administered in at least two 1 week courses have been proven to be effective for clinical resolution. IFN α-2b is a recombinant interferon, a glycoprotein, with antiviral, antimicrobial, antiproliferative, antiangiogenic and cytotoxic properties, that can be used as primary immunoreductants for small corneal/conjunctival tumours or as neoadjuvants for large tumours.¹³ It can be prescribed either topically as drops (1 MIU/mL one drop 4 times/day or 3 MIU/mL one drop 4 times/day) or locally as perilesional subconjunctival injections (dosages ranging from 3 MIU/0.5 cm³ upwards to 9 MIU/0.5 cm³ or downwards to 3, 5, 10 MIU/cm³ once a month). Considering the side effects of surgical excision and presently unproven primary role of IFN α-2b on such a large lesion, our patient was administered three cycles of topical MMC 0.04% following which he was switched to IFN α-2b as its size decreased. The treatment plan was based on side-effect profile of the former drug (MMC induced photophobia, dry eye, punctal stenosis, persistent epithelial defects, limbal stem cell deficiency and allergic reactions) and minimal long-term toxicity, cost-effectiveness, easy availability and affordability of the latter drug in India. As early results are convincing, the patient is being followed-up regularly till complete resolution of the lesion. Whatever might be the choice of treatment, it is important to defer any intraocular surgery till complete resolution of lesions to prevent their intraocular seeding.¹⁴

Overall, PCN has a good prognosis, with little tendency to metastasise and low mortality rate.¹ Unfortunately, tumour recurrences after clinically diagnosed resolution and termination of topical treatment have been reported in up to 39% cases. It is therefore recommended that even after macroscopic clinical regression, IFN α-2b be continued for additional time (1–4 months) to prevent recurrences. However, clinical monitoring alone may give the false impression of tumour resolution thereby resulting in premature termination of topical treatment and increasing risk of recurrence, and more objective tests such as high resolution ASOCT can aid in disease monitoring. In our case, ASOCT demonstrated normalisation of epithelial architecture at the site of the treated lesions and receding tumour margins at every follow-up. Nevertheless, this modality did not provide any detail on intraepithelial blood vessels which were better appreciated clinically. Even though IVCM can distinguish active disease from anterior stromal scarring, neither IVCM nor IC were employed for disease monitoring in our case due to their restricted wide-field view and low negative predictive value, respectively. This again highlights the fact that while newer investigations may aid in monitoring the patient response to treatment, these should always be complemented with meticulous clinical examination for a comprehensive picture even in the present era of advanced corneal imaging.

To conclude, the present case is being reported as diagnosis and management of incidentally detected large PCN has been rarely reported in a patient primarily presenting with cataract, particularly in our clinical setting. Time and again, we emphasise on thorough corneal examination of all elderly patients presenting with cataract to avoid missing-out any PCN lesions. While newer imaging modalities can serve as important surrogate investigations for diagnosing PCN, their negative result do not refute the presence of the disease and it is desirable to undertake multi-modal corneal imaging in cases with high clinical suspicion.

Learning points.

• Primary/isolated corneal neoplasia (PCN) is a rare progressive cancerous lesion of cornea that is usually encountered in the elderly.

• Thorough corneal examination of all elderly patients presenting with cataract is necessary to avoid missing-out any PCN lesions.

• Impression cytology, in vivo confocal microscopy and anterior segment optical coherence tomography can aid diagnosis and management of primary corneal neoplasia.

• While these newer imaging modalities can serve as important surrogate investigations for diagnosing PCN, their negative result do not refute the presence of the disease and it is desirable to undertake multi-modal corneal imaging in cases with high clinical suspicion.

• Primary therapy with mitomycin C 0.02% followed by neoadjuvant interferon α-2b can be safely used for treatment of large PCNs.