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Review

The Management of Ocular Surface Squamous Neoplasia (OSSN)

by
Clarice H. Y. Yeoh
1,
Jerome J. R. Lee
2,
Blanche X. H. Lim
1,2,3,
Gangadhara Sundar
1,3,
Jodhbir S. Mehta
4,5,6,
Anita S. Y. Chan
4,5,6,7,
Dawn K. A. Lim
1,3,
Stephanie L. Watson
8,
Santosh G. Honavar
9,
Ray Manotosh
1,3 and
Chris H. L. Lim
1,3,5,10,*
1
Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
2
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore
3
Department of Ophthalmology, National University Health System, Singapore 119228, Singapore
4
Duke-NUS Graduate Medical School, Singapore 169857, Singapore
5
Singapore Eye Research Institute, Singapore 169856, Singapore
6
Singapore National Eye Centre, Singapore 168751, Singapore
7
Histopathology, Pathology Department, Singapore General Hospital, Singapore 169608, Singapore
8
Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Sydney, NSW 2000, Australia
9
Center for Sight, Hyderabad 500034, India
10
School of Optometry and Vision Science, University of New South Wales, Sydney, NSW 2052, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(1), 713; https://doi.org/10.3390/ijms24010713
Submission received: 7 December 2022 / Revised: 24 December 2022 / Accepted: 28 December 2022 / Published: 31 December 2022
(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 4.0)
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Abstract

:
The rise of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents represents an increasing recognition of the medical management of ocular surface squamous neoplasia (OSSN), which may replace surgery as the standard of care in the future. Currently, there is no consensus regarding the best way to manage OSSN with no existing guidelines to date. This paper seeks to evaluate evidence surrounding available treatment modalities and proposes an approach to management. The approach will guide ophthalmologists in selecting the most appropriate treatment regime based on patient and disease factors to minimize treatment related morbidity and improve OSSN control. Further work can be done to validate this algorithm and to develop formal guidelines to direct the management of OSSN.

1. Introduction

Ocular surface squamous neoplasia (OSSN) encompasses a broad spectrum of neoplastic changes involving the squamous epithelium of the conjunctiva, cornea and limbus ranging from mild dysplasia, intraepithelial neoplasia (carcinoma in situ) to squamous cell carcinoma (SCC) [1].
Exposure to ultraviolet (UV) B radiation is the primary risk factor for OSSN [2]. Non-modifiable risk factors include age and male gender [3,4,5]. Modifiable risk factors include smoking, chronic trauma or inflammation, exposure to chemicals, vitamin A deficiency and local immunosuppression [1,2,4,6]. Human papilloma virus (HPV) and human immunodeficiency virus (HIV) are strongly associated with OSSN [7,8,9,10,11]. Human papilloma virus serotypes 16 and 18 are thought to be cofactors in the development of OSSN [12,13], while OSSN may be the first presentation of HIV [14,15,16,17,18]. Screening for HIV should be performed in atypical cases such as younger patients with OSSN, especially those with risk factors such as having multiple sexual partners and/or a history of sexually transmitted diseases. Interestingly, a separate study [19] found that HPV does not appear to play a significant role in the etiology of OSSN in India. Instead, it is suggested that other factors listed above, such as ultraviolet radiation and immunodeficiency, played a more important role.
Although rare, OSSN is the most common non-pigmented tumour of the ocular surface [20], with a worldwide age-standardised rate of 0.26 cases per 100,000 per year. There is a higher incidence in African countries of 3–3.4 per 100,000/year [2]. Ocular surface squamous neoplasia is becoming more common in Africa, which can be partly attributed to increased survival of HIV-infected patients [2]. A study conducted in Canada also found an increasing incidence of malignant OSSNs, likely in part due to an aging population [21].
OSSN occurs with equal frequency in both men and women in Africa [2] and in parts of Asia including Saudi Arabia [22]. However, in most of the rest of the world, OSSN is more common in men [2]. This is partly due to differing risk factors, with a higher prevalence of HIV and HPV in Africa contributing to the increased risk of developing OSSN in women [2]. Malignant OSSNs generally follow the same epidemiological pattern, with studies finding that they are more common in males in Canada, Iran, and the United States [21,23,24], and equally common among both genders in Africa [2].
Although no causative genetic mutations have been identified [25], several mutations including the tumour suppressor gene p53 [26], the telomerase reverse transcriptase (TERT) gene promoter [27], a disintegrin and metallopeptidase domain 3 (ADAM3) [28,29], matrix metalloproteinase 9 (MMP-9), matrix metallopeptidase 11 (MMP-11) and clusterin [30] have been associated with the pathogenesis of OSSN. Further, DNA hypomethylation at the DNA methyltransferase 3-like (DNMT3L) promoter has been identified in OSSN, however its physiologic significance remains unclear [31].
Clinically, OSSN typically presents as a unilateral vascularized mass, with bilateral or multifocal presentations being less common [1]. Lesion morphology ranges from gelatinous, leukoplakic, papillary, nodular to nodulo-ulcerative [32]. Nodular and papillomatous lesions are associated with higher histopathologic grade [33]. Nodulo-ulcerative lesions are rare, aggressive variants which have been described in a case series of six patients with four having intraocular extension suggesting that they may be more invasive compared to other morphologies [32].
Diagnosis of OSSN is more challenging when associated with other ocular surface lesions sharing risk factors of UV exposure such as pterygia and pinguecula [34]. Histopathological evaluation following an incisional or excisional biopsy is the gold standard for the diagnosis of OSSN [33]. Less invasive modalities include impression [35] or exfoliative cytology [36,37], in vivo confocal microscopy (IVCM) [38,39] and high-resolution or ultra-high-resolution anterior segment optical coherence tomography (HR-OCT) [40].
Surgical excision is the gold standard for the management of OSSN. Excision via Shields’ no touch technique with 4 mm margins, followed by intraoperative cryotherapy with the double freeze-and-slow-thaw technique achieved a low rate of recurrence [41], Surgical management can be associated with the development of complications such as limbal stem cell deficiency, symblepharon formation, conjunctival hyperaemia and conjunctival scarring [6,42,43,44]. Limbal stem cell deficiency may arise as OSSN typically involve the limbal region. In cases with orbital extension resulting from late presentation, delayed or missed diagnosis, and/or incomplete excision, orbital exenteration may be required [45].
Recently, there has been a shift towards medical management including topical chemotherapy drugs and immunomodulatory agents such as 5-fluorouracil (5-FU), mitomycin C (MMC), and interferon alfa-2b (IFNα−2b). Such agents have been used in combination with surgical excision but also as monotherapy due to their ability to treat the entire ocular surface [46].
A combination of surgical and medical methods has also shown to be effective in cases with high recurrence risk. Topical chemo-reduction with MMC may allow for less extensive surgical resection and tissue reconstruction [47]. Post-operative topical IFNα−2b therapy lowered the recurrence rate in patients with positive margins to a level similar to that of negative margins [48]. Topical chemotherapeutics such as IFNα−2b and MMC have been used preoperatively for tumour reduction, especially for extensive tumours which may be less amenable to monotherapy with such topical agents [47,49].
Topical IFN alfa-2a (IFNα−2a) has been used both as primary therapy and tumour reduction prior to surgical management [50,51]. Subconjunctival IFNα−2b has also been used as adjuvant therapy to reduce the risk of recurrence [52]. However, it is less commonly used compared to IFNα−2b. The two drugs differ by an amino acid present at position 23 of the protein. Lysine is present in IFNα−2a in this position, while IFNα−2b has arginine [53].
Adjunctive treatments reported to be in use include radiotherapy, topical anti–vascular endothelial growth factor (anti-VEGF) agents [54,55], topical cidofovir [56,57], topical retinoic acid [54] and photodynamic therapy [58].
Currently, there remains no consensus regarding the best way to manage OSSN. No guidelines exist to advise an approach to management. The purpose of this paper is to summarize treatment options for the management of OSSN and provide recommendations to guide ophthalmologists in selecting the most appropriate treatment regime based on patient and disease factors to minimize treatment related morbidity and improve OSSN control.

2. Surgical Management

Surgical excision is the gold standard for the management of OSSN. The primary method of excision has been described by the Shields group [41]. This technique recommends macroscopic tumour-free margins of at least 4 mm during surgery to increase the likelihood of complete tumour resection [41]. This is followed by intraoperative cryotherapy applied to conjunctival and limbal margins via the double freeze-and- slow- thaw technique to rupture tumour cell membranes and occlude associated feeding blood vessels [59,60]; this further reduces the risk of recurrence [48]. Keratoepitheliectomy can be performed in cases of corneal involvement. Absolute alcohol is applied for 1 min before excision with tumour-free margins of at least 2 mm [41].
For scleral invasion, a partial lamellar sclerectomy can be performed [61]. In rarer cases of intraocular invasion, enucleation [62] should be considered while orbital invasion requires exenteration [63].
Primary wound closure may be performed for small wounds while amniotic membrane coverage is preferred for larger wounds to aid healing and to minimise inflammation and scarring. Despite amniotic membrane closure, extensive excision of the conjunctiva may lead to symblepharon and conjunctival scarring [64,65]. Surgical management can also be associated with other complications such as limbal stem cell deficiency (LSCD) [6,42,43,44]. Surgically induced scleral necrosis (SINS) is a relatively rare but well-documented post-operative complication that is more likely to occur following adjuvant therapy. This can occasionally lead to devastating complications such as scleral melt and perforation [66]. A modified Mohs micrographic excision technique with intraoperative cryotherapy has been proposed to allow for maximal conservation of healthy tissue [61] while concomitant limbal epithelial transplantation has been useful in preventing LSCD [67,68,69]. However, these techniques are time-intensive and require specific surgical expertise.
Surgical excision alone may lead to tumour recurrence due to the presence of residual microscopic disease. Erie et al. [70] found that recurrence of conjunctival intraepithelial neoplasia and squamous cell carcinoma did not correlate with cell type or degree of atypia, but with the presence or absence of positive margins. Recurrence rates with positive margins can be as high as 56% and were reduced to 33% with negative margins [71]. Recently, lower recurrence rates of 0–21% have been reported, likely due to the use of intraoperative cryotherapy, adjunctive postoperative topical MMC and postoperative topical INFα−2b in patients with positive margins [48,72,73]. Thus, to reduce recurrence rates, adjunctive topical chemotherapy with IFNα−2b, 5-FU or MMC should be performed if histopathological evaluation shows positive margins.
Although surgical management potentially shortens the overall treatment period compared to medical treatment, the complications highlighted above may limit its wider application. As proposed by Karp [74], surgery may be preferred for small (<4 clock hours (Shields) [41] or ≤5 mm (American Joint Committee on Cancer (AJCC)) [75]), unifocal lesions, lesions with an uncertain diagnosis and first presentations of OSSN. Considerations of factors such as accessibility and affordability of health services and medications, tolerance of and compliance with treatment, patient comorbidities and preferences also influence the choice between surgical and medical management.

3. Medical Management

To avoid the complications of surgery, there has been a shift towards medical management [76] which uses both topical chemotherapy drugs and immunomodulatory agents such as 5-fluorouracil (5-FU) [77,78,79,80], mitomycin C (MMC) [47,81,82,83,84,85,86,87], and interferon alfa (IFNα) [44,88,89,90,91,92] as monotherapy. These agents can treat the entire ocular surface, thus treating subclinical and microscopic disease [46]. The utility of topical chemotherapy ranges from chemo-reduction prior to surgery [47,89], primary treatment, to adjunctive treatment after surgery to reduce the risk of recurrence [6].
As primary therapy, topical chemotherapy has been shown to be comparable to surgery with similar efficacy and recurrence rates [44]. Karp [74] has suggested that topical chemotherapy may be preferred for large (>4 clock hours (Shields) [41] or ≥5 mm (AJCC) [75]), multifocal and recurrent lesions [88,89].

3.1. 5-Fluorouracil (5-FU)

5-FU is a pyrimidine analog that inhibits thymidine synthase, impairing DNA and RNA synthesis preferentially in cancer cells, thus preventing DNA replication and their proliferation. This mainly affects cells in the S stage of mitosis [42,93].
5-FU is typically applied as a topical ophthalmic formulation. Subconjunctival and perilesional injections have also been used in limited studies [94]. The most widely used protocol recommends 1% 5-FU drops four times daily for 1 week, followed by 3 weeks off as one cycle, for a total of 4 cycles [6]. Table 1 below summarises the effectiveness of different protocols where 5-FU was used as primary therapy.
Studies have shown 5-FU to be very effective as primary therapy for OSSN, with high-resolution rates of 82–100% and low recurrence rates of 6–14%. Its effectiveness has not been affected by patient age, gender, and ethnicity [80,96]. Compared to topical IFNα−2b, rates of tumour resolution, recurrence and time to response were similar with 5-FU [80,97,98].
5-FU is generally well tolerated with mostly mild side effects reported, including pain, redness, eyelid edema, tearing, keratopathy and superficial stromal melting [97]. Many of these adverse effects can be managed through regular use of preservative free artificial tears throughout the course of treatment and short-term use of topical steroids as needed. Punctal and canalicular stenosis have not been reported to arise from topical treatment, although they have resulted from systemic administration of 5-FU for other cancers [96,99].
Although topical 5-FU has fewer reported side effects compared to MMC [96,97], it is associated with more side effects compared to IFNα−2b as it also affects the proliferation of normal rapidly dividing epithelial cells and fibroblasts [89,100]. However, 5-FU generally costs less than IFNα−2b, despite the need for compounding [42]. While 5-FU can be stored at room temperature, refrigeration is recommended [80,101,102].

