Update on the Management of Ocular Surface Squamous Neoplasia

Abstract

Purpose of review:

To review and update the latest findings in diagnosis and management of ocular surface squamous neoplasia (OSSN).

Recent findings:

OSSN is the most common anterior segment neoplastic disease process. Several ocular surface imaging techniques have been developed for the early diagnosis and management of clinical and subclinical ocular surface squamous neoplasia, including high-resolution optical coherence tomography (HR-OCT), in vivo confocal microscopy, and ultrasound biomicroscopy. Treatment modalities include both surgical and medical management, with a recent trend towards primary and adjunctive pharmacotherapy.

Summary:

There is increasing use of HR-OCT for the diagnosis and monitoring of clinical and subclinical OSSN lesions. Topical pharmacotherapy agents, including interferon α−2b, 5-fluorouracil, and mitomycin C, have demonstrable efficacy in the treatment of OSSN and their use may be dictated based upon tumor factors, patient factors, cost, and side effect profile. Both surgical excision and adjunctive topical medications have excellent success, with the favored treatment method trending towards topical pharmacotherapy as primary therapy.

Introduction

Ocular surface squamous neoplasia (OSSN) is a term that encompasses the spectrum of conjunctival epithelial malignancies from mild, moderate, and severe conjunctival epithelial dysplasia, carcinoma in situ, to invasive squamous cell carcinoma (SCC) [1]. It most frequently occurs at the corneoscleral limbus and exposed areas of bulbar conjunctiva [2]. The incidence of OSSN has been reported to range from 0.13 to 1.9 per 100,000 persons, with higher incidence in equatorial regions and in older white males [3, 4]. In the past, surgical excision has been the most widely accepted treatment modality but recently there has been a transition to topical treatment with chemotherapy and immunomodulatory agents. The aim of this review is to report on the most recent trends in the detection and management of OSSN.

Methods

A search of the MEDLINE database was performed using the keywords “ocular surface squamous neoplasia”, “conjunctival carcinoma in situ”, “squamous conjunctival carcinoma”, and “conjunctival intraepithelial neoplasia”. All reports published in English up to May 2020 were included. This article is based on previously conducted studies.

Risk Factors and Pathogenesis

Risk factors for the development of OSSN include cigarette smoking, ultraviolet (UV) light exposure, vitamin A deficiency, chronic trauma or inflammation, systemic and local immunosuppression [5–7]. Non-modifiable risk factors include male gender and age [8–10]. A longitudinal study published in the United States reported that American men have a 12-fold higher incidence rate than American women [11]. Conversely, in African populations OSSN prevalence peaks at a relatively younger age and there is no gender predilection [12, 13].

Human immunodeficiency virus (HIV) seropositivity and human papilloma virus (HPV)-related diseases are also strongly associated with OSSN [14–18]. HPV infection, which is associated with inhibition of the tumor-suppressor protein retinoblastoma (Rb), may potentiate UV radiation-related DNA damage with the formation of pyrimidine dimers and epigenetic changes in p16 gene promoter [19]. HIV seropositivity may potentially act as an enhancer or confounder of HPV carcinogenicity [20]. For example, Ateenyi-Agaba and colleagues detected HPV types in nearly half of OSSN cases in HIV-positive patients, but rarely in HIV-negative patients [18].

There are no definitive genetic mutations that have shown causality in the development of OSSN but there is mounting evidence of potential factors that are associated with its pathogenesis. One of the key events in OSSN pathogenesis is tumor suppressor gene p53 mutations, with a high percentage of CC > TT alterations, which confirms the causative role of UV exposure in the development of these lesions [21]. Additionally, Scholz and colleagues identified mutations in the telomerase reverse transcriptase (TERT) gene promoter in 44% of 48 samples of conjunctival OSSN included in their study [22]. Overexpression of ADAM3A and amplification of chromosome 8p11.22 have been detected by fluorescence in situ hybridization (FISH) in a subset of conjunctival SCC and precursor lesions. Gains predominated in lesions with at least severe dysplasia. Alterations were present in high-grade lesions while sparing non-neoplastic conjunctiva [23, 24].

Clinical Presentation

On clinical examination, OSSN typically presents as a unilateral vascularized mass located in the inter-palpebral limbal area and rarely presents as a bilateral or multifocal mass [2]. Features of conjunctival OSSN include papillary, gelatinous, leukoplakic, and nodular epithelial changes. Corneal involvement appears opalescent [5]. Figure 1 shows a papillary OSSN lesion with opalescent corneal changes. Due to the shared risk factor of UV exposure, OSSN can be associated with other ocular surface lesions including pterygia and pinguecula [25].

