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HomemieyecareOcular Surface Squamous Neoplasia

Ocular Surface Squamous Neoplasia

Ocular surface squamous neoplasia (OSSN) can range from mild dysplasia to invasive squamous cell carcinoma. Traditionally, wide surgical excision with cryotherapy was the treatment of choice but increasingly there has been a shift towards topical chemotherapy as both primary therapy and as an adjunct to surgery.

Dr. Alex Hamilton


Ocular surface squamous neoplasia (OSSN) is a common ocular malignancy, although the incidence varies greatly across geographies, being more common closer to the equator. In Australia the incidence is high and has been reported at up to 19 cases per million people per year. This is thought to be because exposure to ultraviolet-B (UV-B) radiation is a risk factor for OSSN.1 Other risk factors include advanced age, male sex, smoking, and exposure to the human papillomavirus.2 Patients with HIV are at increased risk and underlying immunodeficiency should be considered in young patients who present with OSSN.3,4


OSSN refers to a spectrum of neoplastic changes of the conjunctival and corneal squamous epithelium that are thought to arise from the limbal stem cells. The spectrum of OSSN ranges from noninvasive intraepithelial disease, known as conjunctival and corneal intraepithelial neoplasia (CIN), through to invasive malignancy called squamous cell carcinoma (SCC) if the epithelial basement membrane has been breached.5 In CIN, mild dysplasia occurs when atypical cells are present in less than one third of the epithelial thickness whereas in severe dyplasia, there is near full thickness cellular atypia.6 Carcinoma in situ refers to full thickness cellular atypia without breach of the basement membrane.


Patients may be completely asymptomatic and present with a lesion that was found incidentally, or may present with a wide range of symptoms including foreign body sensation, redness, or pain.

Lesions most commonly occur in the interpalpebral zone, presumably where UV-B exposure has been the greatest. They tend to involve the limbus but can extend to the cornea, bulbar conjunctiva, and even to the tarsal conjunctiva.2,5 It is important to be aware that OSSN can arise in pterygia and pingueculae so close examination of these lesions, looking for suspicious features, is important.7

Topical chemotherapy treats the entire ocular surface and is therefore useful in multifocal disease

Figure 1b. Complete resolution after four months of topical chemotherapy with Interferon-α2b

There are numerous patterns of appearance of OSSN which makes clinical diagnosis challenging. The typical lesion is referred to as gelatinous and is a fixed, fleshy lesion adjacent to the limbus (Figure 1a). There can be clear or poorly defined margins and there may be feeder vessels.2 Raised lesions tend to be of a higher grade than flat lesions.6 Other clinical variants include leukoplakic lesions that have a thickened white surface and papillomatous lesions that have a pink, strawberry-like appearance.2

The differentiation of CIN from invasive SCC can be difficult clinically, but lesions tethered to the underlying sclera suggest invasive SCC.2 Invasive SCC may present with surrounding scleritis (Figure 2).

Occasionally, OSSN can appear clinically to involve only the cornea, although these lesions are thought to still originate from the limbus. The appearance is usually more subtle and the corneal epithelium may have a translucent, greyish groundglass appearance. Lesions are usually avascular with clearly defined borders.2 Pigmented OSSN can occur rarely and these must be carefully differentiated from conjunctival melanoma.8


Excisional biopsy remains the gold standard for OSSN diagnosis, but noninvasive techniques have also been used to aid in the diagnosis.9 Most recently, anterior segment optical coherence tomography (OCT) has gained popularity as a quick and non-invasive technique to help diagnose OSSN.9 The distinctive features on OCT include a thickened hyper-reflective epithelial layer, an abrupt transition from normal to abnormal epithelium, and a distinct plane between the lesion and the underlying tissue.5,9


Surgical excision has been the traditional treatment for OSSN and remains a common approach to management. One major advantage of surgery is that a histopathological specimen is obtained. The surgical technique involves removing the OSSN lesion with at least a 3mm margin of normal conjunctiva in order to remove microscopic tumour that may have a normal clinical appearance. A ‘no touch technique’ is performed and alcohol can be used to remove any abnormal corneal epithelium. Double-freeze thaw cryotherapy to the conjunctival margin and involved limbus is then used to further decrease the rate of disease recurrence (Figure 3).10 Invasive SCC requires a deeper excision and a partial sclerectomy is often performed to remove the involved area of sclera.

Although surgery for OSSN is relatively safe, surgical complications can occur. These include postoperative infection and therefore patients with increasing eye pain, redness, or decreased vision after surgery should be seen urgently. Incomplete excision of OSSN may require surgical re-excision or post-operative topical chemotherapy. Limbal stem cell failure, scarring, and symblepharon formation can occur post-operatively.5


Topical chemotherapy is gaining popularity in the management of OSSN. Topical chemotherapy can be used for primary therapy of OSSN, for tumour debulking (chemoreduction) prior to surgical excision and for postoperative prevention of disease recurrence, particularly after incomplete surgical excision.5

Figure 2. Invasive SCC with surrounding scleritis

Topical chemotherapy used alone as primary therapy of OSSN has been shown to have similar recurrence rates to surgery.11 Topical chemotherapy has the advantage of sparing a patient a surgical procedure. Large lesions, particularly where more than six clock hours of limbus is involved, are suited to topical chemotherapy because there is less risk of damaging enough limbal stem cells to cause limbal stem cell failure than with surgical excision and cryotherapy. Topical chemotherapy treats the entire ocular surface and is therefore useful in multifocal disease.5 Average time to resolution using topical chemotherapy is approximately four months.5

Many different agents have been used but two of the most studied are Interferon-α2b (IFN) and mitomycin C (MMC).5 IFN is most commonly used as a drop four times daily until clinical resolution of the lesion and then is continued for a few months thereafter.5,11 The advantage of IFN is that side effects are usually limited to mild irritation and follicular conjunctivitis. One major limitation of IFN is that long term patient compliance with therapy is required. Retinoic acid is often used in combination with IFN and this combined regimen achieved complete tumour resolution in 98 per cent of cases in one series.12

Fig 3a

MMC has been shown to be effective for OSSN. There is variability in the regimen and concentration of MMC used, but a much shorter duration of treatment is required than for IFN. The problem with MMC is that it is toxic to the epithelium and can cause limbal stem cell failure.5

Punctal stenosis can occur if punctal plugs are not used.

It is important to point out that the role of topical chemotherapy in the management of SCC is less clear and surgery remains the mainstay of treatment in these cases.

Fig 3b


Recurrence of OSSN after surgical excision or primary treatment with chemotherapy can occur.13 Late recurrences, despite clear surgical margins, are not uncommon many years after treatment. Recurrences can be aggressive, can grow rapidly and can be more invasive than the original lesion. Patients with a history of OSSN should therefore be followed up indefinitely and any possible recurrences should be treated aggressively.

Fig 3c. Figure 3a. Surgical approach to OSSN: a. Limbal OSSN marked with a wide margin; b. Surgical excision using ‘no touch technique; c. Performing cryotherapy to limbus.

Dr. Alex Hamilton BMed, MPHTM (Dist), FRANZCO is a Sydney based ophthalmologist specialising in corneal and cataract surgery, refractive surgery, and medical retina. For two years he undertook subspecialty training at Manchester Royal Eye Hospital and Moorfields Eye Hospital in London. He now works at Sydney Eye Hospital where he trains registrars and international fellows in corneal surgery and is in private practice across Sydney.


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