Human Papillomavirus-associated oropharyngeal cancer: an observational study of diagnosis, prevalence and prognosis in a UK population

Abstract

Background: The incidence of Human Papillomavirus (HPV) associated oropharyngeal cancer (OPC) is increasing. HPV-associated OPC appear to have better prognosis than HPV-negative OPC. The aim of this study was to robustly determine the prevalence of HPV-positive OPC in an unselected UK population and correlate HPV positivity with clinical outcome.

Methods: HPV testing by GP5+/6+ PCR, In Situ Hybridisation (ISH) and p16 immunohistochemistry (IHC) was performed on 138 OPCs diagnosed in South Wales (UK) between 2001-06. Kaplan-Meier analysis was used to correlate HPV status with clinical outcome.

Results: Using a composite definition of HPV positivity (HPV DNA and p16 overexpression), HPV was detected in 46/83 (55%) samples where DNA quality was assured. Five year overall survival was 75.4% (95% CI: 65.2 to 85.5) in HPV-positives vs 25.3% (95% CI: 14.2 to 36.4) in HPV negatives, corresponding to a 78% reduction in death rate (HR 0.22, p < 0.001). HPV-positives had less locoregional recurrence but second HPV-positive Head and Neck primaries occurred. Poor quality DNA in fixed pathological specimens reduced both HPV prevalence estimates and the prognostic utility of DNA-based HPV testing methods. As a single marker, p16 was least affected by sample quality and correlated well with prognosis, although was not sufficient on its own for accurate HPV prevalence reporting.

Conclusions: This study highlights the significant burden of OPC associated with HPV infection. HPV positive cases are clinically distinct from other OPC, and are associated with significantly better clinical outcomes. A composite definition of HPV positivity should be used for accurate prevalence reporting and up-front DNA quality assessment is recommended for any DNA-based HPV detection strategy.

Figure 1

Kaplan-Meier plots. A. Overall survival by HPV status. Blue solid line: HPV-positive patients (n = 69), red dotted line: HPV-negative patients (n = 59). 10 patients with equivocal HPV status are excluded. B. Overall survival in 4 groups classified by p16 expression and presence of HPV DNA. Blue solid line: HPV-positive (Group 3, n = 69), brown dashed/dotted line: p16 negative and ISH/PCR positive (Group 2, n = 6), green dashed line: p16 positive and ISH/PCR negative (Group 4, n = 4), red dotted line: HPV negative (Group 1, n = 59). C. Progression free survival by HPV status. Blue solid line: HPV-positive patients (n = 69), red dotted line: HPV-negative patients (n = 59). 10 patients with equivocal HPV status are excluded. D. Progression free survival in radically treated patients by HPV status. Blue solid line: HPV-positive patients (n = 69), red dotted line: HPV-negative patients (n = 48). 21 patients with equivocal HPV status or palliative intent are excluded. E. Overall survival by HPV and smoking status. Blue solid line: HPV-positive not current smokers (n = 38), green dashed line: HPV-positive current smokers (n = 18), red dotted line: HPV-negative current smokers (n = 41), brown dotted/dashed line: HPV-negative not current smokers (n = 10). Cases with equivocal HPV status or unknown smoking status are excluded. F. Overall survival by smoking status. Blue solid line: non-smokers (n = 20), green dashed line: previous smokers (n = 32), red dotted line: current smokers (n = 63). Cases with unknown smoking status are excluded.