Medical and Surgical Management of Ocular Surface Squamous Neoplasia

Initial Considerations

Before focusing on the treatment for OSSN, a systematic ocular inspection must be performed, including thorough bilateral and intraocular examination, upper and lower eyelid eversion, and palpation of regional lymph nodes (pre-auricular, submandibular, and supraclavicular). This initial examination is crucial since, for instance, evidence of intraocular or orbital invasion requires consultation with oculoplastics specialists for possible enucleation or exenteration. Systemic work-up is generally not necessary as metastasis occur in less than 1% of cases.

Underlying predisposing factors should also be explored, such as ultraviolet light exposure, both personal and familial, ocular and dermatologic history of cancer, tobacco use, immunocompromise, and human immunodeficiency virus (HIV) and human papilloma virus (HPV) status, including history of genital warts and abnormal Papanicolaou tests for females. In patients younger than 50, particularly those without a clear predisposition or significant sun exposure, HIV testing should be considered. Older age and male gender are also known risk factors.

Initial documentation and follow-up comparison of OSSN lesions with slit lamp photography is helpful and recommended.

Role of Optical Coherence Tomography in Diagnosis and Management of Ocular Surface Squamous Neoplasia

Although the gold standard for diagnosis of OSSN remains histopathologic analysis, in vivo noninvasive diagnostic techniques have evolved and become very helpful in the management of ocular surface lesions. Additional diagnostic adjuncts to clinical acumen include impression cytologic analysis, ultrasound biomicroscopy (UBM), in vivo confocal microscopy (IVCM), and anterior segment HR-OCT. While none of these imaging techniques is indefectible, OCT has tremendously advanced the diagnostic and therapeutic management of OSSN, especially with high-resolution technology. ^, The distinctive tomographic feature of OSSN, first described in 2011, consists of a thickened, hyperreflective epithelium with an abrupt transition from normal to abnormal epithelial layer ( Fig. 52.1 ). Commercially available US Food and Drug Administration (FDA)-approved HR-OCT with axial resolution of 5–7 μm has proven equivalent to custom-built ultra-high resolution OCT (UHR-OCT; <5 μm). HR-OCT is able to detect subclinical OSSN that is often not appreciated on slit lamp examination and helps elucidate the diagnosis in subtle or equivocal cases of OSSN with coexisting complex ocular surface conditions or non-OSSN tumors ( Fig. 52.2 ). Although outliers exist, studies have shown that epithelial thickness greater than 120 and approximately 140 μm with HR-OCT and UHR-OCT, respectively, maximized the sensitivity and specificity with regards to OSSN and pterygium differentiation. ^,

In a study by Adler et al. in 2013, approximately 50% of the respondents reported that they do not always biopsy suspected OSSN prior to initiation of topical agents. We believe that this percentage has increased since the advent of HR-OCT given its ability to corroborate the diagnosis of OSSN and differentiate it from mimicker lesions, such as amelanotic melanoma and corneal scarring or pannus. We reserve biopsy for patients with equivocal clinical or OCT findings or those who are not responding to treatment as expected. In cases of uncertainty, biopsy is suggested.

HR-OCT devices provide rapid, noncontact image acquisition that do not require a highly skilled operator. Images can be interpreted by experienced and novice clinicians. According to a study by our group, trainees inexperienced with HR-OCT interpretation can quickly improve diagnostic accuracy after a short training session of 20 minutes.

While very helpful in identifying OSSN, the limitations of HR-OCT include optical shadowing of deeper structures that can occur with larger and pigmented lesions and inability to reliably evaluate invasion. In addition, lesions in the fornix and/or caruncle can be difficult to image. ^, While morphologic and internal reflectivity changes can be identified with HR-OCT, at this time the resolution cannot yet identify cellular changes of atypia.

UBM is able to penetrate opaque lesions, assess underlying invasion, and visualize the posterior border of the tumor at the expense of axial resolution (40–50 μm). As opposed to HR-OCT, UBM requires direct contact with the eye.