Figure 1.

Nasal papillary ocular surface squamous neoplasia lesion in the left eye of a white male. A. An elevated, papillary lesion on the conjunctiva with feeder vessels extending onto the cornea from 7 to 9:30 o’clock. B. High resolution optical coherence tomography (HR-OCT) shows hyperreflective, thickened epithelium corresponding with dysplastic tissue (asterisk) with an abrupt transition from normal to abnormal (arrow). C. Examination discloses the transition (arrow) from unremarkable, thin, conjunctival epithelium to dysplastic, thickened epithelium (asterisk) which corresponds to the HR-OCT image (Hematoxylin-eosin; original magnification x 40). D. Higher magnification demonstrates faulty epithelial maturational sequencing that extends up to full thickness overlying fibrovascular cores (arrows) (Hematoxylin-eosin; original magnification x 100). E. Clinical resolution of conjunctival lesion after six cycles of 5- fluorouracil 1% topical treatment. F. HR-OCT confirms normalized, thin epithelium after six cycles of 5- fluorouracil 1% topical treatment (arrows).

While OSSN is usually a slow growing tumor, Kaliki and colleagues recently described a rare, aggressive variant called nodulo-ulcerative OSSN. This lesion is characterized by ulceration and necrosis of the conjunctiva and sclera with surrounding indurated and thickened conjunctiva and sclera with associated feeder vessels [26]. In a case series of six patients, four had intraocular tumor extension and this finding may indicate that nodulo-ulcerative OSSN may have a higher rate of invasive disease. Nodulo-ulcerative OSSN is often misdiagnosed as necrotizing scleritis or sclerokeratitis resulting in delayed diagnosis and mismanagement [26–28]. Additionally, nodular and papillomatous lesions are associated with higher histopathologic grade [29]. In the case of immunocompromised HIV patients, OSSN lesions are often larger, with forniceal extension, and feature more areas of leukoplakia with pronounced feeder vessels [13, 30].

The most common signs and symptoms are red eye, ocular irritation, persistent tearing, and the appearance of a new mass in the eye. In very advanced cases, necrotizing scleritis, associated with severe pain and visual loss, has been described [31, 32].

At the microscopic level, OSSN presents as a range of cellular dysplasia from mild to severe. Distinctly neoplastic cells with an intact basement membrane are characteristic of conjunctival carcinoma in situ. SCC is characterized by invasion through the basement membrane into the substantia propria where the tumor has access to lymphatics and blood vessels with the potential for local and metastatic spread. Some changes suggestive of this malignant transformation include a diffuse or multifocal configuration, median basal diameter of  > 10 mm, and thickness of > 1 mm [29, 33].

Aggressive histopathological variants such as spindle-cell, mucoepidermoid, and adenoid squamous OSSN have an increased risk for metastasis [34–36]. Features suggestive of intraocular invasion of OSSN include anterior chamber cells, raised intraocular pressure, mass present in the anterior chamber angle, and choroidal or exudative retinal detachment [37]. Additional factors associated with higher grade OSSN lesions include male gender, lack of corneal involvement, papillomatous and nodular lesions, microscopic multifocality, and positive margins on biopsy [29].

Differential Diagnosis

Several lesions must be considered in the differential diagnosis of OSSN including pterygium, pinguecula, corneal pannus, vitamin A deficiency, Salzmann’s nodular degeneration, pyogenic granuloma, papilloma, and nevi especially in patients with complexion-associated melanosis. Other neoplastic processes that may masquerade as OSSN include sebaceous cell carcinoma, amelanotic melanoma, conjunctival lymphoma, and keratoacanthoma [38–41].

Diagnosis and Monitoring

Incisional or excisional biopsy with histopathologic evaluation allows for the definitive diagnosis of OSSN [29]. Excisional biopsies may lead to limbal stem cell deficiency, symblepharon, scarring in large lesions and those involving large portions of the limbus, and recurrent lesions [41, 42]. Innovative, noninvasive imaging modalities have been developed for the diagnosis of OSSN, including high-resolution anterior segment optical coherence tomography (HR-OCT), in vivo confocal microscopy, and OCT-angiography (OCT-A) [43–45].

