Overexpression of the cell cycle protein p16INK4a on immunohistochemistry (IHC) is widely applied as a surrogate marker of etiological HPV involvement in oropharyngeal squamous cell carcinomas (OPSCC). However, the accuracy of this marker to identify a transforming HPV infection in OPSCC varies considerably between different studies. We performed a meta-analysis on the accuracy of p16INK4a IHC to identify HPV-transformed OPSCC. The diagnostic accuracy of p16INK4a IHC was compared to that of other commonly applied HPV detection tests.
All available studies that analyzed HPV E6 and/or E7 oncogene transcription by an amplification-based method (gold standard to diagnose a transforming HPV infection) and p16INK4a by IHC in OPSCC were included in the analysis. Pooled sensitivity and specificity of p16INK4a IHC was computed and compared to the diagnostic accuracy of the comparator tests HPV DNA detection by PCR, HPV DNA detection by in situ-hybridization (ISH) and the test combination p16INK4a IHC/HPV DNA detection by PCR.
The inclusion criteria were fulfilled by 24 studies. The pooled sensitivity of p16INK4a IHC, HPV DNA PCR, HPV DNA ISH and combined p16INK4a/HPV DNA PCR was 0.94 (95% confidence interval (CI) 0.91-0.97), 0.97 (95% CI, 0.93-1.00), 0.85 (95% CI, 0.76-0.92) and 0.93 (95% CI, 0.87-0.97), respectively. The pooled specificities were 0.83 (95% CI, 0.78-0.88), 0.86 (95% CI, 0.77-0.93), 0.88 (95% CI, 0.78-0.96) and 0.96 (95% CI, 0.89-1.00), respectively. Relative sensitivity and specificity computation revealed that co-testing for p16INK4a IHC and HPV DNA PCR was as sensitive but significantly more specific than both individual tests.
Our data demonstrate that p16INK4a IHC when used as a single test is very sensitive and moderately specific to diagnose HPV-transformed OPSCC. Co-testing with p16INK4a IHC and HPV DNA detection by PCR significantly increases the diagnostic specificity while maintaining high sensitivity compared to the individual tests. The combined testing is thus suggested as a meaningful testing strategy for the reliable diagnosis of HPV-transformed OPSCC.