Head and neck (HN) cancers, particularly of the oral cavity and oropharynx, also known as oral/oropharyngeal squamous cell carcinoma (OOSCC), represent the 6th leading cause of cancer-related deaths globally. Most cases are diagnosed at advanced stages, with a survival rate around 50%. This highlights the need for improved diagnostic tools that enable early detection, which could significantly improve survival and clinical outcomes for OOSCC patients [1]. OOSCC is notably aggressive, often displaying resistance to chemotherapy and other standard anticancer treatments, resulting in poor therapeutic responses [1]. The five-year survival rates stand at 63% in the United States, approximately 50% in Europe, and even lower in developing regions [1, 2]. Tobacco use remains the leading cause of OOSCC, especially affecting areas like the floor of the mouth, lateroventral tongue, and tonsils [3, 4]. Alcohol consumption exacerbates the risk, particularly when combined with tobacco. Additionally, human papillomavirus (HPV), especially HPV-16, is strongly linked to oropharyngeal cancer. The prevalence of HPV-related OOSCC varies geographically, with the highest rates in North America (60%), followed by intermediate rates in Asia, Oceania, and Europe, and the lowest rates in South and Central America [1]. In the United States, over 60% of oropharyngeal cancers are now attributed to HPV, a trend mirrored in parts of Europe [1].

Currently, OOSCC diagnosis relies on comprehensive medical, social, and dental histories, followed by a physical examination and biopsy if necessary [5]. However, distinguishing between benign, dysplastic, and pre-malignant conditions is challenging. Although several diagnostic technologies (e.g., OraScan™, OralCdx™, VELScope™) exist, their adoption has been limited due to cost, invasiveness, and technical demands [6]. Saliva-based diagnostics have emerged as a promising, less invasive alternative for cancer detection. Saliva can be easily collected, even at the site of potential lesions, without specialized training or equipment [7]. Recent research has identified several salivary proteins, such as CD44, IL-8, and cyclin D, as potential biomarkers for early detection of OOSCC [8, 9].

Research has focused on CD44, a cell surface glycoprotein involved in cell proliferation, migration, and tumor initiation, which is over-expressed in pre-malignant lesions [10,11,12,13]. Soluble CD44, detectable in saliva, is associated with aggressive tumor properties like treatment resistance and recurrence [14]. Earlier studies used total protein levels as a normalizer for solCD44 but found these levels elevated in cancer patients [15,16,17]. A follow-up study confirmed that combining solCD44 and total protein improved predictive accuracy for OOSCC [18]. This led to the development of the OncAlert™ RAPID test, which demonstrated a sensitivity of 71–84% and a negative predictive value (NPV) of 94% in discriminating between cancer and control patients [19]. The primary aim of the current trial is to validate the correlation between the OncAlert™ RAPID test and biopsy results in a high-risk OOSCC population.