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1 Department of Ophthalmology, Julius Maximilians University Würzburg, Germany
2 Institute of Pathology, Julius Maximilians University Würzburg, Germany
Keywords: exenteration; p53; squamous cell carcinoma; conjunctiva; human papillomavirus
Ocular surface squamous neoplasia (OSSN) includes conjunctival intraepithelial neoplasia with dysplasia, carcinoma in situ and conjunctival squamous cell carcinoma (SCC). Beside ultraviolet B irradiation identified as an risk factor, OSSN is associated with human papillomavirus type 16 and 18 (HPV-16, HPV-18).1–5 The exact role and possible prognostic value of p53 overexpression is unclear and little is known about its expression during the development of conjunctival SCC.
Case reports
Patient 1
A 75 year old man was referred with a 10 year history of a conjunctival mass of the left eye with visual acuity of hand movement. Previous biopsies had revealed conjunctival dysplasia. On examination, the tumour of the ocular and tarsal conjunctiva of the lower lid covered the entire corneal surface (fig 1A).
Figure 1 Patient 1. (A) Extensive papillomatous tumour, subtotally covering the corneal surface of the left eye. Nodular thickening of the lower eyelid indicates eyelid involvement. (B) Histological appearance. Papillomatous pattern of the large epithelial lesion with focal invasion above the cornea. Subepithelially, inflammatory cells and some dilated vessels (haematoxylin and eosin, original magnification, x2.5). (C) p53, showing strong diffuse reactivity in invasive region indicating an inactivating p53 mutation (original magnification, x10). (D) p53, showing moderate expression predominantly in the suprabasal layers in dysplastic conjunctiva of the same specimen (original magnification, x10).
Patient 2
A 90 year old patient presented with a 2 year history of an extensive conjunctival papillomatous tumour of the left eye covering three quarters of the cornea with visual acuity of light perception. A full thickness biopsy was performed.
Both patients underwent orbital exenteration including removal of the eyelids. Histopathologically the focal invasive, completely removed tumour of patient 1 grew in a papillomatous manner. The tumour cells of the conjunctival neoplasm showed strongly enlarged nuclei with prominent nucleoli, and formed cohesive units with intercellular bridges (fig 1B).
The exophytic tumour of patient 2 was predominantly intraepithelial with foci of subepithelial invasion. Focal tumour anaplasia was observed in the otherwise moderately differentiated tumour with squamous cell differentiation.
Immunostaining of both specimens revealed strong p53 (monoclonal mouse-anti-human p53-protein DO-7, Dako) overexpression (>26% of epithelium cells) and low expression of p21 (<6% of epithelium cells) of the invasive region of the tumour indicating an inactivating p53 mutation (fig 1C). While in patient 1 expression for p53 was found in all epithelial layers, in patient 2 it was expressed suprabasally. In contrast, both p53 and p21 showed moderate reactivity in the dysplastic region up to the middle layer of the tumour (fig 1D). In the apical layer epithelium cells were occasionally p21 positive.
Immunostaining for HPV (HPV screening antibody, Virofem Diagnostica, Germany) was positive in patient 1.
Comment
The high recurrence rate of OSSN of 9–64% after resection seems to depend on the histopathological grade and status of surgical margins.5 HPV-16 and HPV-18 are considered to be possible cofactors involved in initiation and early progression of OSSN.1–4,7 Though both of the presented tumours were clinically papillomatous, immunostaining for HPV was positive only in patient 1.
The tumour suppressor gene p53 has been found to be inactivated in over 50% of human cancers. In OSSN, overexpression of p53 has been previously reported in some SCC of conjunctiva.6,7 In the SCC of our patients, p53 overexpression indicating inactivating p53 mutations were observed only in the invasive part of the tumour, but not in the carcinoma in situ. While Dushku and coworkers assumed that p53 mutations could be an early event in tumour development consistent with ultraviolet radiation, our findings clearly indicate that mutations of p53 are a late event that occur with disease progression, as observed with other solid tumours.7,8 Karcioglu and associates found a correlation between p53 overexpression and unfavourable clinical course.9 In contrast, Aoki and colleagues found no expression for p53 in SCC but positive staining in dysplasia.10
Our results of two exenterated advanced stages of SCC emphasise the necessity to remove dysplastic OSSN completely to prevent progression to invasive carcinomas. Identification of inactivating p53 mutations may indicate an increased risk for invasiveness. Therefore immunohistochemical analysis of biopsy specimen may help in the management of these tumours.
References
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Dushku N , Hatcher SL, Albert DM, et al. p53 expression and relation to human papillomavirus infection in pingueculae, pterygia, and limbal tumors. Arch Ophthalmol 1999;117:1593–9.
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Aoki S , Kubo E, Nakamura S, et al. Possible prognostic markers in conjunctival dysplasia and squamous cell carcinoma. Jpn J Ophthalmol 1998;42:256–61.