The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma

Irene H. Nauta, Daniëlle A.M. Heideman, Arjen Brink, Berdine van der Steen, Elisabeth Bloemena, Senada Koljenović, Robert J. Baatenburg de Jong, C. René Leemans, Ruud H. Brakenhoff*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)


The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV-status is assessed routinely in clinical practice. Paradoxically, while the oral cavity seems the predilection site for productive HPV-infections, figures on HPV-attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. Major obstacles are the lack of reproducible assays to detect HPV in nonoropharyngeal cancers, the relatively small cohorts studied and consequently the shortfall of convincing data. In our study, we used a validated, nucleic acid-based workflow to assess HPV-prevalence in a consecutive cohort of 1016 OCSCCs, and investigated its prognostic impact. In parallel, we analyzed p16-immunohistochemistry (p16-IHC) as surrogate marker for transforming HPV-infection and independent prognosticator. All OCSCC-patients diagnosed between 2008 and 2014 at two Dutch university medical centers were included (N = 1069). Formalin-fixed, paraffin-embedded (FFPE)-samples of 1016 OCSCCs could be retrieved. Punch biopsies were taken from the tumor area in the FFPE-blocks and tested for HPV. P16-IHC was performed on 580 OCSCCs, including all HPV-positive tumors. From 940 samples (92.5%), nucleic acids were of sufficient quality for HPV-testing. In total, 21 (2.2%) OCSCCs were HPV DNA-positive. All HPV DNA-positive tumors were E6 mRNA-positive and considered as true HPV-positive. There was no difference in survival between HPV-positive and HPV-negative OCSCCs. In total, 46 of 580 (7.9%) OCSCCs were p16-immunopositive, including all HPV-positive tumors. Survival was comparable in p16-positive and p16-negative OCSCCs. To conclude, HPV-prevalence is very low in OCSCC and neither HPV-status nor p16-status affects outcome. Based on these data, determining HPV-status in OCSCC seems irrelevant for clinical management.

Original languageEnglish
Pages (from-to)420-430
Number of pages11
JournalInternational Journal of Cancer
Issue number2
Publication statusPublished - 15 Jul 2021

Bibliographical note

Funding Information:
Daniëlle A. M. Heideman has been on the speakers' bureau of QIAGEN and serves occasionally on the scientific advisory boards of Pfizer and Bristol‐Myers Squibb; Daniëlle A.M. Heideman is minority shareholder of Self‐screen B.V., a spin‐off company of VUmc; Self‐screen B.V. holds patents related to the work (ie, high‐risk HPV test and methylation markers). C. René Leemans has been on the advisory boards of Merck & Co. Inc., Rakuten Medical, and Nanobiotix, and reports research grants from KWF Kankerbestrijding/Dutch Cancer Society, VUmc Cancer Center Amsterdam Foundation, GenMab, BMS and the Hanarth Foundation, outside the submitted work. Ruud H. Brakenhoff reports grants from GenMab, InteRNA technologies, and Agilent and nonfinancial support from AbbVie, outside the submitted work. All the other authors declared no potential conflicts of interest.

Funding Information:
We thank Martijn Bogaarts, Dénira Agard, Marjolein Bekker‐Lettink, Mark Broeckaert, Douwe Buma, Marinda de Groot‐van Moorsel and Marije Graafmans‐Doeleman for their inexhaustible efforts to test more than a thousand OCSCCs for HPV. This study was funded by the European Union (H2020 Grant Agreement 689715 BD2Decide).

Funding Information:
Horizon 2020 Framework Programme, Grant/Award Number: Grant Agreement 689715 BD2Decide Funding information

Publisher Copyright:
© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.


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