3.2. Mitomycin C (MMC)

MMC is an antimetabolite and alkylating agent that exerts its antineoplastic and antibiotic properties through inhibiting DNA synthesis and fibroblast migration as well as by inducing apoptosis. Compared to 5-FU, which mainly affects cells in the S stage of mitosis, MMC affects both proliferating and non-proliferating cells [89].
MMC is typically applied as topical eye drops. The most widely used protocol is 0.04% MMC drops four times daily for 1 week followed by 2–3 weeks off until the eye is quiet, for a total of 3 cycles, sometimes with punctual occlusion during administration [47,73,86,103,104]. However, various protocols have been reported with varying efficacies, as summarized in Table 2 below.
As primary therapy, studies have shown MMC to be very effective in treating OSSN, with high-resolution rates of 92–100% and low recurrence rates. Although the rates of tumour resolution were similar compared to IFNα−2b, MMC had a faster time to resolution of 1.5 months compared to 3.5 months [105].
However, use of MMC is limited by its toxicity. MMC has more frequent and severe ocular side effects compared to 5-FU and IFNα−2b [96,97,105]. These include ocular pain, redness, allergic conjunctivitis, tearing, epitheliopathy, conjunctival hyperaemia, punctate staining of the cornea, punctal stenosis and LSCD [81,82,87,103,105,106,107,108,109,110,111]. Topical preservative free tears and steroids are commonly used throughout the course of treatment to alleviate toxicity while punctal plugs may be used to prevent punctal stenosis [84,89,107,112]. Additionally, ancillary management with hyaluronic acid eye drops results in improvements in both subjective and objective ocular parameters, reducing MMC induced adverse effects [113]. Careful monitoring is needed for early identification of any signs of toxicity, as MMC administration should be halted if epitheliopathy occurs to minimise its toxic effects.
Other disadvantages of MMC include its need for compounding and refrigeration. Although it may be more costly than 5-FU, it is generally cheaper than IFNα−2b.

3.3. Interferon Alfa (INFα)

3.3.1. Interferon Alfa-2b (INFα-2b)

IFNα−2b is a leukocyte derived low molecular weight glycoprotein that functions as an immunomodulatory cytokine. It exerts its anti-proliferative, anti-angiogenic and cytotoxic effects through activating pathways involved in the alteration of gene expression, apoptosis, inhibition of protein synthesis and inducing host anti-tumour immunosurveillance [114,115,116,117]. IFNα−2b also enhances the production of IL-2 and IFN-γ mRNA by the immune system and lowers the production of IL-10 which aids in the recognition and targeting of neoplastic cells [118]. Thus, immunocompetency is required for efficacious use of IFNα−2b [119,120]. The use of non-immunomodulating agents like 5-FU or MMC may be preferred in immunosuppressed patients.
IFNα−2b can be used as a topical eye drop or a subconjunctival perilesional injection. The most widely used protocol for topical drops is 1 million international units (MIU)/mL four times daily until resolution followed by at least one to three more months after resolution with a mean time to resolution of 4 months [6,42,121,122] while subconjunctival perilesional injections are typically given at a dose of 3MIU/0.5cc weekly [121] or 10 MIU/0.5cc monthly until resolution [123]. Table 3 below summarises the effectiveness of different protocols where IFNα−2b was used as primary therapy.
As primary therapy, both forms are highly effective in treating OSSN, with high rates of disease resolution of 81–100% and 87–100% and remarkably low recurrence rates of 0–5% and 0–7% for topical eye-drops and subconjunctival injections, respectively. A study comparing doses of topical IFNα−2b drops found that the 1 MIU/mL formulation is equally effective as the 3 MIU/mL dose with fewer side effects [122]. The effectiveness of both topical and subconjunctival IFNα−2b has not been affected by patient demographics [129].
Compared to 5-FU, the rates of tumour resolution, recurrence and time to response were similar [80,97,98]. When compared to MMC, rates of tumour resolution were also similar. However, time to response was longer for IFNα−2b, with median time to resolution of 3.5 months compared to 1.5 months for MMC. Regardless, IFNα−2b may be preferable to MMC as it is associated with significantly lower adverse effect rates of 12% compared to 88% [105].
Topical IFNα−2b drops are the best tolerated among the topical therapies for OSSN available [89,100,105]. Side effects of topical IFNα−2b are largely limited to mild irritation, conjunctival hyperaemia [52], reactive lymphoid hyperplasia [130] and follicular conjunctivitis [123] as it is an endogenous molecule as opposed to an external chemotherapeutic agent [125,131]. Most side effects resolve with discontinuation of treatment.
While also well tolerated, subconjunctival injections are associated with transient systemic flu-like symptoms such as fever, chills and malaise. However, these are easily alleviated with an oral antipyretic such as acetaminophen, and usually become less severe with repeated injections [121]. The advantages of subconjunctival injections include a faster time to resolution, lower cost, better compliance and greater accessibility as no compounding is necessary [121].
Similar to 5-FU, topical IFNα−2b drops require compounding. However, IFNα−2b requires refrigeration while 5-FU does not. IFNα−2b’s greatest limitation is its high cost and limited accessibility, although it may be less costly and more widely available in some countries, such as India. In addition, its frequent daily application until tumour resolution makes patient compliance a significant consideration when choosing to use topical IFNα−2b drops Thus, weekly or monthly subconjunctival IFNα−2b injections may be a better alternative to ensure compliance.

3.3.2. Interferon Alfa-2a (INFα-2a)

IFNα-2b has been the most commonly used form of IFN in the treatment of OSSN. However, IFNα-2a is described in several case reports as a replacement for IFNα−2b, usually due to the limited accessibility and greater costs of IFNα-2b.
INFα-2a is cheaper and more readily available than IFNα-2b. The pegylated form of INFα-2a is more stable than IFNα-2b and has a longer half-life. When used, IFNα-2a has been administered both intralesionally and topically, both as monotherapy and as tumour reduction prior to surgery [50,51,132]. However, studies with larger sample sizes are required to substantiate the effectiveness of this product. The protocols used in several case reports are summarized in Table 4 below.
Side effects of IFNα−2a are reported to be mild and limited to ocular discomfort without long-term ocular complications [51,132]. However, evidence surrounding the effectiveness, recurrence rates and side effects of IFNα−2a in the treatment of OSSN remains limited.

4. Combined Medical and Surgical Management

In addition to primary therapy, topical chemotherapy may be used in combination with surgery in the form of chemo-reduction [47,89] or as adjunctive treatment to reduce the risk of recurrence [6].
Chemo-reduction may be useful in cases likely to respond poorly to topical monotherapy alone, although the evidence is limited as no studies have compared neoadjuvant chemotherapy to other modalities of treatment. Neoadjuvant chemotherapy refers to chemotherapy given to patients before their primary course of treatment. A case series by Shields et al. [47] found that thick tumours ≥ 4 mm may only show partial regression with MMC despite multiple chemotherapy cycles. Prolonged therapy increases the risk of MMC toxicity leading to serious vision and globe threatening complications [134]. Therefore, topical chemo-reduction followed by surgical resection was recommended, to allow for less extensive surgical resection and tissue reconstruction. The combination of topical neo-adjuvant chemotherapy followed by surgical excision may allow patients to benefit from both modalities by limiting the extent of surgical excision and its associated complications, while facilitating a tissue diagnosis and reducing the risk of tumour recurrence [83].
Meanwhile, there may be a role for systemic neoadjuvant chemotherapy (NAC) in the management of both intraorbital and extraorbital invasive OSSN. A retrospective case series found that systemic NAC was helpful in the management of surgically challenging cases of AJCC grade T3 and T4 OSSN and may be helpful in avoiding orbital exenteration [135].
Adjuvant topical chemotherapy reduces the postoperative risk of tumour recurrence, so termed chemoprevention. Factors associated with a higher risk of recurrence include positive pathological margins, tarsal involvement, higher grade lesions such as CIS and SCC, superior location of tumour, papillomatous morphology and recurrent OSSN [48].
Post-operative topical IFNα−2b therapy (1MIU/mL four times daily for two months) lowered the recurrence rate in patients with positive margins from 13% to 4%, a level comparable to rates reported in patients with negative margins [48]. Excisional biopsy followed by topical IFNα−2b therapy was reported to be the best modality of treatment to minimize tumour recurrence in a literature based analysis comparing surgery and topical IFNα−2b [136].
Similar to IFNα−2b, MMC has also been prescribed post-operatively in the management of positive margins, which decreased the incidence of recurrence from 66.7% to 5.9% [137]. Another study found a 0% recurrence rate in 27 eyes after a mean follow up period of 28 months with the use of postoperative MMC, which was sometimes combined with intraoperative cryotherapy [73]. MMC has also been used intraoperatively as an adjunct to surgical excision. Sarici et al. [59] found that excision of OSSN combined with cryotherapy and intraoperative MMC was effective with a low recurrence rate.
In a randomized, double-blind, placebo-controlled trial by Gichuhi et al. [138], 4 weeks of topical 1% 5-FU after surgical excision of OSSN substantially reduced the 1-year recurrence rate from 36% to 11%.
These studies suggest that surgical excision may not be sufficient to manage all cases of OSSN and highlight the efficacy of adjuvant topical chemotherapy in reducing rates of tumour recurrence, thus supporting their application in cases with high recurrence risk.
It is difficult to make a recommendation regarding the best treatment regime for chemo-reduction or chemoprevention given the lack of randomized controlled trials or comparative studies assessing the different drugs as well as their dosages and schedules.
A systematic review compared treatment results from prospective non-comparative series, found that adjuvant MMC and 5-FU produced similar effects in terms of disease control. Interestingly, MMC was reported to have a better toxicity profile [139].
The same study found limited evidence supporting the use of topical chemotherapy as adjuvant treatment rather than primary monotherapy and vice versa. The only comparative study was done with IFNα−2b, which found that surgical excison followed by adjuvant IFNα−2b resulted in a 100% response rate regardless of the tumour’s AJCC stage, compared to an 82% response rate with IFNα−2b as monotherapy. However, it gave a low level of evidence for this finding.
A retrospective study comparing the recurrence rate and the complications of surgical excision, surgical excision with adjuvant topical MMC, and surgical excision with adjuvant subconjunctival IFNα-2b found adjuvant IFN to have the lowest recurrence rates, with MMC causing ocular complications and IFN causing systemic symptoms [52]. Another retrospective study comparing adjuvant 5-FU and adjuvant MMC found one recurrence in the 5-FU group and no recurrences in the MMC group. Side effects occurred in 69% of the 5-FU patients and 41% of the MMC patients [140].
Further studies are warranted to elucidate the relative efficacy and safety of 5-FU, MMC and IFNα-2b as neoadjuvant or adjuvant topical chemotherapy. These considerations are likely to be similar to those discussed in Section 3.

5. Adjunctive Treatment

A range of alternative treatments have been used sporadically in the management of OSSN. These include photodynamic therapy [141], anti-VEGF agents [55,142,143,144,145], cidofovir [56,57], aloe vera [146], retinoic acid [54,147], proton beam therapy [148,149,150,151,152], plaque brachytherapy [153,154,155,156,157,158], electron beam radiotherapy [159], phototherapeutic keratectomy with excimer laser [160], urea [161], dinitrochlorobenzene [162] and laser photocoagulation [163]. Although these are not primary treatment modalities, they have been investigated for adjunctive management of OSSN.

5.1. Photodynamic Therapy (PDT)

PDT utilizes verteporfin, a photosensitive dye with a high affinity for abnormal blood vessels, that causes apoptosis and immunological destruction of neighbouring structures when exposed to light of specific wavelengths. Barbazetto et al. [141] treated three patients with SCC of the conjunctiva with one to three treatments of verteporfin (6 mg/m2 body surface area, intravenously) with a light dose of 50 J/cm2 1 min after the injection. In this study, PDT was found to be effective in causing localized tumour regression with minimal side effects. This limited evidence suggests that PDT may be a useful adjunct in OSSNs localized to the conjunctiva.

5.2. Anti-Vascular Endothelial Growth Factor (Anti-VEGF)

Anti-VEGF agents are monoclonal antibodies that target VEGF to inhibit angiogenesis. Although VEGF has been detected in conjunctival SCC [164], topical bevacizumab and ranibizumab have had variable success in the treatment of OSSN [55,142,143,144,145]. As studies are limited to a small number of case series and case reports with small sample sizes, there is little evidence to support the efficacy or use of these agents. In one case series of 6 patients, topical bevacizumab was shown to be effective as neoadjuvant therapy combined with surgical excision for the treatment of OSSN, with surgical excision unnecessary in responsive patients [55]. Another case series of 10 patients found perilesional or subconjunctival injections of bevacizumab to be potentially curative in lesions limited to the conjunctiva. However, there was no significant effect in cases with corneal extension of OSSN [142]. There is limited evidence that subconjunctival ranibizumab may be effective in treating extensive SCC refractory to treatment with all other standard agents [144]. However, other studies have not found anti-VEGF agents to be effective in the treatment of OSSN [143], thus their application in clinical practice is questionable. Anti-VEGF agents have been reported to be well tolerated, with side effects limited to mild irritation and epiphora [55,142,143,144,145].

