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Conjunctival intraepithelial neoplasia and carcinoma: distinct clinical and histological features in relation to human papilloma virus status
  1. Ingvild Ramberg1,2,
  2. Peter Bjerre Toft2,
  3. Jeanette Bæhr Georgsen3,
  4. Volkert Dirk Siersma4,
  5. Mikkel Funding5,
  6. David Hebbelstrup Jensen6,
  7. Christian von Buchwald6,
  8. Steffen Heegaard1,2
  1. 1Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  2. 2Department of Ophthalmology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  3. 3Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
  4. 4The Research Unit for General Practice and Section of General Practice, Department of Public Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  5. 5Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark
  6. 6Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  1. Correspondence to Professor Steffen Heegaard, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark; sthe{at}


Aims Human papillomavirus (HPV) is considered a causative agent for the development of a broad range of human carcinomas. The role of HPV in the development of conjunctival intraepithelial neoplasia (CIN) and carcinoma (cSCC) remains unclear. The purpose of the present study was to investigate the HPV prevalence in a nationwide cohort and to describe clinical and histopathological features in relation to HPV status.

Methods All cases of CIN and cSCC in Denmark from 1980 to 2016 were included. We combined p16 immunohistochemistry (IHC), RNA in situ hybridisation (RNA ISH) and HPV DNA PCR to detect HPV. The results were correlated to clinical and histopathological parameters.

Results One hundred twelve primary tumours and 33 recurrent tumours were included for HPV analysis. Twenty-four (21%) of the primary tumours were HPV positive by PCR. Eighteen of out 19 HPV-positive tumours were positive by RNA ISH. HPV16 was the most prevalent genotype (n=18, 75%). The patients with HPV-positive tumours were significantly younger (mean difference 11.5 years, 95% CI 5.2 to 17.9, p=0.0005) and had a higher recurrence compared with patients with HPV-negative tumours (HR 2.30, 95% CI 1.02 to 5.21, p=0.046). The HPV-positive tumours were associated with a positive p16 IHC and a non-keratinising morphology.

Conclusion We describe distinct clinical and histopathological features associated with HPV status in cSCC. The finding of transcriptionally active HPV in this material lends support to a causal role of HPV in a subset of cSCC.

  • conjunctiva
  • epidemiology
  • ocular surface
  • pathology
  • infection

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  • Contributors Substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data for the work: IR, PBT, JBG, VDS, MF, DHJ, CvB, SH. Drafting the work or revising it critically for important intellectual content: IR, PBT, JBG, VDS, MF, DHJ, CvB, SH. Final approval of the version to be published: IR, PBT, JBG, VDS, MF, DHJ, CvB, SH. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: IR, PBT, JBG, VDS, MF, DHJ, CvB, SH.

  • Funding This work was supported by Arvid Schrøder and Ketty Lydia Larsen Schrøder Foundation, the Synoptik Foundation, 'Fight for Sight, Denmark', Faculty of Health and Medical Science, Copenhagen University and the Danish Eye Research Foundation.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Danish Data Protection Agency (Journal no: RH-2013-30-1035, 02288), the Regional Scientific Ethics Committee of the Capital Region of Denmark (Journal no: H-16044879, 55827) and was conducted according to the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on request.

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