Solar Ultraviolet Radiation

Numerous epidemiologic studies have identified ultraviolet B (UV-B) light as a major etiologic factor in the pathogenesis of OSSN.1,2,8,9 Newton et al. demonstrated a 49% decline in the rate of OSSN for each 10-degree increase in latitude, due to the decrease in solar ultraviolet radiation with increasing latitude.⁹

In a case control study, Lee at al. identified fair skin, pale irises, a propensity to sunburn, and prolonged sun exposure in early life as risk factors for OSSN.⁸

UV-B light is known to cause DNA damage through formation of pyrimidine dimers.¹⁰ Patients with xeroderma pigmentosum, who are more susceptible to the effects of sunlight, due to a defect in DNA repair mechanisms, have increased incidences of OSSN.⁶ It has been proposed the effect of UV-B radiation may be due to the overexpression of the p53 tumor suppressor gene.¹¹

Human Immunodeficiency Virus (HIV) Infection

The increased frequency of OSSN since the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, strongly suggests the role of the human immunodeficiency virus (HIV) in increasing the risk of developing OSSN.7,12 In a study in Malawi, 79% of patients diagnosed with OSSN were found to be HIV positive. In HIV patients, OSSN occurs at a younger age and tends to be more aggressive.¹² This emphasizes the importance of testing for HIV in younger patients diagnosed with OSSN, as it may be the first presenting sign of the disease.^7,12

Human Papillomavirus (HPV) Infection

Whereas, the role of HPV in the pathogenesis of cervical cancer has been well established, the role of HPV as an etiologic factor in OSSN remains unclear. Various studies have demonstrated an association between HPV subtypes and OSSN,13,14 while other studies have failed to show any association.^15,16 Further evidence confusing the etiologic role of HPV includes the presence of unilateral OSSN in patients with bilateral conjunctival HPV DNA, the presence of HPV in normal conjunctival tissue, and the persistence of HPV infection many years after eradication of OSSN ^13,17,18 It is possible HPV may not act alone but may require a cofactor, such as HIV or UV-B light, in order to cause disease.^17,19

Other Etiologic Factors

Other risk factors reported in the literature include heavy smoking and exposure to petroleum derivatives.20,21 It has also been reported in association with pterygium.²² Finally, there have been case reports of OSSN in immunosuppressed patients with neoplasia (lymphoma, leukemia) and following organ transplantation.²³

Diagnostic Cytology

Confocal Microscopy

There have been several reports of in vivo confocal microscopy as a useful tool in the diagnosis of OSSN.35,36 Confocal microscopy allows for real-time, noninvasive imaging at the cellular level by optical microscopic sectioning of the ocular surface. Malandrini and colleagues described a case of CIN, with a clear distinction between the healthy and pathological epithelium on confocal microscopy. The epithelial cells near the lesion were larger in size, more irregularly shaped, and demonstrated brighter nuclei.³⁵

Ultra-High Resolution Optical Coherence Tomography

More recently, ultra-high resolution optical coherence tomography (UHR- OCT) has been described as a noninvasive diagnostic tool to evaluate ocular surface lesions. This technology allows for morphologic visualization of the corneal architecture, with an axial resolution of 2–3 µm. Kieval et al. found that UHR-OCT of pterygia and OSSN lesions demonstrated a high degree of correlation to histopathological specimens.³⁷ The UHR-OCT of OSSN showed thickened epithelium with an abrupt transition from normal to neoplastic tissue (Fig. 19.3). UHR-OCT of pterygia demonstrated a normal thin epithelium, with thickening of the underlying subepithelial mucosal layers. The sensitivity and specificity for differentiating between OSSN and pterygia using UHR-OCT with an epithelial thickness cutoff of 142 µm was 94% and 100%, respectively.³⁷

Biopsy

Histopathologic diagnosis, either by incisional or excisional biopsy, is the only definitive method for the diagnosis of OSSN.

Surgical Excision with Cryotherapy

Surgical excision, alone or in combination with medical therapy, is the most established treatment for OSSN. With surgical excision alone, the rate of recurrence is high, ranging from 5% to 33% with negative margins and up to 56% with positive surgical margins.²⁶ A ‘no touch’ technique, in which touching the tumor with any instruments is avoided, reduces the risk of tumor seeding.³⁸ Wide margins of 4–6 mm should be obtained. If the lesion extends into the sclera or cornea, a superficial keratectomy or partial-thickness sclerectomy may be needed.

Absolute alcohol epitheliectomy of the involved cornea is also recommended.

To delineate the margins of the lesion, rose bengal staining or UHR-OCT can be used. However, there is evidence that the microscopic signs of OSSN may extend beyond the macroscopic border the tumor,¹⁷ and many surgeons prefer adjuvant cryotherapy to the limbus and conjunctival margins at the time of excision.

Cryotherapy is thought to work initially by its thermal effect and also by obliteration of the microcirculation, resulting in ischemic infarction and a double freeze–slow thaw technique is recommended.¹ The rates of recurrence with excision and cryotherapy have been reported to be lower than with excision alone, at about 12%.^19,39 Excess cryotherapy should be avoided, since side effects include iritis, abnormal intraocular pressure, sector iris atrophy, hyphema, ablation of the peripheral retina, corneal neovascularization, and limbal stem cell deficiency.^1,19