5.3. Cidofovir

Cidofovir is an antiviral that acts against double-stranded DNA viruses such as HPV. Topical cidofovir has shown to be effective in a small number of patients for the treatment of refractory OSSN in the short to medium term, especially in the presence of a high-risk HPV serotype (HPV-16), and its efficacy raises the possibility of a viral etiology of OSSN in patients resistant to IFNα-2b [56,57]. However, the antitumour effects of cidofovir independent of HPV presence is unknown and comparative clinical trial data lacking.

5.4. Aloe Vera

Aloe Vera in its topical form may be useful in the treatment of OSSN. This is illustrated in an isolated case report where OSSN completely resolved after 3 months of topical aloe vera treatment [146]. However, this case was not biopsy proven as the patient refused biopsy. Further research is required to determine if there is a role for aloe vera in OSSN management.

5.5. Retinoic Acid

Retinoic acid is a metabolite of vitamin A that mediates its functions and plays important roles in cell growth and differentiation. In a case series of 4 patients, topical retinoic acid alone was found to be effective in treating severe squamous metaplasia in cicatrizing diseases of the conjunctiva [147]. Another study found that treatment with topical retinoic acid and IFNα−2b was more effective in treating lesions with minimal self-limited side effects, faster and greater resolution and a longer tumour-free period compared to IFNα−2b alone [54]. This suggests that the combination of topical retinoic acid and IFNα−2b may be a superior alternative to topical IFNα−2b alone in the treatment of CIN. Thus, retinoic acid may be useful as complementary therapy, especially in patients who are not keen on either surgery or injections.

5.6. Radiotherapy

Various forms of radiotherapy including proton beam therapy [148,149,150,151,152], plaque brachytherapy with strontium-90 (Sr-90), ruthenium-106 (Ru-106) and iodine-125 (125I) [153,154,155,156,157,158] and electron beam radiotherapy [159] have been used in the management of OSSN, especially in cases of invasive disease. Plaque radiotherapy may be useful as adjuvant treatment in scleral-invasive SCC [153,154,155,156,157,158], while proton beam therapy or electron beam radiotherapy may be useful in the treatment of recalcitrant SCC of the conjunctiva [148,149,150,151,152,159]. Recently, histopathology-guided use of Ru-106 surface plaque brachytherapy was effectively used as adjuvant therapy in the management of OSSN with corneal stromal and scleral invasion [157].

6. Approach to the Management of OSSN

No guidelines exist to advise an approach to the management of OSSN. Based on available evidence an algorithm was developed (Figure 1, Figure 2, Figure 3 and Figure 4) to summarize the modalities available for treatment and proposes an approach to management. This algorithm may provide ophthalmologists a guide to assist selecting the most appropriate treatment regime based on both patient and disease factors to minimize treatment related morbidity and improve OSSN control.
Diagnosis of OSSN is suggested by clinical examination and investigations including histopathological evaluation following an incisional or excisional biopsy, which is the gold standard to confirm the diagnosis of OSSN [33]. Less invasive modalities such as impression [35] or exfoliative cytology [36,37] are limited to the identification of superficial dysplastic lesions. In vivo confocal microscopy (IVCM) assessment for dysplasia or neoplasia [38,39] and high-resolution or ultra-high-resolution anterior segment optical coherence tomography (HR-OCT) can identify thickened (>120 microns) hyperreflective epithelium with an abrupt transition zone [40]. If the diagnosis is uncertain, HR-OCT and impression cytology can be performed to add to the evidence for the diagnosis before an excisional biopsy is performed.
Although surgical management is currently the gold standard for the management of OSSN and potentially shortens the overall treatment period compared to medical treatment, the complications highlighted in previous sections limit its wider application. Such that there has been a shift towards medical management [76] including topical chemotherapy drugs and immunomodulatory agents including 5-fluorouracil (5-FU) [77,78,79,80], mitomycin C (MMC) [47,81,82,83,84,85,86,87], and interferon alfa-2b (IFNα−2b) [44,88,89,90,91,92] as monotherapy alone due. These topical agents can treat the entire ocular surface enabling management of subclinical and microscopic disease [46].
As proposed by Karp [74], surgery may be preferred for small (<4 clock hours (Shields) [41] or ≤5 mm (AJCC) [75]), unifocal lesions, lesions with an uncertain diagnosis and first presentations of OSSN while topical chemotherapy may be preferred for large (>4 clock hours (Shields) [41] or ≥5 mm (AJCC) [75]), multifocal and recurrent lesions [88,89]. Considerations of patient factors such as affordability, compliance and patient co-morbidities and preference also influence the choice between surgical and medical management. Surgical management is preferred in patients with contraindications to topical ophthalmic chemotherapy. For example, patients receiving systemic treatment for systemic comorbidities may experience ocular side effects that limit the use of topical chemotherapy. In addition, the presence of significant medical comorbidities necessitating polypharmacy may reduce patient compliance to topical medical therapy, especially since most protocols involve a high frequency of dosing (four times a day) over an extended duration of several months. Such sustained compliance is difficult to achieve in the elderly, who make up the majority of OSSN patients.
OSSNs undergoing surgical management are excised primarily via Shields’ no touch technique (4 mm margins) followed by intraoperative cryotherapy with the double freeze slow thaw technique [41]. Kerato-epitheliectomy can be performed in cases of corneal involvement [41] while a partial lamellar sclerectomy can be performed for scleral invasion [61]. In rarer cases of intraocular invasion, enucleation [62] and plaque radiotherapy [153,154,155,156,157] can be considered while orbital invasion requires exenteration [63].
It is recommended that excised conjunctival specimens be sent unrolled and mounted onto filter paper before placing in formalin fixation. Orientation can be marked on the filter paper to allow accurate margin assessment. Larger specimens may be further oriented with sutures in case of dislodgment from filter paper. If histopathological evaluation shows positive margins, adjunctive topical chemotherapy with IFNα−2b, 5-FU or MMC should be performed to reduce recurrence rates. Adjunctive topical chemotherapy can also be considered with negative margins given the presence of factors associated with a higher risk of recurrence including tumours with tarsal involvement, higher grade lesions such as CIS and SCC, superior location of tumour, papillomatous morphology and recurrent OSSN [48].
5-FU, IFNα−2b and MMC are the three main topical monotherapies for OSSNs undergoing medical management (Figure 3). In an isolated case report, topical pegylated interferon-alpha-2a (peg-IFNα-2a) was effectively used as an immunotherapeutic agent for the management of OSSN with no ocular surface toxicity. Thus, it may be a useful adjunct to the main topical monotherapies, although more studies are required to confirm its efficacy [51].
In immunosuppressed individuals including those on steroids, immunosuppressants, or with conditions such as leukemia and multiple myeloma, the use of non-immunomodulating agents like 5-FU or MMC may be preferred [119,120]. In most other cases, 5-FU and IFNα−2b would be preferred to avoid the toxic side effects of MMC, with MMC reserved as a last resort for recalcitrant cases. In these cases, patients should be carefully monitored for early identification of any signs of toxicity, as MMC administration should be halted if epitheliopathy occurs to prevent further toxic effects. The choice between 5-FU and IFNα−2b is dependent on logistical considerations and patient factors. 5-FU is the only drug of the three that does not require refrigeration [80,101,102] and is generally the most cost-effective option despite compounding. IFNα−2b has the best side effect profile, however its use requires greater patient compliance and is limited by its high cost and concerns of accessibility. Between topical IFNα−2b drops and subconjunctival injections, the latter is less costly, more accessible, allows for a faster time to resolution and is less demanding in terms of patient compliance, with the trade-off of more systemic flu-like symptoms such as fever, chills and malaise after administration [121]. Patient preference is likely the deciding factor in choosing between the two forms of IFNα−2b.
Sequential use of or a combination of topical chemotherapeutic drugs may be considered to improve response to therapy and to reduce rates of recurrence if factors associated with poor response to topical monotherapy alone are present. These include multifocality [96], thick tumours (≥4 mm (MMC), >1.5 mm (5-FU)) [47,96], nasal location of tumour [80], circumference of ocular surface involved > 6 clock hours [129] and larger tumour diameter ≥ 21 mm [129]. Combination chemotherapy may also be preferred in time sensitive conditions to expedite response to therapy [129] and in smokers to reduce recurrence rates [165].
Alternatively, a combination of surgical and medical methods such as neoadjuvant debulking followed by surgery or adjuvant topical chemotherapy may be considered.
A range of alternative treatments have been used sporadically in the management of OSSN. These include photodynamic therapy [141], anti-VEGF agents [55,142,143,144,145], cidofovir [56,57], aloe vera [146], retinoic acid [54,147], proton beam therapy [148,149,150,151,152], plaque brachytherapy [153,154,155,156,157,158], electron beam radiotherapy [159], phototherapeutic keratectomy with the excimer laser [160], urea [161], dinitrochlorobenzene [162] and laser photocoagulation [163]. Although these are not primary treatment modalities, limited evidence suggests that they may be useful in the adjunctive management of OSSN. PDT and anti-VEGF agents may be useful adjuncts in OSSNs localized to the conjunctiva. Topical retinoic acid may be useful as complementary therapy with IFN-α-2b. Adjuvant radiotherapy may play a role in the management of invasive disease with plaque radiotherapy being used for scleral-invasive SCC [153,154,155,156] and proton beam therapy or electron beam radiotherapy being used for recalcitrant SCC of the conjunctiva [148,149,150,151,152,159]. Further studies are needed to establish the efficacy and safety of these agents.
Following medical or surgical treatment, high-resolution (5–10 µm) or ultra-high-resolution (3–5 µm) anterior segment optical coherence tomography (HR-OCT) should be performed to confirm resolution of OSSN. HR-OCT has been found to be highly sensitive and specific in the diagnosis and treatment of OSSN [40], and detected subclinical OSSN in 17% of cases with apparent clinical resolution in one study [166]. HR-OCT may be used to prevent premature termination of treatment [167] and to monitor the progression of treatment to reduce the risk of overtreatment with topical chemotherapy, potentially resulting in cost savings and improved safety for patients. If HR-OCT is unavailable or if subclinical disease is present, additional cycles of topical chemotherapy should be performed until resolution. After resolution, HR-OCT may be used for surveillance to monitor for subclinical recurrences during regular follow ups.

7. Future Developments

The growing popularity of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents represents a shift towards medical management of OSSN, which may replace surgery as the standard of care in the future [46]. However, the lack of randomized controlled trials or comparative studies assessing the different drugs as well as their dosages and schedules makes it difficult to recommend best practice guidelines. Further studies, especially prospective randomized trials, are warranted to evaluate the use of these drugs, their dosages, schedules, and concentrations in the treatment of OSSN and compare the outcomes to surgical management. More work can also be done to elucidate the role of combination topical chemotherapy in OSSN management as well as the relative efficacy and safety of 5-FU, MMC and IFNα-2b as neoadjuvant or adjuvant topical chemotherapy.
HR-OCT may assist both the medical and surgical management of OSSN. Studies evaluating the efficacy of HR-OCT in diagnosing OSSN, monitoring treatment progression and resolution, as well as in diagnosing recurrences may support its wider application in clinical practice. The integration of HR-OCT with operating microscopes may improve delineation of tumour margins to aid complete tumour resections, thus reducing the risk of recurrence.

8. Conclusions

The rise of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents has improved the management of OSSN, especially in recurrent or extensive disease and in minimizing morbidity associated with surgery. Complemented by HR-OCT, medical management holds promise for the treatment of complex ocular surface disease. The best modality of treatment is patient-tailored carefully selected on the basis of disease factors, co-morbidities, logistical factors including the need for refrigeration, compounding, accessibility, cost and the input of a well-informed, compliant patient. The algorithm in this paper summarizes the modalities available for treatment and proposes an approach to management in an attempt to guide ophthalmologists in selecting the most appropriate treatment regime to minimize treatment related morbidity and improve OSSN control. Further work can be done to validate this algorithm and to develop formal guidelines to direct the management of OSSN.

Author Contributions

Conceptualization, C.H.L.L. and B.X.H.L.; methodology, C.H.L.L.; investigation, C.H.Y.Y., J.J.R.L., J.S.M. and A.S.Y.C.; resources, C.H.L.L., J.S.M. and A.S.Y.C.; data curation, C.H.Y.Y. and J.J.R.L. and C.H.L.L.; writing—original draft preparation, C.H.Y.Y. and J.J.R.L.; writing—review and editing, C.H.L.L., B.X.H.L., G.S., J.S.M., A.S.Y.C., D.K.A.L., S.L.W., S.G.H. and R.M. visualization, C.H.Y.Y. and J.J.R.L.; supervision, C.H.L.L.; project administration, C.H.L.L.; funding acquisition, C.H.L.L. All authors have read and agreed to the published version of the manuscript.

Funding

Publication fees associated with this article have been funded through the Exxonmobile-NUS grant awarded to Chris Lim.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable to this article.

