Current Management for Ocular Surface Squamous Neoplasia

Ocular surface squamous neoplasia (OSSN) encompasses a spectrum of epithelial neoplasms that affect the conjunctiva and cornea, ranging from mild dysplasia to conjunctival/corneal intraepithelial neoplasia (CIN), to invasive squamous cell carcinoma (SCC).¹

OSSN primarily affects the interpalpebral limbus and typically presents as a unilateral lesion. Its incidence varies globally, with a higher prevalence observed in regions with increased ultraviolet (UV) exposure, such as Australia, where the incidence has been reported to be 19 per million people.² Wide surgical excision with cryotherapy remains the treatment of choice, although increasingly, topical chemotherapy is used both as primary therapy and an adjunctive treatment.

Epidemiology and Risk Factors

OSSN is influenced by a complex interplay of environmental, viral, and host-related factors.

Ultraviolet Radiation

UV radiation, particularly UVB, is a major environmental risk factor for OSSN. The ocular surface is directly exposed to UV rays, which can induce DNA damage and mutations in epithelial cells. There is a strong correlation between cumulative UV exposure and the development of OSSN; proximity to the equator where UV radiation is more intense, increased outdoor time, fair skin, and pale irides being associated with increased risk.³ The nasal limbus is the most commonly affected area.³

Human Papillomavirus Infection

Human papillomavirus (HPV) infection, particularly with high-risk strains such as HPV-16 and HPV-18, has been implicated in the pathogenesis of OSSN. The oncogenic potential of HPV is linked to inhibition of tumour suppressor proteins p53 and Rb.3,⁴ This inhibition leads to uncontrolled cell proliferation and the potential for malignant transformation. HPV may be a particular risk factor in patients presenting at younger age.³

Human Immunodeficiency Virus and Immunosuppression

Human immunodeficiency virus (HIV) positive individuals are at higher risk of developing OSSN compared to the general population.⁵ Immunosuppression associated with HIV infection leads to reduced immune surveillance, allowing for the unchecked growth of dysplastic cells. In HIV and immunosuppressed individuals more broadly, OSSN has higher probability of bilateral presentation, and is typically more aggressive with worse prognosis and higher chance of recurrence.³

Age and Gender

Advancing age is a risk factor for OSSN, with most cases occurring in middle-aged and older adults.⁵ Age-related changes in the immune system and the cumulative effects of UV exposure over time may contribute to this increased risk. There is also a gender predilection, with males being more frequently affected than females.⁶ This may be attributed to greater occupational UV exposure in males.

Other Predisposing Factors

Chronic ocular surface inflammation, as seen in conditions like chronic atopic conjunctivitis, has been associated with an increased risk of OSSN. Persistent inflammation can lead to an environment that favours cellular dysplasia and neoplastic transformation.^3,7 Exposure to tobacco smoke and petroleum chemicals has also been associated with an increased risk of OSSN.³

There is a strong correlation between cumulative UV exposure and the development of OSSN

Pathophysiology

OSSN typically originates from the limbal stem cells located at the junction between the cornea and the sclera. These highly mitotically active cells are crucial for maintaining the integrity and regeneration of the ocular surface epithelium. Under normal conditions, these cells differentiate into mature squamous epithelial cells that migrate to the corneal surface. When exposed to carcinogenic stimuli, they can undergo dysplastic changes, resulting in uncontrolled proliferation and the development of OSSN.⁵

The spectrum of OSSN ranges from mild dysplasia to CIN and invasive SCC. Progression is marked by increasing cellular atypia, loss of normal epithelial architecture, and invasion into deeper layers of the conjunctiva and underlying structures. Histopathological grading is classified as CIN grade I (mild) with dysplasia confined to the lower third of the conjunctival epithelial thickness; grade II (moderate) with dysplasia penetrating two thirds of the epithelial thickness; grade III (severe) with more than two thirds involved; carcinoma in situ involving the full thickness of the epithelium; and SCC defined by dysplastic cells penetrating the epithelial basement membrane and spreading into the conjunctival stroma.⁶

While OSSN is generally considered a locally aggressive tumour with a low metastatic potential, advanced cases of invasive SCC can metastasise to regional lymph nodes or, rarely, to distant organs. The risk of metastasis is increased in immunosuppressed individuals and in cases with poor differentiation and deep stromal invasion.⁵

Clinical Presentation

The clinical presentation of OSSN is highly variable, ranging from flat asymptomatic lesions discovered during routine eye exams to more advanced cases with an obvious mass and significant ocular discomfort and visual impairment.

