Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High‐risk human papillomavirus (HR‐HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de‐escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de‐escalation in HPV‐positive OPSCC.

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Accurate screening of HPV-driven head and neck squamous cell carcinoma is a critical issue. Although there are commercial direct and indirect assays for HPV-related head and neck squamous cell carcinoma, none are ideal. Recently, a novel RNA in situ hybridization test (the RNAscope HPV-test) has been developed for the detection of high-risk HPV E6/E7 mRNA in formalin-fixed paraffin-embedded tissue. However, validation of this assay against the 'gold standard' (identification of high-risk HPV E6/E7 mRNA in fresh-frozen tissue by quantitative real-time (qRT)-PCR) has only been reported by one team. Formalin-fixed paraffin-embedded samples from 50 patients with tonsil or tongue base carcinoma were tested using the RNAscope HPV-test, p16 immunohistochemistry, and chromogenic in situ hybridization for high-risk HPV-DNA. The results were compared with those of qRT-PCR on matched fresh-frozen samples. Compared with the reference test, the sensitivity, specificity, positive, and negative predictive values of the RNAscope HPV-test and of p16 immunohistochemistry were 93%, 94%, 96%, 88% and 96%, 93%, 96%, and 93%, respectively. Five cases were discrepant between the RNAscope HPV-test and p16-immunohistochemisrty. The RNAscope HPV-test demonstrated excellent analytical performance against the 'gold standard' and is easier to interpret than chromogenic in situ hybridization. p16-immunohistochemistry also performed very well, however its main weakness is that it is an indirect marker of the presence of HPV. These data suggest that the RNAscope HPV-test is a promising test that could be developed as a clinical standard for the precise identification of HPV-driven oropharyngeal squamous cell carcinoma.