Acknowledgments

Publication fees associated with this article have been supported through the Exxonmobile-NUS grant.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lee, G.A.; Hirst, L.W. Ocular Surface Squamous Neoplasia. Surv. Ophthalmol. 1995, 39, 429–450. [Google Scholar] [CrossRef] [PubMed]
  2. Gichuhi, S.; Sagoo, M.S.; Weiss, H.A.; Burton, M.J. Epidemiology of Ocular Surface Squamous Neoplasia in Africa. Trop. Med. Int. Health 2013, 18, 1424–1443. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Lee, G.A.; Hirst, L.W. Retrospective Study of Ocular Surface Squamous Neoplasia. Aust. N. Z. J. Ophthalmol. 1997, 25, 269–276. [Google Scholar] [CrossRef] [PubMed]
  4. Napora, C.; Cohen, E.J.; Genvert, G.I.; Presson, A.C.; Arentsen, J.J.; Eagle, R.C.; Laibson, P.R. Factors Associated with Conjunctival Intraepithelial Neoplasia: A Case Control Study. Ophthalmic Surg. 1990, 21, 27–30. [Google Scholar] [CrossRef] [PubMed]
  5. Gichuhi, S.; Macharia, E.; Kabiru, J.; Zindamoyen, A.M.; Rono, H.; Ollando, E.; Wachira, J.; Munene, R.; Onyuma, T.; Jaoko, W.G.; et al. Risk Factors for Ocular Surface Squamous Neoplasia in Kenya: A Case-Control Study. Trop. Med. Int. Health 2016, 21, 1522–1530. [Google Scholar] [CrossRef] [PubMed]
  6. Sayed-Ahmed, I.O.; Palioura, S.; Galor, A.; Karp, C.L. Diagnosis and Medical Management of Ocular Surface Squamous Neoplasia. Expert Rev. Ophthalmol. 2017, 12, 11–19. [Google Scholar] [CrossRef] [Green Version]
  7. McClellan, A.J.; McClellan, A.L.; Pezon, C.F.; Karp, C.L.; Feuer, W.; Galor, A. Epidemiology of Ocular Surface Squamous Neoplasia in a Veterans Affairs Population. Cornea 2013, 32, 1354–1358. [Google Scholar] [CrossRef] [Green Version]
  8. McDonnell, J.M.; McDonnell, P.J.; Sun, Y.Y. Human Papillomavirus DNA in Tissues and Ocular Surface Swabs of Patients with Conjunctival Epithelial Neoplasia. Investig. Ophthalmol. Vis. Sci. 1992, 33, 184–189. [Google Scholar]
  9. Sen, S.; Sharma, A.; Panda, A. Immunohistochemical Localization of Human Papilloma Virus in Conjunctival Neoplasias: A Retrospective Study. Indian J. Ophthalmol. 2007, 55, 361–363. [Google Scholar] [CrossRef]
  10. De Koning, M.N.; Waddell, K.; Magyezi, J.; Purdie, K.; Proby, C.; Harwood, C.; Lucas, S.; Downing, R.; Quint, W.G.; Newton, R. Genital and Cutaneous Human Papillomavirus (HPV) Types in Relation to Conjunctival Squamous Cell Neoplasia: A Case-Control Study in Uganda. Infect. Agents Cancer 2008, 3, 12. [Google Scholar] [CrossRef] [Green Version]
  11. Ateenyi-Agaba, C.; Franceschi, S.; Wabwire-Mangen, F.; Arslan, A.; Othieno, E.; Binta-Kahwa, J.; van Doorn, L.-J.; Kleter, B.; Quint, W.; Weiderpass, E. Human Papillomavirus Infection and Squamous Cell Carcinoma of the Conjunctiva. Br. J. Cancer 2010, 102, 262–267. [Google Scholar] [CrossRef] [PubMed]
  12. Scott, I.U.; Karp, C.L.; Nuovo, G.J. Human Papillomavirus 16 and 18 Expression in Conjunctival Intraepithelial Neoplasia. Ophthalmology 2002, 109, 542–547. [Google Scholar] [CrossRef] [PubMed]
  13. Di Girolamo, N. Association of Human Papilloma Virus with Pterygia and Ocular-Surface Squamous Neoplasia. Eye 2012, 26, 202–211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Guech-Ongey, M.; Engels, E.A.; Goedert, J.J.; Biggar, R.J.; Mbulaiteye, S.M. Elevated Risk for Squamous Cell Carcinoma of the Conjunctiva among Adults with AIDS in the United States. Int. J. Cancer 2008, 122, 2590–2593. [Google Scholar] [CrossRef] [Green Version]
  15. Karp, C.L.; Scott, I.U.; Chang, T.S.; Pflugfelder, S.C. Conjunctival Intraepithelial Neoplasia: A Possible Marker for Human Immunodeficiency Virus Infection? Arch. Ophthalmol. 1996, 114, 257–261. [Google Scholar] [CrossRef]
  16. Porges, Y.; Groisman, G.M. Prevalence of HIV with Conjunctival Squamous Cell Neoplasia in an African Provincial Hospital. Cornea 2003, 22, 1–4. [Google Scholar] [CrossRef]
  17. Kamal, S.; Kaliki, S.; Mishra, D.K.; Batra, J.; Naik, M.N. Ocular Surface Squamous Neoplasia in 200 Patients: A Case-Control Study of Immunosuppression Resulting from Human Immunodeficiency Virus versus Immunocompetency. Ophthalmology 2015, 122, 1688–1694. [Google Scholar] [CrossRef]
  18. Kaliki, S.; Kamal, S.; Fatima, S. Ocular Surface Squamous Neoplasia as the Initial Presenting Sign of Human Immunodeficiency Virus Infection in 60 Asian Indian Patients. Int. Ophthalmol. 2017, 37, 1221–1228. [Google Scholar] [CrossRef]
  19. Manderwad, G.P.; Kannabiran, C.; Honavar, S.G.; Vemuganti, G.K. Lack of Association of High-Risk Human Papillomavirus in Ocular Surface Squamous Neoplasia in India. Arch. Pathol. Lab. Med. 2009, 133, 1246–1250. [Google Scholar] [CrossRef]
  20. Shields, C.L.; Demirci, H.; Karatza, E.; Shields, J.A. Clinical Survey of 1643 Melanocytic and Nonmelanocytic Conjunctival Tumors. Ophthalmology 2004, 111, 1747–1754. [Google Scholar] [CrossRef]
  21. Darwich, R.; Ghazawi, F.M.; Le, M.; Rahme, E.; Alghazawi, N.; Zubarev, A.; Moreau, L.; Sasseville, D.; Burnier, M.N.; Litvinov, I.V. Epidemiology of Invasive Ocular Surface Squamous Neoplasia in Canada during 1992–2010. Br. J. Ophthalmol. 2020, 104, 1368–1372. [Google Scholar] [CrossRef] [PubMed]
  22. Alkatan, H.M.; Alshomar, K.M.; Helmi, H.A.; Alhothali, W.M.; Alshalan, A.M. Conjunctival Lesions: A 5-Year Basic Demographic Data and Clinicopathological Review in a Tertiary Eye Care Hospital. J. Epidemiol. Glob. Health 2021, 12, 25–39. [Google Scholar] [CrossRef]
  23. Asadi-Amoli, F.; Ghanadan, A. Survey of 274 Patients with Conjunctival Neoplastic Lesions in Farabi Eye Hospital, Tehran 2006–2012. J. Curr. Ophthalmol. 2015, 27, 37–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Sun, E.C.; Fears, T.R.; Goedert, J.J. Epidemiology of Squamous Cell Conjunctival Cancer. Cancer Epidemiol. Biomark. Prev. 1997, 6, 73–77. [Google Scholar]
  25. Gichuhi, S.; Ohnuma, S.; Sagoo, M.S.; Burton, M.J. Pathophysiology of Ocular Surface Squamous Neoplasia. Exp. Eye Res. 2014, 129, 172–182. [Google Scholar] [CrossRef] [Green Version]
  26. Ateenyi-Agaba, C.; Dai, M.; Le Calvez, F.; Katongole-Mbidde, E.; Smet, A.; Tommasino, M.; Franceschi, S.; Hainaut, P.; Weiderpass, E. TP53 Mutations in Squamous-Cell Carcinomas of the Conjunctiva: Evidence for UV-Induced Mutagenesis. Mutagenesis 2004, 19, 399–401. [Google Scholar] [CrossRef]
  27. Scholz, S.L.; Thomasen, H.; Reis, H.; Möller, I.; Darawsha, R.; Müller, B.; Dekowski, D.; Sucker, A.; Schilling, B.; Schadendorf, D.; et al. Frequent TERT Promoter Mutations in Ocular Surface Squamous Neoplasia. Investig. Ophthalmol. Vis. Sci. 2015, 56, 5854–5861. [Google Scholar] [CrossRef] [Green Version]
  28. Vizcaino, M.A.; Tabbarah, A.Z.; Asnaghi, L.; Maktabi, A.; Eghrari, A.O.; Srikumaran, D.; Eberhart, C.G.; Rodriguez, F.J. ADAM3A Copy Number Gains Occur in a Subset of Conjunctival Squamous Cell Carcinoma and Its High Grade Precursors. Hum. Pathol. 2019, 94, 92–97. [Google Scholar] [CrossRef]
  29. Asnaghi, L.; Alkatan, H.; Mahale, A.; Othman, M.; Alwadani, S.; Al-Hussain, H.; Jastaneiah, S.; Yu, W.; Maktabi, A.; Edward, D.P.; et al. Identification of Multiple DNA Copy Number Alterations Including Frequent 8p11.22 Amplification in Conjunctival Squamous Cell Carcinoma. Investig. Ophthalmol. Vis. Sci. 2014, 55, 8604–8613. [Google Scholar] [CrossRef] [Green Version]
  30. Mahale, A.; Alkatan, H.; Alwadani, S.; Othman, M.; Suarez, M.J.; Price, A.; Al-Hussain, H.; Jastaneiah, S.; Yu, W.; Maktabi, A.; et al. Altered Gene Expression in Conjunctival Squamous Cell Carcinoma. Mod. Pathol. 2016, 29, 452–460. [Google Scholar] [CrossRef] [Green Version]
  31. Manderwad, G.P.; Gokul, G.; Kannabiran, C.; Honavar, S.G.; Khosla, S.; Vemuganti, G.K. Hypomethylation of the DNMT3L Promoter in Ocular Surface Squamous Neoplasia. Arch. Pathol. Lab. Med. 2010, 134, 1193–1196. [Google Scholar] [CrossRef] [PubMed]
  32. Kaliki, S.; Freitag, S.K.; Chodosh, J. Nodulo-Ulcerative Ocular Surface Squamous Neoplasia in 6 Patients: A Rare Presentation. Cornea 2017, 36, 322–326. [Google Scholar] [CrossRef] [PubMed]
  33. Kao, A.A.; Galor, A.; Karp, C.L.; Abdelaziz, A.; Feuer, W.J.; Dubovy, S.R. Clinicopathologic Correlation of Ocular Surface Squamous Neoplasms at Bascom Palmer Eye Institute: 2001 to 2010. Ophthalmology 2012, 119, 1773–1776. [Google Scholar] [CrossRef] [PubMed]
  34. Oellers, P.; Karp, C.L.; Sheth, A.; Kao, A.A.; Abdelaziz, A.; Matthews, J.L.; Dubovy, S.R.; Galor, A. Prevalence, Treatment, and Outcomes of Coexistent Ocular Surface Squamous Neoplasia and Pterygium. Ophthalmology 2013, 120, 445–450. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Barros, J.D.N.; Lowen, M.S.; Moraes-Filho, M.N.D.; Martins, M.C. Use of Impression Cytology for the Detection of Unsuspected Ocular Surface Squamous Neoplasia Cells in Pterygia. Arq. Bras. Oftalmol. 2014, 77, 305–309. [Google Scholar] [CrossRef] [Green Version]
  36. Semenova, E.A.; Milman, T.; Finger, P.T.; Natesh, S.; Kurli, M.; Schneider, S.; Iacob, C.E.; McCormick, S.A. The Diagnostic Value of Exfoliative Cytology vs. Histopathology for Ocular Surface Squamous Neoplasia. Am. J. Ophthalmol. 2009, 148, 772–778.e1. [Google Scholar] [CrossRef]
  37. Kayat, K.V.; Correa Dantas, P.E.; Felberg, S.; Galvão, M.A.; Saieg, M.A. Exfoliative Cytology in the Diagnosis of Ocular Surface Squamous Neoplasms. Cornea 2017, 36, 127–130. [Google Scholar] [CrossRef]
  38. Xu, Y.; Zhou, Z.; Xu, Y.; Wang, M.; Liu, F.; Qu, H.; Hong, J. The Clinical Value of in Vivo Confocal Microscopy for Diagnosis of Ocular Surface Squamous Neoplasia. Eye 2012, 26, 781–787. [Google Scholar] [CrossRef]
  39. Nguena, M.B.; van den Tweel, J.G.; Makupa, W.; Hu, V.H.; Weiss, H.A.; Gichuhi, S.; Burton, M.J. Diagnosing Ocular Surface Squamous Neoplasia in East Africa: Case-Control Study of Clinical and in Vivo Confocal Microscopy Assessment. Ophthalmology 2014, 121, 484–491. [Google Scholar] [CrossRef] [Green Version]
  40. Kieval, J.Z.; Karp, C.L.; Abou Shousha, M.; Galor, A.; Hoffman, R.A.; Dubovy, S.R.; Wang, J. Ultra-High Resolution Optical Coherence Tomography for Differentiation of Ocular Surface Squamous Neoplasia and Pterygia. Ophthalmology 2012, 119, 481–486. [Google Scholar] [CrossRef]
  41. Shields, J.A.; Shields, C.L.; De Potter, P. Surgical Management of Conjunctival Tumors: The 1994 Lynn B. McMahan Lecture. Arch. Ophthalmol. 1997, 115, 808–815. [Google Scholar] [CrossRef] [PubMed]
  42. Al Bayyat, G.; Arreaza-Kaufman, D.; Venkateswaran, N.; Galor, A.; Karp, C.L. Update on Pharmacotherapy for Ocular Surface Squamous Neoplasia. Eye Vis. 2019, 6, 24. [Google Scholar] [CrossRef] [PubMed]
  43. Nanji, A.A.; Sayyad, F.E.; Karp, C.L. Topical Chemotherapy for Ocular Surface Squamous Neoplasia. Curr. Opin. Ophthalmol. 2013, 24, 336–342. [Google Scholar] [CrossRef] [PubMed]
  44. Nanji, A.A.; Moon, C.S.; Galor, A.; Sein, J.; Oellers, P.; Karp, C.L. Surgical versus Medical Treatment of Ocular Surface Squamous Neoplasia: A Comparison of Recurrences and Complications. Ophthalmology 2014, 121, 994–1000. [Google Scholar] [CrossRef] [Green Version]
  45. Ali, M.J.; Pujari, A.; Dave, T.V.; Kaliki, S.; Naik, M.N. Clinicopathological Profile of Orbital Exenteration: 14 Years of Experience from a Tertiary Eye Care Center in South India. Int. Ophthalmol. 2016, 36, 253–258. [Google Scholar] [CrossRef]
  46. Adler, E.; Turner, J.R.; Stone, D.U. Ocular Surface Squamous Neoplasia: A Survey of Changes in the Standard of Care from 2003 to 2012. Cornea 2013, 32, 1558–1561. [Google Scholar] [CrossRef]
  47. Shields, C.L.; Demirci, H.; Marr, B.P.; Masheyekhi, A.; Materin, M.; Shields, J.A. Chemoreduction with Topical Mitomycin C Prior to Resection of Extensive Squamous Cell Carcinoma of the Conjunctiva. Arch. Ophthalmol. 2005, 123, 109–113. [Google Scholar] [CrossRef] [Green Version]
  48. Galor, A.; Karp, C.L.; Oellers, P.; Kao, A.A.; Abdelaziz, A.; Feuer, W.; Dubovy, S.R. Predictors of Ocular Surface Squamous Neoplasia Recurrence after Excisional Surgery. Ophthalmology 2012, 119, 1974–1981. [Google Scholar] [CrossRef] [Green Version]
  49. Kim, H.J.; Shields, C.L.; Shah, S.U.; Kaliki, S.; Lally, S.E. Giant Ocular Surface Squamous Neoplasia Managed with Interferon Alpha-2b as Immunotherapy or Immunoreduction. Ophthalmology 2012, 119, 938–944. [Google Scholar] [CrossRef]
  50. Kim, S.E.; Salvi, S.M. Immunoreduction of Ocular Surface Tumours with Intralesional Interferon Alpha-2a. Eye 2018, 32, 460–462. [Google Scholar] [CrossRef] [Green Version]
  51. Nuruddin, M.; Roy, S.R.; Hoque, F. Pegylated Interferon-Alpha-2a for the Treatment of Ocular Surface Squamous Neoplasia. Oman J. Ophthalmol. 2022, 15, 81–84. [Google Scholar] [CrossRef] [PubMed]
  52. Blasi, M.A.; Maceroni, M.; Sammarco, M.G.; Pagliara, M.M. Mitomycin C or Interferon as Adjuvant Therapy to Surgery for Ocular Surface Squamous Neoplasia: Comparative Study. Eur. J. Ophthalmol. 2018, 28, 204–209. [Google Scholar] [CrossRef] [PubMed]
  53. Pestka, S. The Human Interferon Alpha Species and Receptors. Biopolymers 2000, 55, 254–287. [Google Scholar] [CrossRef] [PubMed]