Typically, patients present with a gelatinous, leukoplakic or papilliform lesion (or a combination of these appearances) in the interpalpebral conjunctiva with 95% of lesions occurring at the limbus.5 Most OSSNs have the appearance of a gelatinous lesion with a hairpin configuration of conjunctival vessels (Figure 1A). Papilliform OSSN resembles benign papillomas with a frond like appearance.³ Leukoplakic lesions make up 10% of OSSNs and have a white, thickened surface due to surface hyperkeritinisation.⁵

Less commonly encountered are diffuse OSSN presentations that cover a more extensive portion of the ocular surface (Figure 1B).³ Feeder vessels may be present. Corneal involvement typically has a grey, frosted/fimbriated appearance with an adjacent neoplastic pannus.⁵ A lesion that is fixed to the underlying structures is suggestive of invasive disease/SCC (Figure 1C).⁵

Given its varied clinical presentation, OSSN can be mistaken for several other ocular surface conditions. Key differentials include:

• Pterygium: A pterygium is a benign fibrovascular growth that typically arises in the nasal conjunctiva and extends onto the cornea. Unlike OSSN, pterygia are often bilateral and exhibit slow, progressive growth. The absence of keratinisation and feeder vessels can help differentiate a pterygium from OSSN (Figure 2A).⁵
• Pinguecula: A pinguecula is a small, yellowish, slightly raised lesion on the conjunctiva, usually near the limbus. It is benign and typically does not involve the cornea.⁵
• Conjunctival papilloma: Conjunctival papillomas are benign epithelial tumours often associated with HPV infection. These lesions are usually pedunculated, multilobulated, and located on the bulbar or palpebral conjunctiva (Figure 2B).⁵
• Chronic conjunctivitis: Chronic conjunctivitis may present with redness, irritation, and a thickened conjunctiva, which can mimic OSSN.⁵
• Conjunctival lymphoma: Conjunctival lymphoma typically presents as an asymptomatic, sharply demarcated, salmon pink coloured mass on the ocular surface. Lesions are typically non-tender, freely movable on the globe, and lack feeder vessels (Figure 2C).⁵
• Amelanotic melanoma: Uncommonly, melanomas of the ocular surface may be amelanotic (~10%) and simulate a pterygium or other epithelial neoplasm such as OSSN (Figure 2D).⁵

Diagnostic Modalities

Although clinical examination is the primary modality of diagnosis of OSSN, advanced imaging techniques and molecular testing may be used as adjuncts, with cytological and histopathological analysis being required for definitive diagnosis.

Advanced Imaging

• Anterior segment optical coherence tomography: Anterior segment optical coherence tomography (AS-OCT) is a non-invasive imaging modality that provides high-resolution cross-sectional images of the ocular surface. In OSSN, AS-OCT typically reveals a thickened, hyperreflective epithelium with an abrupt transition between normal and abnormal tissue.⁸ AS-OCT can help determine the depth of lesions, differentiate between in situ lesions and invasive disease by identifying breaches in the epithelial basement membrane, and may detect subclinical OSSN.⁸ AS-OCT may be limited by optical shadowing, which can obscure the depth of penetration, especially in thick tumours.⁴
• In vivo confocal microscopy: In vivo confocal microscopy (IVCM) offers real-time, high-resolution imaging of the ocular surface at a cellular level. It can identify features of dysplasia, such as nuclear enlargement, pleomorphism, and increased nuclear-to-cytoplasmic ratio.⁴ IVCM may be used in distinguishing OSSN from other conditions like pterygium, and chronic conjunctivitis. IVCM however, can only be used on small sections of tissue. It lacks cross-sectional visualisation, and is unable to effectively visualise through keratinised/necrotic tissue.⁴
• Ultrasound biomicroscopy: Ultrasound biomicroscopy (UBM) uses high-frequency ultrasound to provide detailed images of the anterior segment. It is rarely needed but is particularly useful in cases where the lesion is large or involves deeper structures. UBM can help assess the thickness of the lesion, the involvement of the sclera, and the presence of any intraocular extension. Although UBM has better depth penetration, it is limited in resolution compared to AS-OCT and IVCM.⁴

