Statistics from Altmetric.com
Ocular surface squamous neoplasia (OSSN) was first described by Lee and Hirst1 as an umbrella term that encompasses intraepithelial and invasive squamous cell carcinoma of the conjunctiva and cornea. The incidence of OSSN ranges from 0.02 to 3.5 per 100 000 population and varies geographically, with greater frequency near the equator. Generally, it is a slow growing tumour that rarely metastasises, but is capable of causing extensive local tissue destruction. Bilateral OSSN is extremely rare2–7 and offers a unique opportunity to study the biological characteristics of bilateral OSSN of the conjunctiva. The following case report describes the clinical presentation, histopathology, and immunohistochemical evaluation of tumour proliferation markers of a patient diagnosed with bilateral OSSN.
An 86 year old white woman was referred to the Doheny Eye Institute because of redness in her right eye that had developed over a period of several months. She had undergone a mastectomy in 1954. She had no history of ocular trauma, toxin exposure, or tobacco use. Her brother and sister died from liver cancer. An ophthalmic examination revealed a visual acuity of 20/100 in each eye. Ectropion and indurated lower eyelid margins were present bilaterally with no loss of cilia. A closer examination revealed a thickened epithelium that lined the palpebral conjunctiva and cul del sac of the right eye (fig 1A). The left lower palpebral conjunctiva showed similar changes. However, there was a focal nodule on the inferior bulbar conjunctiva (fig 1B).
The patient underwent a biopsy of the right palpebral conjunctiva. Histopathological examination of the specimen revealed acanthotic epithelium with squamous metaplasia, occasional dyskeratotic cells, parakeratosis, and hyperkeratosis. Multiple abnormal mitotic figures were present. The basement membrane was intact, and a diagnosis of conjunctival squamous cell carcinoma in situ was diagnosed. A subsequent biopsy of the left conjunctiva revealed full thickness squamous metaplasia of the epithelium with acanthotic and marked dysplastic changes. Multiple abnormal mitotic figures were seen and the basement membrane was also intact, with an extensive chronic inflammatory cell infiltrate in the stroma (fig 1C). These findings were also consistent with a diagnosis of squamous cell carcinoma in situ of the conjunctiva.
Immunohistochemical analysis (Dako, Carpinteria, CA, USA) revealed that neoplastic cells were positive for pankeratin, human papillomavirus (HPV) (fig 1D), and Ki-67 (MIB-1) in both specimens. Moreover, both biopsies indicated the presence of a few bcl-2 positive cells. The right eye biopsy was p53 positive and the left was p53 negative. The immunohistochemically positive cells were counted by methods described previously.8 Table 1 summarises the immunohistochemical findings of both biopsies. Because of the patient’s fragile health, surgical intervention was deferred and she was treated with topical mitomycin C in both eyes. At the follow up examination 13 months after the biopsy, a mass was found in the right lower palpebral conjunctiva, but there was no evidence of such lesion in the left conjunctiva or metastasis.
The aetiology of bilateral OSSN remains unclear. Causative factors that are believed to contribute to the development of unilateral OSSN include ultraviolet light exposure, ocular trauma, predisposing genetic factors, and infection with HPV. Previous reports have provided convincing evidence of an association with HPV type 16 in some cases of bilateral conjunctival dysplasia.3,4 It has been postulated that the interaction between HPV and ultraviolet light may have a role in the development of HPV related tumours in patients who are exposed to the sun.9 However, both conjunctival lesions in the present case were located in areas that were not exposed to sunlight, suggesting a possibility that HPV infection in both eyes may have led to the development of bilateral OSSN.
Conjunctival OSSN has been described as a slow growing, well differentiated tumour of low grade malignancy that responds to local excision and rarely metastasises. Immunohistochemical studies of bilateral lesions allow comparison of the proliferative potency in both eyes, and offer a unique opportunity to study some biological aspects of bilateral tumours under the same environmental conditions at the same point in time. In recent years p53, bcl-2, and MIB-1 have been used as markers of proliferative potency.8,10 The p53 gene is a common cellular target in human carcinogenesis and is thought to have an important role in cellular proliferation. In contrast with the wild type p53, mutants of the p53 gene produce an abnormal protein with a long half life and are thus immunohistochemically detectable. Also, p53 has been reported to be a prognostic marker in several tumours.8,10 Bcl-2 is a proto-oncogene that is thought to have a role in oncogenesis by inhibiting programmed cell death and preserving cells from p53 induced apoptosis.8 However, the mutant p53 protein also induces apoptosis and decreases the expression of bcl-2 proteins. Mahomed et al8 suggested that the interplay between the effects of the increased mutant p53 proteins and the absence of bcl-2 expression in tumorigenesis may promote clonal expansion, leading to progressively increased genomic instability. The synergy of the presence of mutant p53 and absence of bcl-2 in the present case might have allowed the progression of the tumour in the right conjunctiva.
Ki-67 is a nuclear antigen expressed in all stages of the cell cycle except the resting stage. MIB-1 is a monoclonal antibody that recognises the Ki-67 antigen, which is a marker of cellular proliferation and reported to be a prognostic factor for various cancers. The high immunoreactivity of MIB-1 in conjunctival OSSN is usually associated with highly aggressive tumour growth.8 Our results demonstrate a higher immunoreactivity of MIB-1 in the right conjunctival specimen. These findings indicate that the right conjunctival specimen is more aggressive than the left, and is consistent with this patient’s clinical course.
In conclusion, this case represents a rare example of conjunctival pathology: OSSN as a bilateral tumour. To our knowledge, this is also the first report that compares the right and left biopsies of conjunctival OSSN by immunohistochemical analysis of potential oncogenic factors. Enhanced expression of MIB-1 and presence of mutant p53 protein in the absence of bcl-2 may contribute to the aggressive biology of OSSN.
This work was supported in part by NEI core grant Ey03040 and by an unrestricted grant from Research to Prevent Blindness Inc, New York, USA.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.