HR-OCT aids in the diagnosis and treatment of OSSN and has been found to be highly sensitive and specific [45]. The typical HR-OCT findings include thickened, hyperreflective epithelium and an abrupt transition from healthy to diseased epithelium [39, 45, 46]. This mirrors the morphological findings seen on histopathology. Studies have shown that distinctive HR-OCT findings allow for the diagnosis OSSN in the setting of in the setting of co-existing ocular surface diseases, including pterygia, ocular rosacea, Salzmann’s nodular degeneration, and limbal stem cell deficiency [47, 48]. HR-OCT is a noninvasive and noncontact diagnosis modality that can be performed in the clinical setting with results immediately available. HR-OCT can be used to guide topical medical management of OSSN for lesions with apparent clinical resolution but continue to show subclinical disease [49]. This prevents the premature termination of pharmacotherapeutic intervention [39]. Monitoring for tumor resolution with HR-OCT can also potentially prevent overuse of topical therapy which can lead to ocular toxicity and increased cost to the patient. Limitations in the use of HR-OCT include technician experience in determining the region of scanning, optical shadowing which can obscure the depth of penetration especially in thick tumors, and difficulty with evaluating invasion into the substantia propria [5, 45, 47, 48, 50].

Confocal microscopy is an additional imaging technique that can help distinguish abnormalities at the cellular level including cytoplasmic ratio, pleomorphism, and hyperreflectivity. Advantages of confocal microscopy include the ability to examine neoplastic tissue and view cytologic details at the microscopic level in the neoplastic tissue in 5–20 μm sections. Disadvantages include that only a small section of tissue can be visualized, the lack of cross-sectional visualization, and the inability to effectively visualize through keratinized and necrotic neoplastic tissue. Interpretations of confocal imaging of neoplastic tissue are therefore more challenging compared to healthy corneal and conjunctival tissues [44, 51].

Another diagnostic imaging modality, ultrasound biomicroscopy, is helpful in detecting intraocular extension and infiltration into adjacent structures due to its higher optical penetration and ability to achieve higher resolution of the posterior margin of these lesions [52]. It is not able to give epithelial details as seen in HR-OCT or confocal microscopy. Tumors that may be at high risk for intraocular invasion include thick, nodular lesions of greater than five mm, nodular or ulcerative lesions, and those that underwent prior surgical intervention [53].

OCT-A is a new technology which allows visualization of the vasculature in OSSN lesions. Liu and colleagues demonstrated that vessel area density (VAD) is a potential marker for identifying “feeder” vessels in subclinical OSSN lesions [54]. OCT-A has the potential for better understanding of the pathophysiology of OSSN and aiding in management.

New potential immunochemistry markers have been demonstrated in the histological examination of conjunctival SCC. The tumor suppressor gene p16, which is widely used to diagnose HPV-related squamous neoplasias of the cervix and head and neck tissues, has been recently described to be associated with invasive conjunctival SCC in HIV-infected patients [55]. There is also potential for IL-6 to be a marker for dysplastic conjunctival tissue [56].

Treatment

Surgical excision has been considered the standard of care for OSSN. However, surgery has potential disadvantages including limbal stem cell deficiency and conjunctival scarring. Residual disease, due to incomplete excision, may lead to tumor recurrence. Thus, topical medical treatments have become more common as an alternative to surgery. Several topical agents have been utilized as adjuvant and primary topical treatments, including chemotherapy, immunomodulatory agents, antiviral medications, and photodynamic therapy [57–60]. Topical immunomodulatory therapy, interferon α−2b (IFNα−2b), and chemotherapy, mitomycin C (MMC) and fluorouracil (5-FU), have gained popularity as primary and adjuvant therapies [5]. These agents are typically utilized as adjuvants in the presence of positive surgical margins or for the treatment of recurrent tumors [61]. Topical therapy provides treatment of the entire ocular surface to address potential areas of subclinical disease [62].

The no touch method is most often used for surgical excision. Visualized tumor-free margins of at least four mm at the time of surgery increase the likelihood of complete tumor removal [60]. Cryotherapy is then applied to the conjunctival and limbal margins in a “double freeze slow thaw” technique, which achieves the rupture of tumor cell membranes and occlusion of associated feeding blood vessels [63, 64]. If histopathological evaluation shows positive surgical margins, additional surgery or postoperative adjunctive topical chemotherapeutic agents may be applied, including IFNα−2b, 5-FU, and MMC. MMC has also been used as an intraoperative adjunctive treatment [63, 65, 66].

