We want to bring attention to the significant findings of recent studies. [1][2][3] HPV status definitively represents a robust and independent prognosticator for survival among patients with oropharyngeal squamous cell cancer (OPSCC). 4 In the clinical practice, however, HPV status is frequently determined by only evaluating the expression of p16 through immunohistochemistry. 1,4 Despite the fact that p16 is an excellent surrogate for HPV association in many contexts, discrepancies are reported between its expression and actual HPV status. 1 Numerous efforts are being recently made to optimize treatment of patients with OPSCC through de-escalation protocols and initiatives focused on identifying early markers of relapse or response to treatment. Nevertheless, it is becoming apparent that we are still unable to accurately identify a subset of patients truly suffering from HPV-related carcinomas. Mehanna et al., 1 in particular, revealed a critical gap in understanding of the disease and clinical practice, reporting that 10.9% of p16+ OPSCC patients were actually HPVÀ.This phenomenon is more pronounced in regions where the proportion of HPV-related OPSCC is lower. Southern Europe, which has a lower prevalence of HPV-related OPSCC (the so-called attributable fraction), exhibits the highest rate of discordance between p16 positivity and HPV negativity. 1 Moreover, in Southern Europe, the lifestyle habits of p16+/HPVÀ patients resemble those of p16À/ HPVÀ, with smoking-a well-known negative prognosticator for both HPV+ and HPVÀ patients-being prevalent. 1,4 Emerging data also show that ethnicity may play a role, leading to differences in the prevalence of concordant and discordant classes even within the same geographic region. 5 This confirms that genetic heritage contributes to defining risk, alongside lifestyle habits, and sexual behavior. 6 Understanding the actual prevalence of discordant cases (p16+/HPVÀ or p16À/HPV+) is therefore crucial. Moreover, it is essential to consider the impact that HPV status can have on therapeutic decisions, considering that discordant cases are characterized by worse oncologic outcomes than those with p16+/HPV+ disease. Without such an insight, guidelines based on studies conducted in countries with different HPV-attributable fractions may lead to over-or undertreatment in other populations. In fact, according to the most recent NCCN guidelines, 7 there are cases where the