Histopathology and Cytology

• Excisional biopsy: Excisional biopsy remains the gold standard for the definitive diagnosis of OSSN. The procedure involves the complete surgical removal of the lesion, followed by histopathological examination. Immunohistochemical staining may be employed to detect markers such as p53, Ki-67, and HPV-related proteins, which can provide additional diagnostic and prognostic information.⁹ Excisional biopsy is discussed further below.
• Incisional biopsy: In cases where the lesion is large or involves critical ocular structures, an incisional biopsy may be performed to obtain a representative tissue sample. This approach allows for histopathological analysis while preserving as much healthy tissue as possible.
• Impression cytology: Impression cytology involves applying a cellulose acetate filter or other membrane to the ocular surface to collect superficial epithelial cells. These cells are then stained and examined under a microscope for signs of dysplasia or neoplasia. Impression cytology is minimally invasive and can be performed in an outpatient setting but may not provide a definitive diagnosis as only superficial cells are examined. Depth of disease cannot be assessed.^5,10

Ancillary Testing

• Human immunodeficiency virus testing: Given the strong association between HIV and OSSN, especially in regions with high HIV prevalence, HIV testing should be considered in patients presenting with OSSN, particularly those younger than 40 years of age, or with atypical or aggressive presentations. Early identification of HIV can significantly influence the management and prognosis of OSSN.

Management Options

OSSN may be treated surgically, with chemotherapy, or with a combination of surgery and chemotherapy. The choice of treatment is influenced by factors such as the size, location, and extent of the lesion, as well as patient factors.

Surgical Excision

Surgical excision remains the gold standard for OSSN management, particularly for primary lesions that are well circumscribed. The procedure involves the complete removal of the conjunctival lesion along with a 2–4 mm margin of healthy tissue to ensure clear surgical margins (Figure 3A).^5,8

A ‘no-touch’ technique is employed to minimise the risk of tumour cell dissemination (Figure 3B).^5,8 After excision, absolute alcohol may be applied to involved/adjacent cornea. For tumours adherent to the stromal bed, a partial sclerectomy may be required.⁸ Double-freeze-thaw cryotherapy is applied to the bordering conjunctiva and limbus of the excision site to reduce the chance of recurrence from microscopic disease (Figure 3C).^5,8 The excised tissue is sent for histopathological examination to confirm the diagnosis, assess the degree of dysplasia and invasion, and determine involvement of surgical margins. The excision site may be left bare, closed primarily, or covered with a conjunctival autograft or amniotic membrane.⁸ Risks of surgical excision include limbal stem cell deficiency, scarring, symblepharon and, associated ocular surface anomalies. The risk of complications increases with lesions involving a larger proportion of the limbus.⁵

Surgical excisions, in which the histopathological assessment reveals positive margins, may have recurrence rates of up to 56%.⁸ As such, adjuvant topical chemotherapy is often used in these scenarios. When margins are clear, adjuvant chemotherapy may be used, or careful observation may be undertaken for several years, as the one-year recurrence rate is up to 10% and five-year recurrence up to 21%.^4,8

Topical Chemotherapy

Several chemotherapeutic agents are available and may be offered as primary therapy, with benefits including avoiding surgery and treating the entire ocular surface. Chemotherapeutic agents are particularly useful in multifocal disease, for larger lesions (where topical chemotherapy may be used as neoadjuvant therapy to chemo-reduce lesions before excision), and for cases of incomplete surgical excision (Figures 4A and B).^4,5,8

Unless an incisional biopsy is performed, treatment with topical therapy does not provide a histopathologic diagnosis to confirm the nature of the tumour, or depth of invasion.

Treatment with topical therapy requires patient cooperation and compliance for an extended period of time (including factors such as manual dexterity to instil drops, ability to attend follow up appointments, financial constraints, and other social considerations).⁵ Chemotherapy should not be used as sole treatment in cases of suspected SCC.

• Interferon Alpha-2b: Interferon alpha-2b (IFNα2b) is an immunomodulatory agent that enhances the immune response against neoplastic cells. It is usually used as topical therapy but can also be used as a subconjunctival injection. Topical IFNα2b is typically administered as a one million international units per millilitre (IU/mL) solution, four-times daily until one to three months after clinical resolution. Topical IFNα2b is very well tolerated with minimal side effects (mild ocular irritation, conjunctival injection).^10,11 IFN is now the most commonly used agent for OSSN.¹²
• 5-fluorouracil: 5-fluorouracil (5FU) is a pyrimidine analogue that interferes with DNA replication.⁸ 5FU has been shown to have resolution rates of 82–100% with low recurrence rates of 10–14%.⁸ It is generally well-tolerated, with side effects such as mild ocular irritation, conjunctival hyperaemia, and transient keratopathy. In one study of 44 patients, 61% experienced at least one side effect, but only one patient discontinued treatment due to side-effects.¹³ The use of 5-FU has been increasing, and it is now the second most commonly used agent for OSSN.¹²