IFNα−2b is increasingly favored given its low toxicity and similar efficacy as surgical excision [67]. Interferons, including IFNα−2b, are leukocyte-derived proteins that can enhance phagocytic and cytotoxic mechanisms, inhibit biosynthetic enzymes, decrease blood vessel proliferation, induce apoptosis, and inactivate viral RNA. Intralesional injections of IFNα−2b enhance the production of IL-2 and IFN-γ mRNA by the immune system and lower the production of IL-10 which aids in the recognition and targeting of neoplastic cells [68]. IFNα−2b is used for OSSN as a topical eye drop, subconjunctival injections, or a combination of both for either primary or adjuvant treatment. The most commonly prescribed IFNα−2b topical dose is 1 million IU/ml. Typically, the medication is used four times a day, without interruption until clinical resolution. The average time for clinical resolution is approximately 4 months [5, 69, 70]. The drop is usually used for one or two more months after clinical resolution. The side effects of subconjunctival injections, including flu-like symptoms, are more common than topical drops but have the benefit of decreased out-of-pocket costs, quicker resolution, easier accessibility, and assured patient adherence [69]. IFNα−2b is an effective immunotherapy agent for OSSN tumors and serves as a tumor debulking agent for larger tumors in 26% cases [71]. Immunosuppression is a possible risk factor for interferon nonresponse of OSSN lesions [72].

Many studies have examined the efficacy of IFNα−2b as a primary treatment for OSSN. In a study of 98 eyes, topical IFNα−2b (n = 49) was compared to surgical excision (n = 49). Of the 49 eyes receiving IFNα−2b, 40 eyes were treated with topical IFNα−2b, one received subconjunctival injections, and eight eyes received both modalities. Recurrence rates were similar between the groups with a one-year OSSN recurrence rate of 3% in the IFNα−2b group and 5% in the surgical excision group. There was no increased risk of recurrence with respect to AJCC classification of the tumor [67]. Literature-based analysis comparing surgery versus IFNα−2b treatment demonstrated that excisional biopsy followed by IFNα−2b for positive margins was the best modality to minimize tumor recurrence [73]. While IFNα−2b is well-tolerated, it is only available through compounding pharmacies, requires refrigeration, and is costly for patients. The cost of IFNα−2b in the United States is approximately $800 for a one month supply [5]. In some parts of the world such as India, the drug is very inexpensive.

Topical chemotherapeutic agents, 5-FU and MMC, have high success rates in the treatment of OSSN. 5-FU is a pyrimidine analog that blocks thymidine synthase, resulting in inhibition of DNA formation and apoptosis [74]. 5-FU is well-tolerated and is an effective agent in the primary and adjuvant treatment of OSSN [75–77]. In a study of 44 eyes, 5-FU 1% was used as a primary therapy for the treatment of OSSN, administered 4 times daily for a week followed by 3 weeks of no treatment for a mean of 4 cycles [69]. With this therapy, 36 eyes (82%) had complete tumor resolution, 4 (9%) had partial resolution, and 4 (9%) had no response. A large study compared topical 5-FU 1% to topical IFNα−2b for the primary treatment of OSSN in over 100 patients and found comparable tumor resolution and low recurrence rates between the two groups. 52 of 54 eyes (96%) had complete resolution with 5-FU 1% compared to 39 of 48 eyes (81%) with IFNα−2b [77]. Compared to IFNα−2b, 5-FU is more cost effective for patients. However, 5-FU has more side effects than IFNα−2b which include pain, redness, eyelid swelling, filamentary keratitis, and rarely superficial stromal melting [5, 75, 77]. 5-FU has fewer side effects than MMC. A one-month supply of 5-FU costs approximately $50 in the United States [5].

Mitomycin (MMC) is an alkylating agent with antineoplastic and antibiotic properties that causes inhibition of DNA synthesis. MMC induces apoptosis and inhibition of fibroblast migration [78]. When used as primary treatment for OSSN, MMC is typically compounded into a concentration between 0.02 – 0.04% [79–81]. MMC has more frequent and severe adverse effects when compared to IFNα−2b or 5-FU, including ocular pain and epitheliopathy. In addition, allergic conjunctivitis, hyperemia, ectropion, and punctal stenosis have all been described [82, 83]. When MMC is utilized as the only treatment, recurrence rates by histopathologic evaluation were 0% for conjunctival intraepithelial neoplasia (CIN) while 67% for SCC [84]. When utilized as an adjunct to surgical excision, long-term recurrence of localized OSSN is rare with the use of topical MMC or 5-FU [85]. Due to the side effects of MMC including pain, hyperemia, conjunctivitis, and corneal toxicity, 5-FU and IFNα−2b are more commonly used as initial treatment modalities. Thus, MMC is often reserved for recalcitrant OSSN cases that have failed alternative therapies. MMC requires refrigeration and typically costs $100–190 per treatment cycle in the United States but is inexpensive in other countries.