  54. Krilis, M.; Tsang, H.; Coroneo, M. Treatment of Conjunctival and Corneal Epithelial Neoplasia with Retinoic Acid and Topical Interferon Alfa-2b: Long-Term Follow-Up. Ophthalmology 2012, 119, 1969–1973. [Google Scholar] [CrossRef]
  55. Asena, L.; Dursun Altınörs, D. Topical Bevacizumab for the Treatment of Ocular Surface Squamous Neoplasia. J. Ocul. Pharmacol. Ther. 2015, 31, 487–490. [Google Scholar] [CrossRef] [Green Version]
  56. Ip, M.H.; Coroneo, M.T. Treatment of Previously Refractory Ocular Surface Squamous Neoplasia with Topical Cidofovir. JAMA Ophthalmol. 2017, 135, 500–502. [Google Scholar] [CrossRef] [PubMed]
  57. Ip, M.H.; Robert George, C.R.; Naing, Z.; Perlman, E.M.; Rawlinson, W.; Coroneo, M.T. Topical Cidofovir for Treatment-Refractory Ocular Surface Squamous Neoplasia. Ophthalmology 2018, 125, 617–619. [Google Scholar] [CrossRef]
  58. Cekiç, O.; Bardak, Y.; Kapucuoğlu, N. Photodynamic Therapy for Conjunctival Ocular Surface Squamous Neoplasia. J. Ocul. Pharmacol. Ther. 2011, 27, 205–207. [Google Scholar] [CrossRef]
  59. Sarici, A.M.; Arvas, S.; Pazarli, H. Combined Excision, Cryotherapy, and Intraoperative Mitomycin C (EXCRIM) for Localized Intraepithelial and Squamous Cell Carcinoma of the Conjunctiva. Graefes Arch. Clin. Exp. Ophthalmol. 2013, 251, 2201–2204. [Google Scholar] [CrossRef]
  60. Peksayar, G.; Soytürk, M.K.; Demiryont, M. Long-Term Results of Cryotherapy on Malignant Epithelial Tumors of the Conjunctiva. Am. J. Ophthalmol. 1989, 107, 337–340. [Google Scholar] [CrossRef]
  61. Buus, D.R.; Tse, D.T.; Folberg, R.; Buuns, D.R. Microscopically Controlled Excision of Conjunctival Squamous Cell Carcinoma. Am. J. Ophthalmol. 1994, 117, 97–102. [Google Scholar] [CrossRef] [PubMed]
  62. Shields, J.A.; Shields, C.L.; Gunduz, K.; Eagle, R.C. The 1998 Pan American Lecture Intraocular Invasion of Conjunctival Squamous Cell Carcinoma in Five Patients. Ophthal. Plast. Reconstr. Surg. 1999, 15, 153–160. [Google Scholar] [CrossRef] [PubMed]
  63. Rajabi, M.T.; Ghasemi, H.; Safizadeh, M.; Jamshidi, S.; Asadi-Amoli, F.; Abrishami, Y.; Oestreicher, J.H. Conjunctival Squamous Cell Carcinoma with Intraocular Invasion after Radiotherapy in Epidermodysplasia Verruciformis. Can. J. Ophthalmol. 2014, 49, e43–e46. [Google Scholar] [CrossRef] [PubMed]
  64. Hanada, K.; Nishikawa, N.; Miyokawa, N.; Yoshida, A. Long-Term Outcome of Amniotic Membrane Transplantation Combined with Mitomycin C for Conjunctival Reconstruction after Ocular Surface Squamous Neoplasia Excision. Int. Ophthalmol. 2017, 37, 71–78. [Google Scholar] [CrossRef] [PubMed]
  65. Xie, H.-T.; Zhang, Y.-Y.; Jiang, D.-L.; Wu, J.; Wang, J.-S.; Zhang, M.-C. Amniotic Membrane Transplantation with Topical Interferon Alfa-2b after Excision of Ocular Surface Squamous Neoplasia. Int. J. Ophthalmol. 2018, 11, 160–162. [Google Scholar] [CrossRef] [PubMed]
  66. Feizi, S.; Esfandiari, H. Recurrent Conjunctival Squamous Cell Carcinoma and Intraocular Tumor Extension after Topical Erythropoietin: A Case Report. Case Rep. Ophthalmol. 2022, 13, 89–95. [Google Scholar] [CrossRef]
  67. Kaliki, S.; Mohammad, F.A.; Tahiliani, P.; Sangwan, V.S. Concomitant Simple Limbal Epithelial Transplantation After Surgical Excision of Ocular Surface Squamous Neoplasia. Am. J. Ophthalmol. 2017, 174, 68–75. [Google Scholar] [CrossRef]
  68. Mittal, V.; Narang, P.; Menon, V.; Mittal, R.; Honavar, S. Primary Simple Limbal Epithelial Transplantation Along with Excisional Biopsy in the Management of Extensive Ocular Surface Squamous Neoplasia. Cornea 2016, 35, 1650–1652. [Google Scholar] [CrossRef]
  69. Narang, P.; Mittal, V.; Menon, V.; Bhaduri, A.; Chaudhuri, B.R.; Honavar, S.G. Primary Limbal Stem Cell Transplantation in the Surgical Management of Extensive Ocular Surface Squamous Neoplasia Involving the Limbus. Indian J. Ophthalmol. 2018, 66, 1569–1573. [Google Scholar] [CrossRef]
  70. Erie, J.C.; Campbell, R.J.; Liesegang, T.J. Conjunctival and Corneal Intraepithelial and Invasive Neoplasia. Ophthalmology 1986, 93, 176–183. [Google Scholar] [CrossRef]
  71. Newton, R.; Ziegler, J.; Ateenyi-Agaba, C.; Bousarghin, L.; Casabonne, D.; Beral, V.; Mbidde, E.; Carpenter, L.; Reeves, G.; Parkin, D.M.; et al. The Epidemiology of Conjunctival Squamous Cell Carcinoma in Uganda. Br. J. Cancer 2002, 87, 301–308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Bowen, R.C.; Soto, H.; Raval, V.; Bellerive, C.; Yeaney, G.; Singh, A.D. Ocular Surface Squamous Neoplasia: Outcomes Following Primary Excision with 2 Mm Margin and Cryotherapy. Eye 2021, 35, 3102–3109. [Google Scholar] [CrossRef] [PubMed]
  73. Chen, C.; Louis, D.; Dodd, T.; Muecke, J. Mitomycin C as an Adjunct in the Treatment of Localised Ocular Surface Squamous Neoplasia. Br. J. Ophthalmol. 2004, 88, 17–18. [Google Scholar] [CrossRef] [PubMed]
  74. Karp, C. Ocular Surface Squamous Neoplasia Lecture; Bascom Palmer Eye Institute and Oftalmo University: Miami, FL, USA, 2020. [Google Scholar]
  75. Amin, M.B.; Edge, S.B. ; American Joint Committee on Cancer. AJCC Cancer Staging Manual; Springer: Berlin/Heidelberg, Germany, 2017; ISBN 978-3-319-40617-6. [Google Scholar]
  76. Stone, D.U.; Butt, A.L.; Chodosh, J. Ocular Surface Squamous Neoplasia: A Standard of Care Survey. Cornea 2005, 24, 297–300. [Google Scholar] [CrossRef] [PubMed]
  77. de Keizer, R.J.; de Wolff-Rouendaal, D.; van Delft, J.L. Topical Application of 5-Fluorouracil in Premalignant Lesions of Cornea, Conjunctiva and Eyelid. Doc. Ophthalmol. Adv. Ophthalmol. 1986, 64, 31–42. [Google Scholar] [CrossRef]
  78. Yeatts, R.P.; Engelbrecht, N.E.; Curry, C.D.; Ford, J.G.; Walter, K.A. 5-Fluorouracil for the Treatment of Intraepithelial Neoplasia of the Conjunctiva and Cornea. Ophthalmology 2000, 107, 2190–2195. [Google Scholar] [CrossRef]
  79. Midena, E.; Boccato, P.; Angeli, C.D. Conjunctival Squamous Cell Carcinoma Treated with Topical 5-Fluorouracil. Arch. Ophthalmol. 1997, 115, 1600–1601. [Google Scholar] [CrossRef]
  80. Joag, M.G.; Sise, A.; Murillo, J.C.; Sayed-Ahmed, I.O.; Wong, J.R.; Mercado, C.; Galor, A.; Karp, C.L. Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia. Ophthalmology 2016, 123, 1442–1448. [Google Scholar] [CrossRef] [Green Version]
  81. Wilson, M.W.; Hungerford, J.L.; George, S.M.; Madreperla, S.A. Topical Mitomycin C for the Treatment of Conjunctival and Corneal Epithelial Dysplasia and Neoplasia. Am. J. Ophthalmol. 1997, 124, 303–311. [Google Scholar] [CrossRef]
  82. Frucht-Pery, J.; Sugar, J.; Baum, J.; Sutphin, J.E.; Pe’er, J.; Savir, H.; Holland, E.J.; Meisler, D.M.; Foster, J.A.; Folberg, R.; et al. Mitomycin C Treatment for Conjunctival-Corneal Intraepithelial Neoplasia: A Multicenter Experience. Ophthalmology 1997, 104, 2085–2093. [Google Scholar] [CrossRef]
  83. Frucht-Pery, J.; Rozenman, Y.; Pe’er, J. Topical Mitomycin-C for Partially Excised Conjunctival Squamous Cell Carcinoma. Ophthalmology 2002, 109, 548–552. [Google Scholar] [CrossRef] [PubMed]
  84. Kemp, E.G.; Harnett, A.N.; Chatterjee, S. Preoperative Topical and Intraoperative Local Mitomycin C Adjuvant Therapy in the Management of Ocular Surface Neoplasias. Br. J. Ophthalmol. 2002, 86, 31–34. [Google Scholar] [CrossRef] [PubMed]
  85. Siganos, C.S.; Kozobolis, V.P.; Christodoulakis, E.V. The Intraoperative Use of Mitomycin-C in Excision of Ocular Surface Neoplasia with or without Limbal Autograft Transplantation. Cornea 2002, 21, 12–16. [Google Scholar] [CrossRef] [PubMed]
  86. Shields, C.L.; Naseripour, M.; Shields, J.A. Topical Mitomycin C for Extensive, Recurrent Conjunctival-Corneal Squamous Cell Carcinoma. Am. J. Ophthalmol. 2002, 133, 601–606. [Google Scholar] [CrossRef]
  87. Hirst, L.W. Randomized Controlled Trial of Topical Mitomycin C for Ocular Surface Squamous Neoplasia: Early Resolution. Ophthalmology 2007, 114, 976–982. [Google Scholar] [CrossRef]
  88. Zarei-Ghanavati, S.; Alizadeh, R.; Deng, S.X. Topical Interferon Alpha-2b for Treatment of Noninvasive Ocular Surface Squamous Neoplasia with 360° Limbal Involvement. J. Ophthalmic Vis. Res. 2014, 9, 423–426. [Google Scholar] [CrossRef]
  89. Rudkin, A.K.; Dempster, L.; Muecke, J.S. Management of Diffuse Ocular Surface Squamous Neoplasia: Efficacy and Complications of Topical Chemotherapy. Clin. Exp. Ophthalmol. 2015, 43, 20–25. [Google Scholar] [CrossRef]
  90. Maskin, S.L. Regression of Limbal Epithelial Dysplasia with Topical Interferon. Arch. Ophthalmol. 1994, 112, 1145–1146. [Google Scholar] [CrossRef]
  91. Hu, F.R.; Wu, M.J.; Kuo, S.H. Interferon Treatment for Corneolimbal Squamous Dysplasia. Am. J. Ophthalmol. 1998, 125, 118–119. [Google Scholar] [CrossRef]
  92. Vann, R.R.; Karp, C.L. Perilesional and Topical Interferon Alfa-2b for Conjunctival and Corneal Neoplasia. Ophthalmology 1999, 106, 91–97. [Google Scholar] [CrossRef]
  93. Abraham, L.M.; Selva, D.; Casson, R.; Leibovitch, I. The Clinical Applications of Fluorouracil in Ophthalmic Practice. Drugs 2007, 67, 237–255. [Google Scholar] [CrossRef] [PubMed]
  94. Sun, Y.; Hua, R. Long-Term Efficacy and Safety of Subconjunctival/Perilesional 5-Fluorouracil Injections for Ocular Surface Squamous Neoplasia. Drug Des. Dev. Ther. 2020, 14, 5659–5665. [Google Scholar] [CrossRef] [PubMed]
  95. Parrozzani, R.; Lazzarini, D.; Alemany-Rubio, E.; Urban, F.; Midena, E. Topical 1% 5-Fluorouracil in Ocular Surface Squamous Neoplasia: A Long-Term Safety Study. Br. J. Ophthalmol. 2011, 95, 355–359. [Google Scholar] [CrossRef] [Green Version]
  96. Parrozzani, R.; Frizziero, L.; Trainiti, S.; Testi, I.; Miglionico, G.; Pilotto, E.; Blandamura, S.; Fassina, A.; Midena, E. Topical 1% 5-Fluoruracil as a Sole Treatment of Corneoconjunctival Ocular Surface Squamous Neoplasia: Long-Term Study. Br. J. Ophthalmol. 2017, 101, 1094–1099. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Venkateswaran, N.; Mercado, C.; Galor, A.; Karp, C.L. Comparison of Topical 5-Fluorouracil and Interferon Alfa-2b as Primary Treatment Modalities for Ocular Surface Squamous Neoplasia. Am. J. Ophthalmol. 2019, 199, 216–222. [Google Scholar] [CrossRef] [PubMed]
  98. Shields, C.L.; Chien, J.L.; Surakiatchanukul, T.; Sioufi, K.; Lally, S.E.; Shields, J.A. Conjunctival Tumors: Review of Clinical Features, Risks, Biomarkers, and Outcomes—The 2017 J. Donald M. Gass Lecture. Asia-Pac. J. Ophthalmol. 2017, 6, 109–120. [Google Scholar] [CrossRef]
  99. Caravella, L.P.; Burns, J.A.; Zangmeister, M. Punctal-Canalicular Stenosis Related to Systemic Fluorouracil Therapy. Arch. Ophthalmol. 1981, 99, 284–286. [Google Scholar] [CrossRef]
  100. Rudkin, A.K.; Muecke, J.S. Adjuvant 5-Fluorouracil in the Treatment of Localised Ocular Surface Squamous Neoplasia. Br. J. Ophthalmol. 2011, 95, 947–950. [Google Scholar] [CrossRef]
  101. Kim, J.W.; Abramson, D.H. Topical Treatment Options for Conjunctival Neoplasms. Clin. Ophthalmol. 2008, 2, 503–515. [Google Scholar] [CrossRef] [Green Version]
  102. Cohen, V.M.L.; O’Day, R.F. Management Issues in Conjunctival Tumours: Ocular Surface Squamous Neoplasia. Ophthalmol. Ther. 2020, 9, 181–190. [Google Scholar] [CrossRef] [Green Version]
  103. Ballalai, P.L.; Erwenne, C.M.; Martins, M.C.; Lowen, M.S.; Barros, J.N. Long-Term Results of Topical Mitomycin C 0.02% for Primary and Recurrent Conjunctival-Corneal Intraepithelial Neoplasia. Ophthal. Plast. Reconstr. Surg. 2009, 25, 296–299. [Google Scholar] [CrossRef] [PubMed]
  104. Gupta, A.; Muecke, J. Treatment of Ocular Surface Squamous Neoplasia with Mitomycin C. Br. J. Ophthalmol. 2010, 94, 555–558. [Google Scholar] [CrossRef] [PubMed]
  105. Kusumesh, R.; Ambastha, A.; Kumar, S.; Sinha, B.P.; Imam, N. Retrospective Comparative Study of Topical Interferon A2b Versus Mitomycin C for Primary Ocular Surface Squamous Neoplasia. Cornea 2017, 36, 327–331. [Google Scholar] [CrossRef] [PubMed]
  106. Billing, K.; Karagiannis, A.; Selva, D. Punctal-Canalicular Stenosis Associated with Mitomycin-C for Corneal Epithelial Dysplasia. Am. J. Ophthalmol. 2003, 136, 746–747. [Google Scholar] [CrossRef] [PubMed]
  107. Khong, J.J.; Muecke, J. Complications of Mitomycin C Therapy in 100 Eyes with Ocular Surface Neoplasia. Br. J. Ophthalmol. 2006, 90, 819–822. [Google Scholar] [CrossRef] [Green Version]
  108. Daniell, M.; Maini, R.; Tole, D. Use of Mitomycin C in the Treatment of Corneal Conjunctival Intraepithelial Neoplasia. Clin. Exp. Ophthalmol. 2002, 30, 94–98. [Google Scholar] [CrossRef]
  109. Prabhasawat, P.; Tarinvorakup, P.; Tesavibul, N.; Uiprasertkul, M.; Kosrirukvongs, P.; Booranapong, W.; Srivannaboon, S. Topical 0.002% Mitomycin C for the Treatment of Conjunctival-Corneal Intraepithelial Neoplasia and Squamous Cell Carcinoma. Cornea 2005, 24, 443–448. [Google Scholar] [CrossRef]
  110. Russell, H.C.; Chadha, V.; Lockington, D.; Kemp, E.G. Topical Mitomycin C Chemotherapy in the Management of Ocular Surface Neoplasia: A 10-Year Review of Treatment Outcomes and Complications. Br. J. Ophthalmol. 2010, 94, 1316–1321. [Google Scholar] [CrossRef]
  111. Dudney, B.W.; Malecha, M.A. Limbal Stem Cell Deficiency Following Topical Mitomycin C Treatment of Conjunctival-Corneal Intraepithelial Neoplasia. Am. J. Ophthalmol. 2004, 137, 950–951. [Google Scholar] [CrossRef]