• Mitomycin C: Mitomycin C (MMC) is an alkylating agent that inhibits DNA synthesis and cell division. MMC is typically administered as a 0.02–0.04% topical solution. Many different regimens have been studied.⁸ In our institution, 0.04% is used four times a day for one week, followed by one week of no treatment until resolution. MMC has had reported resolution rates ranging from 76%–100% with low recurrence rates ranging from 0–20%.⁸ MMC has a higher intensity side effect profile compared to 5-FU and IFNα2b, including ocular surface irritation, conjunctival hyperaemia, punctate keratopathy, punctal stenosis, and – less commonly – limbal stem cell failure.⁸ As such, its use has decreased over time.¹² Topical steroids and artificial tears may be used to help alleviate symptoms, and punctual occlusion and/or punctal plugs to prevent punctal stenosis.⁸

• Retinoic acid: Retinoic acid is a vitamin A derivative that has growth restricting properties in normal, pre-malignant, and malignant cells. In most studies of retinoic acid for OSSN, 0.01% retinoic acid has been added to IFNα2b treatment and, as such, its role in sole treatment is not clear.¹¹ The typical regimen is second daily, in conjunction with IFNα2b, particularly in cases of recalcitrant tumours that do not respond to IFNα2b alone.⁵
  
  

  Figure 4A. Extensive OSSN with significant limbal involvement. This lesion is too large for surgical resection

  

  Figure 4B. Complete resolution after treatment with interferon (IFN) and retinoic acid.

Radiotherapy

Radiation therapies, such as brachytherapy and external beam radiotherapy, are typically used in cases of OSSN with scleral invasion, recalcitrant disease, or when the lesion is unable to be excised.5 Brachytherapy involves the placement of a radioactive plaque on the ocular surface to deliver targeted radiation to the lesion with a decreased dose to the surrounding tissue, and sparing of more distant tissues. External beam radiotherapy is another radiotherapeutic option, particularly for larger or more invasive lesions that involve the orbit or surrounding structures. Both forms of radiotherapy are associated with risks of cataract formation, keratoconjunctivitis sicca, neovascular glaucoma, and radiation keratopathy. Radiotherapy is generally reserved for cases where other treatment modalities have failed or are contraindicated.⁴

Other Adjunctive Treatment

A range of alternative treatments have been reported in the literature for OSSN including checkpoint inhibitors (e.g. PD-1 inhibitors), photodynamic therapy, anti-vascular endothelial growth factor agents, cidofovir, phototherapeutic keratectomy with excimer laser and photocoagulation. These treatments, however, do not form the mainstay of OSSN treatment and require further investigation.¹⁰

Recurrence

Recurrence rates of OSSN are primarily a function of adequacy of margin clearance of the initial surgical excision, HIV infection status, HPV, and higher histopathological grade.^4,5 When recurrent, the lesion tends to be more widespread, with invasive SCC a greater concern. Treatment of recurrence is tailored to the extent of disease with wide local excision and cryotherapy and/or topical chemotherapy as options.⁵

Recurrence rates of OSSN are primarily a function of adequacy of margin clearance of the initial surgical excision, HIV infection status, HPV, and higher histopathological grade.

Conclusion

Ocular surface squamous neoplasia is a potentially sight-threatening condition that requires prompt diagnosis and appropriate management to achieve favourable outcomes. The prognosis of OSSN is generally favourable for early-stage lesions treated promptly and appropriately. Larger, invasive, or recurrent lesions carry a higher risk of poor outcomes, including recurrence, vision loss, the need for enucleation or exenteration, and in rare cases, metastasis. Advances in diagnostic modalities and treatment options have significantly improved the outlook for many patients, but close follow-up and vigilant monitoring remain essential to ensure the best possible outcomes.

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Dr Andrew Kam BMed MD GradCert (Clinical Redesign) is an ophthalmology registrar at the Sydney Eye Hospital and clinical associate lecturer at the University of Sydney. He has an interest in corneal, cataract and refractive surgery, and more broadly in public health and clinical systems improvement.

 

 

 

 

 

 

 

Dr Robert McDonald BSc (Hons) BMed (Hons) MPH FRANZCO is a Sydney-based ophthalmologist specialising in cataract, corneal, and refractive surgery. He has undertaken subspecialty training at St Thomas’ Hospital and Moorfields Eye Hospital in London. He is the director of clinical training and the head of the department of cataract surgery at Sydney Eye Hospital, and is in private practice in Sydney.

 

 

 

 

 

 

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

 

 

 

 

 

 

 

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