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Does human papillomavirus cause pterygium?
  1. T W Reid,
  2. N Dushku
  1. 1Ophthalmology Department, Texas Tech University HSC, Lubbock, TX 79430, USA
  2. 2Ophthalmology Department, Kaiser Permanente Medical Center, Sacramento, CA 95815, USA

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    HPV is not necessary for the formation of a pterygium

    Human papillomavirus (HPV) is the only DNA tumour virus where a large body of evidence implicates it in human cancers. The evidence for a causative role of HPV in human cervical cancer, was recently reviewed by zur Hausen,1 and is the following: (1) expression of specific HPV genes (such as E6 and E7) were shown in cervical cancer cell lines and cancer biopsies2; (2) viral DNA was shown to have immortalisation properties3,4; (3) viral oncogene expression was shown to be required for the maintenance of the malignant phenotype in specific cervical cancer cell lines5,6; (4) a substantial number of epidemiological studies have been performed which point to high risk HPV as a primary risk factor for cervical cancer. In addition, large case-control and prospective epidemiological studies supported this idea, and indicated that persisting HPV infections were the most significant risk factor in cervical cancer.7,8

    Different types of HPV have been identified in a high percentage of non-melanoma skin cancers (basal and squamous cell carcinomas). However, these basal and squamous cell carcinomas occur preferentially in light exposed sites. This could suggest an interaction between ultraviolet light and a low risk (non-mutagenic) papillomavirus infection.9 This would make it a possible candidate in pterygia, which are thought to have aetiology involving ultraviolet irradiation.

    The binding to the p53 protein of the E6 oncoprotein, encoded by HPV types 16 and 18, results in the rapid degradation of p53 protein through the ubiquitin mediated pathway. This HPV infection mechanism leads to a damaged p53 dependent programmed cell death pathway,10,11 which is similar to that caused by mutations in the p53 gene. Low levels of normal nuclear p53 protein permit mutations in other genes to accumulate and allow the multistep development of tumours. Also, reduced bioavailability of p53 protein has been shown to be a key regulatory event in perturbation of CD95 signalling in HPV16 immortalised keratinocytes.12 HPV and p53 overexpression also commonly coexist in oropharngeal carcinomas,13 penile carcinomas,14 grade III cervical intraepithelial neoplasia,15 and invasive squamous cell carcinomas of the cervix.15 Since increased nuclear p53 expression without apoptosis was found in the limbal epithelium of pterygia, limbal tumours, and most pingueculae,16 this would be consistent with HPV playing a part in the formation of pterygia.

    The paper by Piras et al, in this issue of the BJO (864), shows a 100% incidence (17/17) of HPV in pterygia from Italian cases and a 21% (5/24) incidence from Ecuadorean cases. A recent study by Gallagher et al17 showed a 50% (5/10) incidence of HPV in pterygia in the United Kingdom. Detorakis et al18 found 15 pterygia contained type 18 HPV, for a total of 30% (15/50) in Greece. In addition they found that 8% of the associated conjunctiva contained HPV (4/50). In other studies Dolmetsch et al19 found HPV-16 in 100% of their pterygia (16/16) from Canada using immunohistochemical techniques.

    The above results are in contrast with the results of McDonnell et al,20 who found HPV-16 in 88.1% (37/42) of their patients with conjunctival epithelial neoplasia but none in six pterygia from America. Dushku et al21 also found no evidence of HPV in 13 pterygia and 10 limbal tumours from American cases. McDonnell et al20 also found HPV in tissue swabs from eyes with no visible lesions in 66.7% (4/6) of patients with unilateral conjunctival epithelial neoplasia and in one patient who showed a persistence of infection many years after successful eradication of the lesion. This is consistent with the finding of Karcioglu and Issa22 who found HPV in 57% of in situ squamous cell carcinomas, 55% of invasive squamous cell carcinomas; however, they also found HPV in non-neoplastic lesions (20% of climatic droplet keratopathy and 35% of scarred corneas) as well as 32% of normal conjunctival tissue obtained during routine cataract extractions. Thus, it would appear that HPV is not required for a pterygium and that even in its presence it cannot act alone in the development of conjunctival epithelial neoplasia.

    At the moment several companies and research laboratories are carrying out preclinical and clinical trials of vaccines against high risk HPV.23–25 Since experiments with purified papillomavirus structural proteins as vaccines showed protection against the primary infection of dogs and rabbits,26,27 an effective prevention can also be expected for the human vaccine. If this is true it may allow us to know whether prevention of HPV decreases or blocks the incidence of different cancers. It would also be of interest to see whether vaccinated individuals show a lower incidence of pterygia.

    Since Koch’s postulates cannot be fulfilled and unless more definitive results are obtained such as those from future HPV vaccine trials, we can only make the following statements for the role of HPV in the occurrence of pterygia: (1) HPV is not necessary for the formation of a pterygium; (2) it is unlikely that HPV can act as the sole cause of a pterygium; (3) HPV may have a role in the formation of some pterygia; (4) pterygia and limbal dysplasias in the interpalpebral area, which regress after topical antiviral treatment with interferon α2b, may be due to HPV.28,29

    Note in Proof

    HPV is not necessary for the formation of a pterygium

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