Accuracy of p16 IHC in Classifying HPV-Driven OPSCC in Different Populations

Simple Summary p16 IHC is the HPV detection method suggested by the current version of the TNM (AJCC 8th edition) for oropharyngeal squamocellular carcinoma. However, its reliability has been extensively discussed, and its applicability in every context, especially the enrollment of patients in de-intensification protocols, is debatable. Here, we discuss its limits, especially in populations with a low prevalence of HPV-driven oropharyngeal squamocellular carcinoma, and suggest the possible actions to be taken to overcome such limitations. High-risk human papillomavirus (HPV) infection is a defined etiopathogenetic factor in oropharyngeal carcinogenesis with a clear prognostic value. The P16 IHC (immunohistochemistry) is a widely accepted marker for HPV-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC); in the present paper, we discuss its reliability as a standalone marker in different populations. The literature suggests that rates of p16 IHC false positive results are inversely correlated with the prevalence of HPV-driven carcinogenesis in a population. We propose a formula that can calculate such a false positive rate while knowing the real prevalence of HPV-driven OPSCCs in a given population. As it has been demonstrated that p16 positive/HPV negative cases (i.e., false positives at p16 IHC) have the same prognosis as p16 negative OPSCC, we conclude that despite the valuable prognostic value of p16 IHC, relying only on a p16 IHC positive result to recommend treatment de-intensification could be risky. For this aim, confirmation with an HPV nucleic acid detection system, especially in areas with a low prevalence of HPV-related OPSCCs, should be pursued.