The third currently available imaging modality is confocal microscopy, which offers en face images with the highest resolution (1 μm or less), allowing differentiation at a cellular level not feasible with HR-OCT or UBM. However, images derive from a very narrow window (0.4 mm × 0.4 mm) instead of a cross-sectional view seen on HR-OCT. In addition, IVCM is time intensive, requires a highly trained operator, and is not as helpful in conjunctiva as compared to the cornea. While some studies have shown positive results in the evaluation of OSSN with IVCM, others have had discouraging outcomes, even with last generation confocal technology. Additionally, a learning curve in both image acquisition and interpretation can be a limiting factor for IVCM use. Current commercially available confocal microscopy devices require patient cooperation and implicate longer scanning times and challenging ocular surface contact, although noncontact devices are available. Cinotti et al. recently demonstrated the value of a portable handheld skin IVCM in the diagnosis of 295 eyelid and conjunctival lesions, including 11 conjunctival squamous cell carcinomas (SCCs). While the portable device facilitated acquisition of confocal images, which agreed with histopathologic analysis in all SCC cases with 100% sensitivity and specificity, larger studies are warranted.

Anterior segment imaging technology has evolved with improved image quality, easier operation, and expanded applications. Therefore noninvasive OSSN diagnosis and surveillance have become a reality. For instance, HR-OCT has high sensitivity (range 94%–100%) and specificity (100%) for diagnosis of OSSN as compared to histopathologic diagnosis. ^, All techniques available in the toolbox of anterior segment imaging technologies have distinct applications and results mutually complementary.

Choice of Treatment Modality for Ocular Surface Squamous Neoplasia

Once the diagnosis and extent of the tumor have been established, there are several factors to consider before deciding on the best treatment path. Initial management may comprise medical treatment or surgical excision, and the choice of modality depends on patient age, systemic comorbidities, ability to comply with medications and/or undergo surgery, and financial constraints. Both surgical and medical treatment for OSSN are successful approaches.

It is important for patients to understand that OSSN is a cancer of the surface of the eye and that treatment requires frequent long-term follow-up to assess response to therapy and detect recurrences. Quality of life (QoL) considerations before, during, and after OSSN treatment also deserve attention and should be discussed with patients. A recent study comparing vision-related and psychosocial QoL in medical versus surgical management of OSSN found that overall QoL factors for medical and surgical treatment of OSSN were similar. As expected, drops precipitated more ocular symptoms, such as tearing and itchiness, while patients who had surgery reported more pain. In terms of motivations to choose either option, patients preferred chemotherapy due to fear of surgery and/or prior literature review and surgical excision when aiming for immediate resolution.

The size and location of the tumor is also an important consideration. For example, tumors with extensive involvement of the limbus may portend a higher risk for limbal stem cell deficiency (LSCD) after standard resection with 3–4 mm margins. Such tumors may benefit from primary topical medical treatment or neoadjuvant topical chemotherapy to reduce tumor burden prior to surgical removal.

Medical Management of Ocular Surface Squamous Neoplasia

Noninvasive treatments for OSSN are advantageous in that they treat the entire ocular surface, therefore treating microscopic and subclinical disease. They spare the maximum amount of normal ocular surface tissue and do not impart any direct risk of scarring or infection. However, unlike with surgical resection, the success of any medical treatment of OSSN is heavily reliant on patient cooperation. The willingness and capability of each individual patient to comply with prescribed treatment regimens must be assessed early and often. This includes the ability to instill eye drops, family support, the willingness to come to follow-up appointments, financial constraints, and regional drug availability and cost.

It is important to explain to patients in the United States that although medical treatment of OSSN is known to be effective, ^, the chemotherapeutic and immunomodulatory agents prescribed are off label use of FDA-approved medications. As a result, some insurance plans do not cover these compounded agents, and patients may need to bear a significant out-of-pocket expense.

Early identification of individuals who are likely to fail medical therapy for any of the above reasons enables the clinician to appropriately tailor each patient’s treatment plan to maximize the chances of achieving a cure.

Topical Immunomodulatory and Chemotherapeutic Agents

The introduction of topical therapy has largely replaced older, more invasive treatments in the management of OSSN. The principal medications used are IFN α-2b, 5-FU, and MMC. Several studies have reviewed the efficacy of these agents in the primary treatment of OSSN. Table 52.1 summarizes these medications, their mechanisms of action, and major side effects.

