Human papillomaviruses (HPV) would be detected in 70–80% of oropharyngeal cancers, the incidence of which had reached epidemic proportions. Regarding the status of the viral genome in these cancers, the current paradigm includes three types; one is the episomal viral genome, the other two are respectively the integration between viral genome and the host genome, and the mixture of the second one with the episomal HPV genomes. The last one had been confirmed the mischaracterizing by integrated HPV genomes and consisted of virus–human hybrid episomes. Most of the hybrid episomes are consistent with the replication of original HPV.

       According to the data from the Cancer Genome Atlas (TCGA), head and neck cancer was resulted from three types of HPV genome. Combined all the present data, “mixed” tumors were studied and confirmed to be derived from the replicated sequences between the viral and human. As integrated with viral genomes, the interpretation of outcome for HPV-positive patients was muddied. During de-escalation trials which were important for patients at increased risk, result shown that the patients should be the people with truly integrated tumors. More works need to be done in further. In current, researchers had studied on establishing cell lines from head and neck cancers, through the status of the viral genome at very early passage, to ensure that the viral genome would not be integrated by medium-term cell culture. If E2/E5 expression was lack in situ hybridization between E6/E2/E5 RNA and tumor samples, worse clinical outcomes would appear. The HPV and clinical research organizations should open mind about the proposed model and study further.