Radiation therapies, such as plaque brachytherapy and proton beam radiation therapy, are pursued in cases with scleral invasion, recalcitrant disease, or when the lesion is unable to be excised [2, 86–88]. Plaque radiotherapy provides targeted therapy to affected structures with decreasing dose to immediately surrounding tissues and relatively low dose to more remote normal tissue. The tumor dimensions are important in plaque configuration and seed orientation. Plaque brachytherapy is delivered over a mean of three days and can be an effective alternative to enucleation for residual scleral-invasive conjunctival SCC. In a case series of 15 eyes, local tumor control was achieved in all cases [86]. Graue and colleagues utilized electron beam radiation therapy for recurrent conjunctival SCC with a 75% rate of local tumor control [89]. However, radiation-induced complications include cataract, lid alopecia, keratoconjunctivitis sicca, eyelid dermatitis, and neovascular glaucoma [90].

Subconjunctival anti-vascular endothelial growth factor, such as ranibizumab, has also been tried with variable results [91, 92]. Vitamin A and retinoic acid are involved in various cellular processes such as differentiation and growth. Retinoids have potent antineoplastic effects, including regulation of cellular growth by blocking cell maturation and modulating apoptosis [6]. In limited studies, retinoic acid has been used alone or as a combination therapy with IFNα−2b for OSSN treatment [93, 94].

Limited cases have reported an encouraging clinical resolution of OSSN with the use of the antiviral medication Cidofovir. Cidofovir is a monophosphate nucleotide analogue that demonstrates in vitro activity against several DNA viruses. Limited studies of the antiviral cidofovir have shown encouraging results when utilized as a secondary treatment in multi-refractory OSSN [57]. Since HPV has been implicated in the etiology of OSSN, the antiviral effects of cidofovir may underlie the efficacy seen in this case [95].

Prognosis

Overall, OSSN has a good prognosis, with a low tendency for metastasis and a low mortality rate. However, if OSSN is left untreated, it can lead to visual compromise, limbal stem cell deficiency, and invasion into the sclera or orbit [96]. Surgically excised OSSN lesions have a one-year recurrence rate of 10% and a five-year recurrence rate of 21%. Conjunctival SCC has a recurrence rate of up to 39% as reported in five studies [4, 97–100]. The recurrence rate after surgical excision with positive surgical margins has been reported at 56% [101]. Recurrence occurs most frequently within the first six months after surgical resection and is associated with the presence of positive surgical margins, presence of feeder vessels, HIV infection status, and histopathologic grade [101–104]. Higher-grade lesions are associated with lack of corneal involvement, temporal and superior locations, papillomatous and nodular appearance, and positive biopsy margins [29]. In patients with positive margins, the use of postoperative topical IFNα−2b lowers the recurrence rate to a level similar to that of patients with negative margins [105].

Conjunctival SCC tends to be more locally invasive rather than spreading via metastasis. A large series demonstrated a conjunctival SCC orbital invasion rate of approximately 10%, and a metastatic rate of less than 1% [106, 107]. Intraocular tumor involvement of OSSN occurs via direct extension of the tumor through the sclera, inoculation from intraocular surgical incision, or extension along the anterior ciliary vessels [37, 108–110].

Recent literature demonstrates that conjunctival SCC may be more aggressive than previously described. A case series of 26 patients with metastatic conjunctival SCC demonstrated a mortality rate of 8% [97]. These patients had a higher histopathologic grade and displayed conjunctival SCC orbital involvement at the time of surgical intervention. Additionally, a case series of 1661 patients in the USA reported a metastatic conjunctival SCC mortality rate of up to 24% [111].

Very rarely, spontaneous regression of OSSN has been reported after incisional biopsy [96, 112]. The hypothesis behind this rare occurrence is called the “danger model”, which postulates that trauma to a tumor bed can result in an immunogenic response leading to tumor regression [96].

Conclusion

The aim of this review is to provide an update on the latest developments in the diagnosis and medical management of OSSN. HR-OCT is increasingly used for the diagnosis and monitoring of clinical and subclinical OSSN lesions. There is the potential for OCT-A to provide useful imaging information in the assessment of OSSN lesions. IFNα−2b, 5-FU, and MMC are effective topical pharmacotherapies that are increasingly being used as both primary and adjunctive therapies. Topical pharmacotherapy is preferred with large, multifocal lesions, and limbal lesions that allow for adequate treatment of the ocular surface while decreasing the risk for limbal stem cell deficiency. Clinicians should consider cost, access to healthcare, side effect profile, and patient preference when deciding on the appropriate treatment regimen for their patients.