## 2 Oral Cancer  
Except for rare non-epithelial tumors [6; 7; 8], oral squamous cell carcinoma (OSCC) is the central and most common oral malignancy. OSCC is a malignant neoplasia of epithelial origin, of the head and neck district, at the seventh place for worldwide prevalence among cancers [9]. OSCC may arise from potentially malignant oral diseases (OPMDs), which are precursor lesions and conditions with an increased risk of malignancy [10]. Furthermore, OSCC recognizes a series of risk factors--mainly alcohol and/or tobacco consumption [11], betel quid chewing [12], chronic traumatism [13], micronutrient deficiencies [14], and infections [15; 16; 17; 18]--which contribute both to keratinocyte derailment toward cancerogenesis and sustain the related chronic inflammation, posing the ideal environment for tumor growth [19; 20; 21]. In 2020, the lip and oral cavity cancer incidence counted 264,000 new cases in males (70% of total cases) and 113,000 in females, with a male/female ratio equal to 2.3:1; a prevalence in 5 years of over 656,000 and 303,000 and mortality for over 125,000 and 53,000, respectively. Among them, the cases attributable to alcohol were 67,000 for males and 8200 for women [22]. In 2011, [PERSON] et al. [23] retrospectively reported clinical and demographic differences between 278 patients (159 males and 119 females) with OSCC followed up meanly for 36 months. While the overall median age was similar in both sexes (61 years for males, 65 years for females), their results revealed a slightly higher proportion of females (54%) over men (46%) in the OSCC patients older than 70 years. Smoking was reported in 76% of males and 51% of females; alcohol in 80% and 48%, respectively; conversely, neither alcohol nor tobacco consumption was reported in 14% of males and 39% of females, who were predominantly affected by maxillary OSCC. Furthermore, clinical stage and metastases still seem sex-independent prognostic factors. However, the literature usually did not often correlate the classical prognostic indicators and main outcome with sex [24], merely considering their distribution by sex but not focusing on the differential predictive meaning they could have in different sexes from a statistical point of view [25; 26; 27]. More recently, [PERSON] et al. [28] compared the prevalence by biological sex of head and neck (HN) cancers in 10 million healthy Korean during a 10-year follow-up. In that period, almost 11,000 subjects developed HN cancers, whose 1698 were oral cancers (84% in males and 16% in females). Additionally, in this case, the gap between males/females decreased over 70 years of age. Among men and women who developed oral cancers, the percentages of never smokers were 31% of males and 95% of females; similarly, non-alcohol consumers were 32% of males and 75% of females; both differences were statistically significant. The authors also discussed the higher prevalence of HN cancers in males, also regardless of smoking and drinking, and addressed this evidence to the role of sex hormones, mainly androgens, as associated with higher risks and poor outcomes in men, contrary to estrogen's protective effects in females [29; 30]. Conversely, further gender-specific differences in OSCC survival could also be related to protective gene polymorphisms for males but not for females, which are significantly associated with smoking, as [PERSON] et al. reported [31]. Furthermore, biological sex differences in the humoral and cell-mediated immune responses also seem to participate in the differences among biological sex on the onset of oral and HN cancers [32], while the detection of HPV, human papillomavirus, was not always investigated, despite its crucial role in a subset of HN cancers, mainly, but not exclusively, of the pharyngeal region [15].