  112. Kopp, E.D.; Seregard, S. Epiphora as a Side Effect of Topical Mitomycin C. Br. J. Ophthalmol. 2004, 88, 1422–1424. [Google Scholar] [CrossRef] [Green Version]
  113. Sammarco, M.G.; Pagliara, M.M.; Savino, G.; Giannuzzi, F.; Carlà, M.M.; Caputo, C.G.; Blasi, M.A. Supportive Treatment to Chemotherapy with MMC, in Patients with Ocular Surface Squamous Neoplasia or Conjunctival Melanocytic Tumor. J. Cancer Res. Clin. Oncol. 2022. ahead of print. [Google Scholar] [CrossRef]
  114. González-Navajas, J.M.; Lee, J.; David, M.; Raz, E. Immunomodulatory Functions of Type I Interferons. Nat. Rev. Immunol. 2012, 12, 125–135. [Google Scholar] [CrossRef]
  115. Darnell, J.E. STATs and Gene Regulation. Science 1997, 277, 1630–1635. [Google Scholar] [CrossRef] [PubMed]
  116. Lekmine, F.; Uddin, S.; Sassano, A.; Parmar, S.; Brachmann, S.M.; Majchrzak, B.; Sonenberg, N.; Hay, N.; Fish, E.N.; Platanias, L.C. Activation of the P70 S6 Kinase and Phosphorylation of the 4E-BP1 Repressor of MRNA Translation by Type I Interferons. J. Biol. Chem. 2003, 278, 27772–27780. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Bracarda, S.; Eggermont, A.M.M.; Samuelsson, J. Redefining the Role of Interferon in the Treatment of Malignant Diseases. Eur. J. Cancer 2010, 46, 284–297. [Google Scholar] [CrossRef]
  118. Houglum, J.E. Interferon: Mechanisms of Action and Clinical Value. Clin. Pharm. 1983, 2, 20–28. [Google Scholar] [CrossRef] [PubMed]
  119. Mata, E.; Conesa, E.; Castro, M.; Martínez, L.; de Pablo, C.; González, M.L. Conjunctival squamous cell carcinoma: Paradoxical response to interferon eyedrops. Arch. Soc. Esp. Oftalmol. 2014, 89, 293–296. [Google Scholar] [CrossRef] [PubMed]
  120. Ashkenazy, N.; Karp, C.L.; Wang, G.; Acosta, C.M.; Galor, A. Immunosuppression as a Possible Risk Factor for Interferon Nonresponse in Ocular Surface Squamous Neoplasia. Cornea 2017, 36, 506–510. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Karp, C.L.; Galor, A.; Chhabra, S.; Barnes, S.D.; Alfonso, E.C. Subconjunctival/Perilesional Recombinant Interferon A2b for Ocular Surface Squamous Neoplasia: A 10-Year Review. Ophthalmology 2010, 117, 2241–2246. [Google Scholar] [CrossRef]
  122. Galor, A.; Karp, C.L.; Chhabra, S.; Barnes, S.; Alfonso, E.C. Topical Interferon Alpha 2b Eye-Drops for Treatment of Ocular Surface Squamous Neoplasia: A Dose Comparison Study. Br. J. Ophthalmol. 2010, 94, 551–554. [Google Scholar] [CrossRef]
  123. Shields, C.L.; Kaliki, S.; Kim, H.J.; Al-Dahmash, S.; Shah, S.U.; Lally, S.E.; Shields, J.A. Interferon for Ocular Surface Squamous Neoplasia in 81 Cases: Outcomes Based on the American Joint Committee on Cancer Classification. Cornea 2013, 32, 248–256. [Google Scholar] [CrossRef] [PubMed]
  124. Schechter, B.A.; Schrier, A.; Nagler, R.S.; Smith, E.F.; Velasquez, G.E. Regression of Presumed Primary Conjunctival and Corneal Intraepithelial Neoplasia with Topical Interferon Alpha-2b. Cornea 2002, 21, 6–11. [Google Scholar] [CrossRef] [PubMed]
  125. Kusumesh, R.; Ambastha, A.; Sinha, B.; Kumar, R. Topical Interferon α-2b as a Single Therapy for Primary Ocular Surface Squamous Neoplasia. Asia-Pac. J. Ophthalmol. 2015, 4, 279–282. [Google Scholar] [CrossRef] [PubMed]
  126. Shields, C.L.; Constantinescu, A.B.; Paulose, S.A.; Yaghy, A.; Dalvin, L.A.; Shields, J.A.; Lally, S.E. Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b: Comparative Analysis of Outcomes Based on Original Tumor Configuration. Indian J. Ophthalmol. 2021, 69, 563–567. [Google Scholar] [CrossRef]
  127. Ghaffari, R.; Barijani, S.; Alivand, A.; Latifi, G.; Ghassemi, H.; Zarei-Ghanavati, M.; Djalilian, A.R. Recombinant Interferon Alpha-2b as Primary Treatment for Ocular Surface Squamous Neoplasia. J. Curr. Ophthalmol. 2021, 33, 260–265. [Google Scholar] [CrossRef]
  128. Nava-Castañeda, Á.; Hernández-Orgaz, J.; Garnica-Hayashi, L.; Ansart, A.; Matus, G.; Tovilla-Canales, J.L. Management of Ocular Surface Squamous Neoplasia with Topical and Intralesional Interferon Alpha 2B in Mexicans. Nepal. J. Ophthalmol. 2018, 10, 143–150. [Google Scholar] [CrossRef] [Green Version]
  129. Kaliki, S.; Bejjanki, K.M.; Desai, A.; Mohamed, A. Interferon Alfa 2b for Ocular Surface Squamous Neoplasia: Factors Influencing the Treatment Response. Semin. Ophthalmol. 2019, 34, 465–472. [Google Scholar] [CrossRef]
  130. Lee, G.A.; Hess, L.; Glasson, W.J.; Whitehead, K. Topical Interferon Alpha-2b Induced Reactive Lymphoid Hyperplasia Masquerading as Orbital Extension of Ocular Surface Squamous Neoplasia. Cornea 2018, 37, 796–798. [Google Scholar] [CrossRef]
  131. Karp, C.L.; Moore, J.K.; Rosa, R.H. Treatment of Conjunctival and Corneal Intraepithelial Neoplasia with Topical Interferon Alpha-2b. Ophthalmology 2001, 108, 1093–1098. [Google Scholar] [CrossRef]
  132. Cruzado-Sánchez, D.; Salas-Diaz, M.; Tellez, W.A.; Alvarez-Matos, S.E.; Serpa-Frías, S. Interferon Alpha-2a as Alternative Treatment for Conjunctival Squamous Cell Carcinoma. Arch. Soc. Esp. Oftalmol. 2017, 92, 539–542. [Google Scholar] [CrossRef]
  133. Park, J.; Han, J.; Chung, T.-Y.; Lim, D.H.; Choi, C.Y. Pegylated Interferon Alpha 2a for the Treatment of Ocular Surface Squamous Neoplasia. Cornea 2022, 41, 1271–1275. [Google Scholar] [CrossRef] [PubMed]
  134. Rubinfeld, R.S.; Pfister, R.R.; Stein, R.M.; Foster, C.S.; Martin, N.F.; Stoleru, S.; Talley, A.R.; Speaker, M.G. Serious Complications of Topical Mitomycin-C after Pterygium Surgery. Ophthalmology 1992, 99, 1647–1654. [Google Scholar] [CrossRef] [PubMed]
  135. Meel, R.; Dhiman, R.; Kashyap, S.; Agrawal, S.; Pushker, N.; Bakhshi, S. Systemic Neoadjuvant Chemotherapy in Non-Resectable Invasive Squamous Cell Carcinoma of Ocular Surface. Eur. J. Ophthalmol. 2021, 32, 11206721211014376. [Google Scholar] [CrossRef] [PubMed]
  136. Siedlecki, A.N.; Tapp, S.; Tosteson, A.N.A.; Larson, R.J.; Karp, C.L.; Lietman, T.; Zegans, M.E. Surgery Versus Interferon Alpha-2b Treatment Strategies for Ocular Surface Squamous Neoplasia: A Literature-Based Decision Analysis. Cornea 2016, 35, 613–618. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Birkholz, E.S.; Goins, K.M.; Sutphin, J.E.; Kitzmann, A.S.; Wagoner, M.D. Treatment of Ocular Surface Squamous Cell Intraepithelial Neoplasia with and without Mitomycin C. Cornea 2011, 30, 37–41. [Google Scholar] [CrossRef]
  138. Gichuhi, S.; Macharia, E.; Kabiru, J.; Zindamoyen, A.M.; Rono, H.; Ollando, E.; Wachira, J.; Munene, R.; Maina, J.; Onyuma, T.; et al. Topical Fluorouracil after Surgery for Ocular Surface Squamous Neoplasia in Kenya: A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Glob. Health 2016, 4, e378–e385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Viani, G.A.; Fendi, L.I.D. Adjuvant Treatment or Primary Topical Monotherapy for Ocular Surface Squamous Neoplasia: A Systematic Review. Arq. Bras. Oftalmol. 2017, 80, 131–136. [Google Scholar] [CrossRef] [PubMed]
  140. Bahrami, B.; Greenwell, T.; Muecke, J.S. Long-Term Outcomes after Adjunctive Topical 5-Flurouracil or Mitomycin C for the Treatment of Surgically Excised, Localized Ocular Surface Squamous Neoplasia. Clin. Exp. Ophthalmol. 2014, 42, 317–322. [Google Scholar] [CrossRef] [PubMed]
  141. Barbazetto, I.A.; Lee, T.C.; Abramson, D.H. Treatment of Conjunctival Squamous Cell Carcinoma with Photodynamic Therapy. Am. J. Ophthalmol. 2004, 138, 183–189. [Google Scholar] [CrossRef]
  142. Faramarzi, A.; Feizi, S. Subconjunctival Bevacizumab Injection for Ocular Surface Squamous Neoplasia. Cornea 2013, 32, 998–1001. [Google Scholar] [CrossRef]
  143. Paul, S.; Stone, D.U. Intralesional Bevacizumab Use for Invasive Ocular Surface Squamous Neoplasia. J. Ocul. Pharmacol. Ther. 2012, 28, 647–649. [Google Scholar] [CrossRef] [PubMed]
  144. Finger, P.T.; Chin, K.J. Refractory Squamous Cell Carcinoma of the Conjunctiva Treated with Subconjunctival Ranibizumab (Lucentis): A Two-Year Study. Ophthal. Plast. Reconstr. Surg. 2012, 28, 85–89. [Google Scholar] [CrossRef] [PubMed]
  145. Teng, C.C.; Chin, K.J.; Finger, P.T. Subconjunctival Ranibizumab for Squamous Cell Carcinoma of the Conjunctiva with Corneal Extension. Br. J. Ophthalmol. 2009, 93, 837–838. [Google Scholar] [CrossRef] [PubMed]
  146. Damani, M.R.; Shah, A.R.; Karp, C.L.; Orlin, S.E. Treatment of Ocular Surface Squamous Neoplasia with Topical Aloe Vera Drops. Cornea 2015, 34, 87–89. [Google Scholar] [CrossRef]
  147. Herbort, C.P.; Zografos, L.; Zwingli, M.; Schoeneich, M. Topical Retinoic Acid in Dysplastic and Metaplastic Keratinization of Corneoconjunctival Epithelium. Graefes Arch. Clin. Exp. Ophthalmol. 1988, 226, 22–26. [Google Scholar] [CrossRef]
  148. Caujolle, J.-P.; Maschi, C.; Chauvel, P.; Herault, J.; Gastaud, P. Surgery and additional protontherapy for treatment of invasive and recurrent squamous cell carcinomas: Technique and preliminary results. J. Fr. Ophtalmol. 2009, 32, 707–714. [Google Scholar] [CrossRef]
  149. Santoni, A.; Thariat, J.; Maschi, C.; Herault, J.; Baillif, S.; Lassalle, S.; Peyrichon, M.L.; Salleron, J.; Caujolle, J.-P. Management of Invasive Squamous Cell Carcinomas of the Conjunctiva. Am. J. Ophthalmol. 2019, 200, 1–9. [Google Scholar] [CrossRef]
  150. El-Assal, K.S.; Salvi, S.M.; Rundle, P.A.; Mudhar, H.S.; Rennie, I.G. Treatment of Invasive Ocular Surface Squamous Neoplasia with Proton Beam Therapy. Eye 2013, 27, 1223–1224. [Google Scholar] [CrossRef] [Green Version]
  151. Ramonas, K.M.; Conway, R.M.; Daftari, I.K.; Crawford, J.B.; O’Brien, J.M. Successful Treatment of Intraocularly Invasive Conjunctival Squamous Cell Carcinoma with Proton Beam Therapy. Arch. Ophthalmol. 2006, 124, 126–128. [Google Scholar] [CrossRef] [Green Version]
  152. Ndlovu, N.; Ndarukwa, S.; Kadzatsa, W.; Rusakaniko, S. Evaluation of the Radiotherapy Management of Ocular Surface Squamous Neoplasia in a High HIV Prevalence Setting—A Retrospective Review. Infect. Agents Cancer 2016, 11, 18. [Google Scholar] [CrossRef] [Green Version]
  153. Shields, J.A.; Shields, C.L.; Freire, J.E.; Brady, L.W.; Komarnicky, L. Plaque Radiotherapy for Selected Orbital Malignancies: Preliminary Observations: The 2002 Montgomery Lecture, Part 2. Ophthal. Plast. Reconstr. Surg. 2003, 19, 91–95. [Google Scholar] [CrossRef] [PubMed]
  154. Lecuona, K.; Stannard, C.; Hart, G.; Rice, J.; Cook, C.; Wetter, J.; Duffield, M. The Treatment of Carcinoma in Situ and Squamous Cell Carcinoma of the Conjunctiva with Fractionated Strontium-90 Radiation in a Population with a High Prevalence of HIV. Br. J. Ophthalmol. 2015, 99, 1158–1161. [Google Scholar] [CrossRef]
  155. Kearsley, J.H.; Fitchew, R.S.; Taylor, R.G. Adjunctive Radiotherapy with Strontium-90 in the Treatment of Conjunctival Squamous Cell Carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 1988, 14, 435–443. [Google Scholar] [CrossRef] [PubMed]
  156. Zehetmayer, M.; Menapace, R.; Kulnig, W. Combined Local Excision and Brachytherapy with Ruthenium-106 in the Treatment of Epibulbar Malignancies. Ophthalmologica 1993, 207, 133–139. [Google Scholar] [CrossRef] [PubMed]
  157. Rao, R.; Honavar, S.G.; Lahane, S.; Mulay, K.; Reddy, V.P. Histopathology-Guided Management of Ocular Surface Squamous Neoplasia with Corneal Stromal or Scleral Invasion Using Ruthenium-106 Plaque Brachytherapy. Br. J. Ophthalmol. 2021; ahead of print. [Google Scholar] [CrossRef] [PubMed]
  158. Kaufman, A.R.; Kang, K.B. Iodine-125 Plaque Brachytherapy for Aggressive Squamous Cell Carcinoma with Corneal and Scleral Invasion. Oman J. Ophthalmol. 2022, 15, 255–257. [Google Scholar] [CrossRef] [PubMed]
  159. Murthy, R.; Gupta, H.; Krishnatry, R.; Laskar, S. Electron Beam Radiotherapy for the Management of Recurrent Extensive Ocular Surface Squamous Neoplasia with Orbital Extension. Indian J. Ophthalmol. 2015, 63, 672–674. [Google Scholar] [CrossRef]
  160. Spadea, L.; Petrucci, R.; Balestrazzi, E. Excimer Laser Phototherapeutic Keratectomy for Recurrent Intraepithelial Corneoconjunctival Carcinoma. J. Cataract Refract. Surg. 2002, 28, 2062–2064. [Google Scholar] [CrossRef]
  161. Danopoulos, E.D.; Danopoulou, I.E.; Liarikos, S.B.; Merkuris, K.M. Effects of Urea Treatment in Malignancies of the Conjunctiva and Cornea. Ophthalmol. J. Int. D’ophtalmologie Int. J. Ophthalmol. Z. Fur Augenheilkd. 1979, 178, 198–203. [Google Scholar] [CrossRef]
  162. Ferry, A.P.; Meltzer, M.A.; Taub, R.N. Immunotherapy with Dinitrochlorobenzene (DNCB) for Recurrent Squamous Cell Tumor of Conjunctiva. Trans. Am. Ophthalmol. Soc. 1976, 74, 154–171. [Google Scholar]
  163. Rodriguez, E.E.C.; Sancho, K.F.C.B.; Kange, P.M.; Barros, J.D.N.; Toledo, A.S.; Morales, M.; Belfort Neto, R. Novel Low-Cost Approach to the Treatment of Ocular Surface Squamous Neoplasia Using Pattern Scanning Laser Photocoagulation. Arq. Bras. Oftalmol. 2020, 83, 505–510. [Google Scholar] [CrossRef] [PubMed]
  164. Dong, Z.; Kase, S.; Ando, R.; Fukuhara, J.; Kinoshita, S.; Dong, Y.; Takashina, S.; Kanda, A.; Noda, M.; Noda, K.; et al. Expression of AB-Crystallin and Vascular Endothelial Growth Factor in Conjunctival Squamous Cell Carcinoma. Anticancer Res. 2013, 33, 3745–3751. [Google Scholar] [PubMed]
