Pathophysiology of ocular surface squamous neoplasia

Abstract

The incidence of ocular surface squamous neoplasia (OSSN) is strongly associated with solar ultraviolet (UV) radiation, HIV and human papilloma virus (HPV). Africa has the highest incidence rates in the world. Most lesions occur at the limbus within the interpalpebral fissure particularly the nasal sector. The nasal limbus receives the highest intensity of sunlight. Limbal epithelial crypts are concentrated nasally and contain niches of limbal epithelial stem cells in the basal layer. It is possible that these are the progenitor cells in OSSN. OSSN arises in the basal epithelial cells spreading towards the surface which resembles the movement of corneo-limbal stem cell progeny before it later invades through the basement membrane below. UV radiation damages DNA producing pyrimidine dimers in the DNA chain. Specific CC → TT base pair dimer transformations of the p53 tumour-suppressor gene occur in OSSN allowing cells with damaged DNA past the G1-S cell cycle checkpoint. UV radiation also causes local and systemic photoimmunosuppression and reactivates latent viruses such as HPV. The E7 proteins of HPV promote proliferation of infected epithelial cells via the retinoblastoma gene while E6 proteins prevent the p53 tumour suppressor gene from effecting cell-cycle arrest of DNA-damaged and infected cells. Immunosuppression from UV radiation, HIV and vitamin A deficiency impairs tumour immune surveillance allowing survival of aberrant cells. Tumour growth and metastases are enhanced by; telomerase reactivation which increases the number of cell divisions a cell can undergo; vascular endothelial growth factor for angiogenesis and matrix metalloproteinases (MMPs) that destroy the intercellular matrix between cells. Despite these potential triggers, the disease is usually unilateral. It is unclear how HPV reaches the conjunctiva.

Squamous cell carcinoma in the anophthalmic socket: a series of four cases with HPV-16 profiling

“…The presence of HPV-16 in both benign and malignant conjunctival lesions has been reported—suggesting that the virus alone is incapable of initiating SCC, but may be a cofactor 22. Gichuhi and colleagues identified microabrasions of the ocular surface caused by vitamin A deficiency as a risk factor in conjunctival SCC, allowing HPV to invade the conjunctival basement membrane and epithelial cells 21. We propose that similar microabrasions could be caused by long-term prosthesis wear.…”

“…A review of the pathophysiology of ocular surface squamous neoplasia was recently published, which detailed the mechanism of solar ultraviolet radiation, HIV and HPV in the transformation of limbal stem cells and the development of the disease 21. The presence of HPV-16 in both benign and malignant conjunctival lesions has been reported—suggesting that the virus alone is incapable of initiating SCC, but may be a cofactor 22.…”

Conjunctival Squamous Cell Neoplasia Associated With Ocular Cicatricial Pemphigoid

“…DNA damage, mutations in the tumor suppressor gene, and immunosuppression impairing tumor immune surveillance are also thought to lead to SCC. 2,3,4 There is one prior report in the literature of conjunctival SCC occurring in the setting of OCP. 5 We report two additional cases in which unilateral conjunctival neoplasia occurred in the setting of bilateral OCP.…”

“…1 Squamous cell dysplasia eventuating in invasive carcinoma (SCC) of the conjunctiva is strongly associated with ultraviolet radiation, human immunodeficiency virus (HIV), and human papillomavirus (HPV). 2,3 It most commonly arises in the para-limbal bulbar conjunctiva and is treated with surgical excision and/or topical therapy with interferon alpha-2b or anti-metabolites. 4 Two cases are described in this study who had squamous cell neoplasia (a term embracing both dysplasia and carcinoma) of the inferior palpebral conjunctiva developing in the setting of OCP.…”

<i>In vitro</i> comet assay in cultured human corneal epithelial cells

“…Direct drug application into the eye using formulations such as eye-drops leads to a high drug concentration at the administration site, especially on the corneal surface (Acheampong et al, 2002). In addition, there exist reports regarding neoplastic transformation of corneal epithelium in human (Gichuhi et al, 2014) and animals (Horikiri et al, 1994;Ogawa et al, 2010). Corneal cells are considered appropriate for genotoxicity evaluation of topically applied ophthalmic drugs.…”