If left untreated, late-stage ocular surface squamous neoplasia (OSSN) can lead to devastating consequences, including disfigurement, intraocular extension, and metastases. (See “OSSN: An Overview”.) Therefore, it is imperative that corneal specialists accurately diagnose and effectively treat the condition.
Here, we explain how this can be accomplished.
Accurate Diagnosis
The presenting symptoms of OSSN can be complaints of varying degrees of ocular irritation, redness, and visual impairment.1 Alternatively, OSSN patients can present without symptoms, underscoring the importance of a routine, comprehensive examination.
Slit lamp exam commonly reveals fleshy lesions that have leukoplakic, papillomatous (see Figure 1), or gelatinous qualities.2 OSSN lesions may be further highlighted using lissamine green, Rose Bengal, and methylene blue stains.3 Further, the interpalpebral conjunctiva is the most affected site.1,3
Figure 1: Note the slit lamp photograph of a large papillomatous OSSN present on the bulbar conjunctiva of a patient’s right eye.
IMAGE COURTESY OF JENNIFER A. TRAN, MD
These clinical findings can be elucidated with the following imaging modalities:
- HR-OCT. This is highly sensitive and specific for the diagnosis. OSSN specifically has a characteristic appearance of abnormally thickened and hyperreflective epithelium, arising from an abrupt transition from normal epithelium.4,5
- In vivo confocal microscopy. This may reveal cells that have atypical features, such as high nuclear to cytoplasmic ratio, pleomorphism, or active mitosis.6,7
- Exfoliative cytology. This allows for the examiner to sample superficial tissue for microscopic analysis. The results can be comparable to histopathology with regard to malignant tissue.8 However, it cannot replace excisional biopsy.9
Clinical diagnosis alone is accurate between 40% to 86% of the time.1,10 The gold standard for a definitive diagnosis is histopathology following excisional biopsy.11
Effective Treatment
Surgical excision, topical agents (either in combination with surgery or as monotherapy), and alternative therapeutic options are available to treat OSSN:
- Surgical excision. Typically, this involves a no-touch technique with 4 mm margins, followed by cryotherapy via the double-freeze slow-thaw technique and/or application of absolute alcohol (see Figure 2).12 Closure can occur via primary wound closure for smaller wounds, while amniotic membrane closure may be employed for larger wounds (see Figure 3).13
Figure 2. Intra-operative photograph showing wide, 4 mm, margin excision of the OSSN lesion.
IMAGE COURTESY OF JENNIFER A. TRAN, MD
Figure 3: Intra-operative photograph showing placement of a cryopreserved amniotic membrane after excision is complete.
IMAGE COURTESY OF JENNIFER A. TRAN, MD
Of note: Partial lamellar sclerectomy,14 enucleation,15 or exenteration16,17 could be considered for significantly advanced forms of OSSN, or for lesions that involve scleral, intraocular, or orbital invasion.
Benefits. These include the certainty of removing clinically obvious lesions, the ability to determine a specific diagnosis with histopathology, and shortening the overall timeframe for treatment.13
Drawbacks. Conjunctival scarring, symblepharon, and conjunctival hyperemia are possible sequelae.2,18 Additionally, depending on the location of the lesion, some degree of limbal stem cell deficiency may be present.19 Further, OSSN has been recognized as a multifocal disease that may not be adequately managed with surgery alone.19,20 Finally, the recurrence rate of OSSN following surgical excision can be up to 56%.1,21 - Topical agents. Topical immunomodulating (i.e., interferon alfa-2b) and chemotherapeutic agents (i.e., 5-fluorouracil and mitomycin C) can treat the entire ocular surface, ostensibly minimizing the area for surgical resection and treating subclinical disease. HR-OCT can potentially minimize disease recurrence here by either aiding in the confirmation of disease resolution or revealing subclinical OSSN in eyes that would benefit from extended topical therapy.22
Interferon alfa-2b benefits. This immunomodulatory cytokine works to protect against microbes and viruses. It has an efficacy rate of up to 100%,23 can be used topically or as a subconjunctival injection, and causes few side effects.
Interferon alfa-2b drawbacks. This medication must be refrigerated, and it’s hard to come by. Since the COVID-19 pandemic, the sole manufacturer discontinued it “for business reasons,” so the existing supply continues to dwindle. Dosing is typically daily, with each cycle spanning 4 weeks.
5-fluorouracil benefits. This chemotherapeutic agent interrupts DNA formation.