  165. Shields, C.L.; Paulose, S.A.; Yaghy, A.; Dalvin, L.A.; Constantinescu, A.B.; Lally, S.E.; Shields, J.A. Ocular Surface Squamous Neoplasia Managed with Primary Interferon A2b: A Comparative Analysis of 212 Tumors in Smokers Versus Nonsmokers. Cornea 2021, 40, 1387–1394. [Google Scholar] [CrossRef] [PubMed]
  166. Tran, A.Q.; Venkateswaran, N.; Galor, A.; Karp, C.L. Utility of High-Resolution Anterior Segment Optical Coherence Tomography in the Diagnosis and Management of Sub-Clinical Ocular Surface Squamous Neoplasia. Eye Vis. 2019, 6, 27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Thomas, B.J.; Galor, A.; Nanji, A.A.; El Sayyad, F.; Wang, J.; Dubovy, S.R.; Joag, M.G.; Karp, C.L. Ultra High-Resolution Anterior Segment Optical Coherence Tomography in the Diagnosis and Management of Ocular Surface Squamous Neoplasia. Ocul. Surf. 2014, 12, 46–58. [Google Scholar] [CrossRef]
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Figure 1. Flowchart guiding the choice between medical and surgical management of ocular surface squamous neoplasia (OSSN).
Figure 1. Flowchart guiding the choice between medical and surgical management of ocular surface squamous neoplasia (OSSN).
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Figure 2. Flowchart guiding the choice of adjuvant topical chemotherapy following surgical management of OSSN.
Figure 2. Flowchart guiding the choice of adjuvant topical chemotherapy following surgical management of OSSN.
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Figure 3. Flowchart guiding the choice of topical chemotherapy as primary medical therapy for OSSN, and the need for sequential or combination topical chemotherapy.
Figure 3. Flowchart guiding the choice of topical chemotherapy as primary medical therapy for OSSN, and the need for sequential or combination topical chemotherapy.
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Figure 4. Flowchart guiding the monitoring of OSSN resolution and surveillance of disease recurrence.
Figure 4. Flowchart guiding the monitoring of OSSN resolution and surveillance of disease recurrence.
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Table
Table 1. Summary of study protocols using 5-Fluorouracil (5-FU) as sole treatment of ocular surface squamous neoplasia (OSSN).
Table 1. Summary of study protocols using 5-Fluorouracil (5-FU) as sole treatment of ocular surface squamous neoplasia (OSSN).
StudyProtocolOutcomes
Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a
long-term safety study [95]
Study location: Italy
Number of patients: 22 		Dose: 1% 5-FU topical QDS for 4 weeks, adjunctive courses administered after 3 months of chemotherapy-free interval
Eye ointment applied to inferior eyelid to minimise skin contact, and inferior lacrimal punctum briefly occluded
Endpoint: Until clinical and cytological tumour regression		Response: 22 (100%)
Time to response: Not specified
Recurrence: 3 (14%)
Side effects: not reported
Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia [80]
Study location: United States
Number of patients: 44		Dose: 1% topical 5-FU QDS for 1 week followed by a drug holiday of 3 weeks
No punctal plugs
Endpoint: Until clinical resolution or failure to respond within 4 or more cycles		Response: 36 (82%)
Time to response: 3.8 cycles
(median: 4, range: 2–9)
Recurrence: 4 (6% at 1 y, 15% at 2 y)
Side effects: pain (17, 39%), tearing (10, 23%), photophobia (6, 14%), itching (4, 9%), swelling (2, 5%), infection (1, 2%), no long-term complications
Topical 1% 5-fluoruracil as a sole treatment of corneoconjunctival ocular surface squamous neoplasia: long-term study [96]
Study location: Italy
Number of patients: 41		Dose: 1% 5-FU topical QDS for 4 weeks, adjunctive courses administered after 1 month of chemotherapy-free interval
Eye ointment applied to the inferior eyelid skin to minimise skin contact, no punctal occlusion
Endpoint: Until clinical resolution or clinical evidence of lack of further tumour response		Response: 34 (83%)
Time to response: 11 ± 9 weeks
(range: 3–22 weeks)
Recurrence: 4 (9%)
2 were treated with topical MMC and 2 were treated with topical MMC + surgery, all responded completely.
Side effects: photophobia (20, 51%), conjunctival hyperemia (19, 48%), irritation (17, 43%), pain (14, 36%), superficial punctate keratitis (11, 28%), lid erythema (4, 8%)
Comparison of Topical 5-Fluorouracil and Interferon Alfa-2b as Primary Treatment Modalities for Ocular Surface Squamous Neoplasia [97]
Study location: United States
Number of patients: 54		Dose: 1% topical 5-FU QDS for 1 week followed by a drug holiday of 3 weeks
Endpoint: Until clinical resolution or failure to respond within 2 cycles		Response: 52 (96%)
Time to response: 6.6 ± 4.5
Recurrence: 6 (12%),
mean of 7.7 ± 9.1 months
Side effects: pain (12, 22%), tearing (12, 22%), redness (11, 20%), eyelid edema (5, 93%), keratopathy (4, 7%), no long-term complications
Table
Table 2. Summary of study protocols using Mitomycin C (MMC) as sole treatment of OSSN.
Table 2. Summary of study protocols using Mitomycin C (MMC) as sole treatment of OSSN.
StudyProtocolOutcomes
Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution [87]
Study location: Australia
Number of patients: 26 with MMC vs. 22 with placebo		Dose: MMC 0.4 mg/mL QDS for 3 weeks
Advised punctal plugs or manual occlusion
Endpoint: Until resolution by slit lamp examination or failure to regress by 6 weeks		Response: 24 (92%)
Time to response: 121 days
(range: 73–169)
Recurrence: Not specified
Side effects: redness, irritation
Long-Term Results of Topical Mitomycin C 0.02% for Primary and Recurrent Conjunctival-Corneal Intraepithelial Neoplasia [103]
Study location: Brazil
Number of patients: 18		Dose: 0.02% topical MMC QDS for 14 days, followed by 14 more days if no resolution
Manual punctal occlusion for 3 min
Endpoint: For 28 consecutive days		Response: 18 (100%)
Time to response: 28 days
Recurrence: 0 (0%)
Side effects: conjunctival hyperemia, tearing, corneal epithelial erosions
(2, 11%)
Retrospective Comparative Study of Topical Interferon α2b Versus Mitomycin C for Primary Ocular Surface Squamous Neoplasia [105]
Study location: India
Number of patients: 25		Dose: MMC 0.4 mg/mL QDS in 1 week on and 1 week off cycles
Advised punctal occlusion for 5 min during treatment course
Endpoint: Until clinical resolution or failure to regress after 2 cycles 		Response: 23 (92%)
Time to response: 1.5 ± 0.54
(median 1.5)
Recurrence: 0 (0%)
Side effects: Conjunctival hyperemia (11, 44%), hyperemia with burning sensation (9, 36%), corneal epitheliopathy (3, 12%), photophobia with blepharospasm (2, 8%), punctal stenosis (1, 4%)
Table
Table 3. Summary of study protocols using Interferon alfa-2b (IFNα−2b) as sole treatment of OSSN.
Table 3. Summary of study protocols using Interferon alfa-2b (IFNα−2b) as sole treatment of OSSN.
StudyProtocolOutcomes
Topical
Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b [124]
Study location: United States
Number of patients: 7		Dose: 1 MIU/mL IFNα−2b 4–6 times daily
Endpoint: Until 1 month beyond complete clinical resolution via slit-lamp biomicroscopy		Response: 7 (100%)
Time to response: median: 54 days, mean: 77 days, range: 28–188 days
Recurrence: 0 (0%)
Side effects: conjunctival hyperemia and follicular conjunctivitis (4, 57%)
Topical Interferon α-2b as a Single Therapy for Primary Ocular Surface Squamous Neoplasia [125]
Study location: India
Number of patients: 24		Dose: 1 MIU/mL topical IFNα−2b QDS
Endpoint: Until clinical resolution or failure to regress within 3 months		Response: 22 (92%)
Time to response: median: 3.25, range: 2–4
Recurrence: 0 (0%)
Side effects: intratumoural bleeding (2, 8%), conjunctival congestion (1, 4%), foreign body sensation (1, 4%)
Retrospective Comparative Study of Topical Interferon α2b Versus Mitomycin C for Primary Ocular Surface Squamous Neoplasia [105]
Study location: India
Number of patients: 26		Dose: 1 MIU/mL topical IFN IFNα−2b QDS
Endpoint: Until clinical resolution or failure to regress after 2 months 		Response: 23 (89%)
Time to response: 3.1 ± 0.73
(median 3.5)
Recurrence: 1 (4%) at 18 m
Side effects: conjunctival hyperemia (2, 8%), hyperemia with burning sensation (1, 4%)
Comparison of Topical 5-Fluorouracil and Interferon Alfa-2b as Primary Treatment Modalities for Ocular Surface Squamous Neoplasia [97]
Study location: United States
Number of patients: 48		Dose: 1 MIU/mL topical IFNα−2b QDS
Endpoint: Not specified		Response: 39 (81%)
Time to response: 5.5 ± 2.9
Recurrence: 2 (5%), mean of 9.9 ± 11.4 months
Side effects: pain (9, 20%), redness (6, 13%), blurred vision (6, 13%), tearing (2, 4%), no long-term complications
Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration [126]
Study location: United States
Number of patients: 61		Dose: 1 MIU/mL topical IFNα−2b QDS
Endpoint: Until biomicroscopic evidence of tumour resolution or until the time a secondary treatment was deemed necessary due to poor response		Response: 59 (95%) complete response; 2 (3%) had partial response; additional treatment required for complete response in 7 (11%)
Time to response: 5.8 (median: 5, range: 1–17.8)
Recurrence: 2 (3%)
Side effects: follicular reaction (4, 6%), corneal epithelial defect (2, 3%), irritation (1, 2%)
Recombinant Interferon Alpha-2b as Primary Treatment for Ocular Surface Squamous Neoplasia [127]
Study location: Iran
Number of patients: 92
* Data was combined with perilesional IFNα−2b used in some patients as second line		Dose: 3 MIU/mL topical IFNα−2b QDS
Endpoint: Until 1 month beyond complete tumour resolution then tapered to BD for 2 months, or until failure to regress tumour in 2 subsequent monthly visits		Response: 89 (97%); 8 required perilesional IFNα−2b
Time to response: 4.64 ± 1.92 months (median: 5, range: 1–10)
Recurrence: Not specified
Side effects: conjunctival hyperemia (4, 4%), follicular reaction (2, 2%), punctate epithelial erosions (1, 1%), chemosis (1, 1%)
Subconjunctival
Management of Ocular Surface Squamous Neoplasia with Topical and Intralesional Interferon Alpha 2B in Mexicans [128]
Study location: Mexico
Number of patients: 6		Dose: 3 MIU/0.5 mL intralesional IFNα−2b once weekly
Endpoint: Until resolution		Time to response: 6.5 months, range: 4–11 months
Recurrence: 0 (0%)
Side effects: None reported
Subconjunctival/Perilesional Recombinant Interferon α2b for Ocular Surface Squamous Neoplasia: A 10-Year Review [121]
Study location: United States
Number of patients: 15
* Some eyes were recurrences of OSSN 		Dose: 3 MIU/0.5 mL perilesional subconjunctival IFNα−2b weekly
(10 eyes had concomitant topical IFN, but the study found no difference in resolution)
Endpoint: Until resolution		Response: 13 (87%)
Time to response: median: 1.4 months, range 0.6–5.7
Recurrence: 1 (7%)
Side effects: stinging and irritation (4, 27%), fever and malaise (5, 33%)
Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia [92]
Study location: United States
Number of patients: 6
* All eyes had concomitant topical IFNα−2b		Dose: 3 MIU/0.5 mL perilesional subconjunctival IFNα−2b once followed by 1MIU/mL topical IFNα−2b QDS
Endpoint: Until 1 month after clinical resolution		Response: 6 (100%)
Time to response: within 6 weeks
Recurrence: 0 (0%)
Side effects: fever and myalgia
(2, 33%)
Table
Table 4. Case reports describing the use of Interferon alfa-2a (IFNα−2a) in the treatment of OSSN.
Table 4. Case reports describing the use of Interferon alfa-2a (IFNα−2a) in the treatment of OSSN.
StudyProtocolOutcomes
Interferon alpha-2a as alternative treatment for conjunctival squamous cell carcinoma [132]
Study location: Peru
Number of patients: 1		Dose: 1 MIU/mL topical IFNα−2a, one drop every 6 h
Endpoint: For 4 months		Complete tumour resolution at the end of treatment
No recurrence at 24 months
Immunoreduction of ocular surface tumours with intralesional interferon alpha-2a [50]
Study location: United Kingdom
Number of patients: 3
* IFNα−2a was used as tumour reduction prior to surgery		Dose: 3 MIU intralesional IFNα−2a 28d prior to surgeryReduction in size and inflammation clinically and histological regression at surgery
No side effects reported
Pegylated interferon-alpha-2a for the treatment of ocular surface squamous neoplasia [133]
Study location: South Korea
Number of patients: 8		Dose: 180 mcg / 0.5 mL intralesional pegylated IFNα−2a injection initially and 4 weeks later
Together with 36 mcg/mL topical pegylated IFNα−2a QDS until 8 weeks following clinical resolution		Complete resolution after 12 weeks of initiation of treatment
No recurrence at 6 months
No side effects reported
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Yeoh, C.H.Y.; Lee, J.J.R.; Lim, B.X.H.; Sundar, G.; Mehta, J.S.; Chan, A.S.Y.; Lim, D.K.A.; Watson, S.L.; Honavar, S.G.; Manotosh, R.; et al. The Management of Ocular Surface Squamous Neoplasia (OSSN). Int. J. Mol. Sci. 2023, 24, 713. https://doi.org/10.3390/ijms24010713

