Abstract
Consistent discrepancies in the p16/HPV-positivity have been observed in head and neck squamous cell carcinoma (HNSCC). It is therefore questionable, if all HPV(+) and/or p16(+) tested cancers are HPV-driven. Patients down-staged according to the HPV-dependant TNM are at risk for undertreatment and data in clinical trials may be skewed due to false patient inclusion. We performed a meta-analysis to classify clinical outcomes of the distinct subgroups with combined p16 and HPV detection. 25 out of 1677 publications fulfilled the inclusion criteria. The proportion of the subgroups was 35.6% for HPV(+)/p16(+), 50.4% for HPV(-)/p16(-), 6.7% for HPV(-)/p16(+) and 7.3% for HPV(+)/P16(-). The HPV(+)/p16(+) subgroup had a significantly improved 5-year overall-survival (OS) and disease-free-survival in comparison to others both for HNSCC and oropharyngeal cancers. The 5-year OS of the HPV(-)/p16(+) HNSCC was intermediate while HPV(+)/p16(-) and HPV(-)/p16(-) had the shortest survival outcomes. The clearly distinct survival of HPV(-)/p16(+) cancers may characterize a new relevant HPV-independent subtype yet to be biologically characterized. The possibility also exists that in some HPV(+)/p16(+) cancers HPV is an innocent bystander and p16 is independently positive. Therefore, in perspective, HPV-testing should distinguish between bystander HPV and truly HPV-driven cancers to avoid potential undertreatment in HPV(+) but non-HPV-driven HNSCC.