TABLE 52.1

Summary of Topical Chemotherapeutic Agents for Treatment of Ocular Surface Squamous Neoplasia

Agent	Mechanisms of Action	Common Formulations	Common Dosing	Major Side Effects
Interferon α-2b	Multiple; possible enhancement of host antitumor immune activity, induction of tumor cell apoptosis	Topical: 1 million IU/mL solution Subconjunctival: 3 million IU/0.5 mL	Topical : 4 times daily until 1 month after clinical resolution Subconjunctival : Generally 1–3 times weekly until clinical resolution	Follicular conjunctivitis; flu-like symptoms with injections
5-Fluorouracil	Pyrimidine analog; blocks DNA and RNA synthesis.	1% solution	Topical: 4 times daily for 1 week, followed by 3-week holiday until resolution. Alternative: 4 times daily for 2–7 days up to 4 weeks, followed by drug holiday for 3 weeks-3 months	Conjunctivitis, keratitis, hyperemia
Mitomycin C	DNA alkylation; inhibition of nucleic acid and protein synthesis	0.02%–0.04% solution	Topical : MMC 0.04%: 4 times daily for 1 week, followed by 2-week holiday or until white and quiet. Usually 3–4 cycles	Conjunctivitis, keratitis, recurrent corneal erosion, limbal stem cell deficiency, punctal stenosis

MMC , Mitomycin C.

Immunomodulators

Interferon α-2b

IFN is an endogenous immunomodulatory glycoprotein released by various immune cells with antiviral, antimicrobial, and antineoplastic functions that is used in recombinant form. The use of topical IFN α-2b for treatment of OSSN was first reported by Maskin in 1994. The association between HPV and OSSN was emerging at that time, and the therapeutic effects of IFN were initially attributed to its known antiviral properties, but the exact mechanism of the antineoplastic effect remains unknown.

Numerous studies, reaching collectively a total of 332 individuals, have evaluated the use of IFN as a primary agent for OSSN. Resolution was achieved in an average of 95% of cases (range 75%–100%). Recurrences were seen in 4%–20% of cases, and most occurred within the first year. ^{, ,}

Most groups used ophthalmic IFN drops at a concentration of 1 million IU/mL (MIU/mL) administered four times daily (range 2–6 months). Others have used a higher concentration (3 MIU/mL), with one study reporting 100% resolution after a 2-month administration and no recurrences during an average follow-up of 10.2 months. However, higher IFN concentrations do not result in a significant difference in efficacy, so 1 MIU/mL is generally used.

IFN can also be given as a subconjunctival perilesional injection. Resembling treatment regimens of conventional IFN for systemic cancers and hepatitis, thrice weekly subconjunctival IFN injections of 3 MIU in 0.5 mL (6 MIU/mL) were previously favored. However, weekly injections of the same concentration have proven equally effective and more practical. Other groups inject 10 MIU/mL of IFN monthly with effective results. Mean total injection doses in the literature range from 15 to 23 MIU. A 10-year retrospective review of 15 patients treated with IFN injections (3 MIU in 0.5 mL) showed tumor resolution in 13 of 15 eyes after an average of 1.4 months (range 0.6–5.7) and a mean of 6 injections (range 2–11). After an average follow-up of 55 months, only 1 of 15 eyes showed recurrence 4 months after clinical resolution.

Even giant OSSN (defined as tumor basal diameter of 15 mm or involvement of ≥6 clock hours of the limbus) treated with IFN monotherapy (topical and/or injections) resolved in up to 72% of cases ( Fig. 52.3 ), with reduction in size also seen in the remaining tumors. Furthermore, primary treatment with IFN has shown equivalent outcomes as compared to primary surgical excision with long-term recurrence rates of 3% in the IFN group and 5% in the surgery group 1 year out of treatment. ^,

IFN is arguably the best tolerated of all topical agents. The eye drops are very well tolerated and gentle except for occasional conjunctival hyperemia and follicular conjunctivitis. Subconjunctival injections may cause flu-like symptoms in a third of the patients, including transient myalgias and fevers, which can be ameliorated by administering 1000 mg of oral acetaminophen at the time of injection and every 6 hours thereafter. Perilesional IFN injections have the advantage of assured compliance. Additionally, since the drug is commercially available, no compounding is needed. Injections are usually reserved for when compliance is an issue, there is an inability to obtain compounded drops, with those who have extensive disease predominantly involving tarsal conjunctiva, or those with residual or recurrent tumor.

One of the disadvantages of IFN treatment is its more expensive cost compared to 5-FU or MMC (approximately $500 dollars per month in the United States), although it may be much less in other countries. Furthermore, issues to consider include the need for continuous treatment and compliance and the requirement for refrigeration.

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