5-fluorouracil drawbacks. Side effects may include ocular surface irritation, filamentary keratitis, and superficial stromal melting. Dosing is typically 4 times daily for 1 week to 2 weeks, with a drug holiday of 2 weeks to 4 weeks.
Mitomycin C benefits. This chemotherapeutic agent inhibits RNA and protein synthesis. It also has an efficacy rate of up to 100%.24
Mitomycin C drawbacks. It poses a risk of ocular surface toxicity and can cause hyperemia, conjunctivitis, and punctal stenosis. (Punctal plugs are placed by some providers to reduce punctal damage.) Dosing is typically 4 times daily for 1 week to 2 weeks, with a drug holiday of 2 weeks to 4 weeks. - Alternative therapeutic options. These include photodynamic therapy (PDT), radiation, anti-VEGF agents, human papillomavirus vaccinations, and Aloe vera.
PDT benefits. This uses photosensitive agents to convert light into chemical reactions, resulting in the release of free radicals and offering a targeted option against malignant cells that limits the destruction of surrounding healthy tissue.
PDT drawbacks. There are limited studies on its use in OSSN.25
Radiation benefits. This treatment, which kills and hampers cancer cell growth via DNA damage, has been described as an adjuvant to surgery and can come in various forms, such as proton radiation, electron beam radiation, brachytherapy, stereotactic radiotherapy, etc.26 The type of radiation used may depend on the extent of the disease.
For example, electron beam radiation has been highlighted in a case report of OSSN with orbital extension.26 In less invasive cases, such as in OSSN that has scleral involvement, brachytherapy can be considered.27
Radiation drawbacks. Depending on the type of radiotherapy and treatment location, patients may develop persistent epithelial defects,27 corneal ulceration, and limbal stem cell deficiency.28
Anti-VEGF benefits. Limited studies demonstrate improved vascularity and size following treatment with topical or subconjunctival bevacizumab.29,30
Anti-VEGF drawbacks. Use of these agents in the presence of an epithelial defect may prevent corneal wound healing.31
HPV vaccination benefits. They may potentially lend themselves to novel immunomodulatory therapies against ocular surface neoplasias, as suggested in the case of a conjunctival papilloma refractory to 5-fluorouracil that subsequently responded to two vaccinations.32 Although HPV is not required for OSSN development, it is thought to play a role in a subset of OSSN cases, with groups theorizing that widespread vaccination could prevent future OSSN cases.33 Studies are currently underway to explore the potential of this as an intervention.34
Aloe vera benefits. This antineoplastic plant that has anti-inflammatory properties is credited with the resolution of OSSN in one published case report, in which the patient had begun using topical aloe vera drops resulting in the disappearance of her lesion within three months of treatment initiation.35
Aloe vera drawbacks. Further studies are needed to confirm whether aloe vera has utility against OSSN.
OSSN: AN OVERVIEW
Ocular surface squamous neoplasia (OSSN) is a term that encompasses a spectrum of neoplastic changes involving the cornea and conjunctiva.
OSSN is the most common ocular surface epithelial squamous tumor,36 and its incidence appears to be increasing in certain African populations.37,38
Of note: Patients who have HIV/AIDS demonstrate larger-sized lesions and higher-grade malignancy.39,40 Additionally, OSSN in these immunocompromised individuals may evolve to result in scleral or orbital invasion, requiring enucleation or exenteration.15,17
The pathophysiology of OSSN is largely unclear but likely multifactorial, owing to the various associated risk factors. Higher rates of OSSN are correlated with higher levels of ultraviolet light exposure,41,42 immunocompromised status (such as in HIV/AIDS40,43), human papilloma virus (HPV) infection,44 smoking,45 chemical exposure, or mutation or deletions of tumor suppressor gene p53.46 The clinical presentation may vary greatly.
Some diagnostic red flags for OSSN may include the presence of prominent feeder vessels, increased vascularity of the lesion, and corneal involvement, specifically with sharp, fimbriated borders.47,48
A Call to Action
Because unidentified and untreated OSSN can cause disfigurement, intraocular extension, and metastases, it’s crucial that corneal specialists be aware of the condition’s characteristics, employ the necessary diagnostic technology to aid in detection, perform histopathology following excisional biopsy for a definitive diagnosis, and treat the condition using surgery, topical agents, or alternative therapeutic options. Overall, the process of deciding among management approaches should include considerations of cost, patient compliance, and patient preference. CP
References are available in the online version of this article.
