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

Abstract

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.

Keywords: human papillomavirus; oral cavity squamous cell carcinoma; p16-immunohistochemistry; prevalence; prognosis.

FIGURE 1

Human papillomavirus (HPV) test algorithm for oral cavity squamous cell carcinoma (OCSCC) [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Prevalence of high‐risk human papillomavirus (HPV) in oral cavity squamous cell carcinoma (OCSCC) [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Kaplan‐Meier curves of human papillomavirus (HPV)‐negative and HPV‐positive oral cavity squamous cell carcinomas (OCSCCs). A, Overall survival (OS) of HPV‐negative (blue line, 5‐year OS 60.3%) and HPV‐positive (red line, 5‐year OS 45.3%) OCSCC patients. Log‐rank analysis showed no difference in OS between HPV‐negative and HPV‐positive OCSCCs (P = .255). B, Disease‐free survival (DFS) of HPV‐negative (blue line, 5‐year DFS 52.7%) and HPV‐positive (red line, 5‐year DFS 45.3%) OCSCC patients. Log‐rank analysis showed no difference in DFS between HPV‐negative and HPV‐positive OCSCCs (P = .685) [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Kaplan‐Meier curves of p16‐negative and p16‐positive oral cavity squamous cell carcinomas (OCSCCs). A, Overall survival (OS) of p16‐negative (blue line, 5‐year OS 58.2%) and p16‐positive (red line, 5‐year OS 51.9%) OCSCC patients. Log‐rank analysis showed no difference in OS between p16‐negative and p16‐positive OCSCCs (P = .482). B, Disease‐free survival (DFS) of p16‐negative (blue line, 5‐year DFS 53.2%) and p16‐positive (red line, 5‐year DFS 41.9%) OCSCC patients. Log‐rank analysis showed no difference in DFS between p16‐negative and p16‐positive OCSCCs (P = .262) [Color figure can be viewed at wileyonlinelibrary.com]