Since wide excisions are recommended, surgical excision often results in large defects, necessitating the use of a conjunctival autograft, an oral mucosal graft, or an amniotic membrane transplant. A number of studies have described successful reconstruction of the ocular surface with preserved amniotic membrane after excision of CIN, SCC, primary acquired melanosis, and melanoma.40,41 Amniotic membrane is a helpful technique, since defects of any size can be closed, and the membrane has additional properties of promoting epithelialization, and reducing neovascularization, scarring and fibrosis.⁴⁰ In addition, the use of fibrin glue, instead of sutures to secure the membrane reduces inflammation.⁴² The use of a conjunctival autograft of adequate size from either the same or opposite eye is an option. Care needs to be taken to avoid large areas of stem cell removal, which may lead to scarring, symblepharon, and limbal stem cell deficiency. Thick buccal or labial grafts are generally reserved for cases with extensive symblephara and might potentially interfere with the ability to observe for recurrence of the underlying tumor.⁴⁰

In summary, the preferred technique for OSSN removal involves excision of the tumor with wide margins, absolute alcohol epitheliectomy of the involved cornea, cryotherapy using a double freeze–slow thaw cycle to the limbus and conjunctival margins, and amniotic membrane transplantation (Fig. 19.5).

Topical Chemotherapy

Due to high recurrence rates of OSSN, medical therapies have been increasingly used. Mitomycin-C (MMC), 5-fluorouracil (5-FU) and interferon α-2b (IFN-α-2b) are useful in the treatment of the OSSN.

A potential advantage of medical therapy is the ability to treat the entire ocular surface, theoretically treating microscopic and subclinical disease. It is useful as primary treatment in patients who are not surgical candidates and for patients with recurrent, annular, or diffuse disease. In addition to its role in the primary treatment of OSSN, it can also be used as an adjunct to surgery, providing chemo-reduction prior to excision. Postoperatively, it is indicated when there are positive margins after excision and when there is tumor recurrence.

Antimetabolites

MMC is an alkylating agent that inhibits DNA synthesis by the production of free radicals. It is used as a topical drop at concentration of 0.02% or 0.04% four times daily for 7 to 14 days in cycles. One week is allowed between cycles to minimize ocular toxicity. Excellent responses raging from 87.5% to 100% have been reported.43,44 Side effects include conjunctival hyperemia, blepharospasm, corneal punctate erosions, punctal stenosis, and limbal stem cell deficiency.⁴⁴ Punctal plugs should be used to prevent punctal stenosis. Refrigeration is required and at our institution (Bascom Palmer Eye Institute) the cost is about US$225 per bottle.

5-FU is a pyrimidine analogue that inhibits the incorporation of thymidine into DNA, during the S-phase of the cell cycle. It is prescribed as a 1% topical solution applied four times daily for 4 to 7 days, with 30–35 days off for a total of two to five cycles.⁴⁵ It has also been used for 4 weeks continuously.⁴⁶ 5-FU may lead to ocular surface irritation and thus, 4 to 7 days a month dosing is preferred by the authors. Unlike MMC, it does not require refrigeration and is less costly (about US$75 per bottle).

Interferon α-2b

Interferon α is a family of proteins, secreted by leukocytes, with antiviral and antineoplastic properties. It has been used in the treatment of many cancers, including cervical intraepithelial neoplasia,⁴⁷ cutaneous squamous cell carcinoma,⁴⁸ and renal cell carcinoma.⁴⁹ It has also been used to treat viral lesions, including hepatitis B and C, and condyloma acuminata.⁵⁰ INF α-2b is a recombinant protein that has been used in the treatment of OSSN with success rates of above 80%.^51,52 It can be given as topical eye drops or a subconjunctival injection, and a combination of both may be used.

Topical INF α-2b is much better tolerated than MMC and 5-FU. Interferon drops are very gentle and well tolerated. Reported side effects include mild conjunctival hyperemia and follicular conjunctivitis.⁵³ Topical INF α-2b (1 million IU/mL) is dosed four times daily and given continuously until the tumor resolves. It is not cycled like MMC and 5-FU and the cost is about US$225 per month for the eye drops. On average, the time on the medication is 3 months. Figure 19.6 demonstrates the case of a 54-year-old male with OSSN, which resolved after 12 weeks of treatment with topical INF α-2b.

Interferon can also be given as subconjunctival injections. These may be given once to thrice weekly. Side effects of subconjunctival delivery include fever, chills, headache, myalgias, and arthralgias, which may last a few hours after the injection. Acetaminophen at a dose of 1000 milligrams every 6 hours is helpful. The time to tumor resolution is generally faster with subconjunctival injections (average 1.4 months), as compared to resolution topical INF α-2b drops (average 2.8 months).51,52 The subconjunctival dose is 0.5 mL (3 million IU/0.5 mL solution) repeated one to three times a week until clinical resolution occurs.

A comparison of MMC, 5-FU, and INF-α-2b are summarized in Table 19.1.

Conjunctival Nevus

A conjunctival nevus is a pigmented or nonpigmented mass, which is mobile, circumscribed, and elevated. It is the most common conjunctival tumor, accounting for 28% of all conjunctival tumors and 52% of those classified as melanocytic tumors.⁵ Nevi usually present in childhood or early adolescence, most commonly located in the bulbar conjunctiva, caruncle, or plica semiluminaris. Intralesional cysts are commonly visible at the slit lamp (Fig. 19.7). Growth may occur with hormonal changes, such as during puberty or pregnancy, but otherwise the lesion size remains stable. In a study of 410 patients with conjunctival nevi, 1% showed evolution into melanoma over an interval of 7 years.⁵⁶

Primary Acquired Melanosis

Conjunctival primary acquired melanosis (PAM) accounts for 11% of all conjunctival tumors and 21% of melanocytic lesions.⁵ It presents as a unilateral, patchy area of conjunctival pigmentation in middle-aged or elderly adults with fair skin (Fig. 19.8). The pigmentation can wax or wane over time.²⁸

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