AMA Style

Yeoh CHY, Lee JJR, Lim BXH, Sundar G, Mehta JS, Chan ASY, Lim DKA, Watson SL, Honavar SG, Manotosh R, et al. The Management of Ocular Surface Squamous Neoplasia (OSSN). International Journal of Molecular Sciences. 2023; 24(1):713. https://doi.org/10.3390/ijms24010713

Chicago/Turabian Style

Yeoh, Clarice H. Y., Jerome J. R. Lee, Blanche X. H. Lim, Gangadhara Sundar, Jodhbir S. Mehta, Anita S. Y. Chan, Dawn K. A. Lim, Stephanie L. Watson, Santosh G. Honavar, Ray Manotosh, and et al. 2023. "The Management of Ocular Surface Squamous Neoplasia (OSSN)" International Journal of Molecular Sciences 24, no. 1: 713. https://doi.org/10.3390/ijms24010713

APA Style

Yeoh, C. H. Y., Lee, J. J. R., Lim, B. X. H., Sundar, G., Mehta, J. S., Chan, A. S. Y., Lim, D. K. A., Watson, S. L., Honavar, S. G., Manotosh, R., & Lim, C. H. L. (2023). The Management of Ocular Surface Squamous Neoplasia (OSSN). International Journal of Molecular Sciences, 24(1), 713. https://doi.org/10.3390/ijms24010713

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