Liquid Biopsy in Head and Neck Squamous Cell Carcinoma: A Systematic Review of the Scientific Literature

Head and neck squamous cell carcinoma (HNSCC) presents a significant global health challenge, characterized by late-stage diagnosis and high rates of locoregional recurrence. Traditional tissue biopsy, while considered the gold standard, is invasive and often fails to capture the spatial and temporal heterogeneity of the tumor. Liquid biopsy has emerged as a transformative, noninvasive paradigm for molecular diagnostics, leveraging circulating biomarkers found in blood and saliva. This systematic review critically evaluates current evidence regarding the diagnostic accuracy, prognostic value, and molecular validity of circulating tumor cells, circulating tumor DNA (ctDNA), and the transcriptomic landscape of coding and noncoding RNAs (miRNAs, lncRNAs, and circRNAs) in HNSCC. Our review highlights the specificity of ctDNA for monitoring minimal residual disease, particularly in human papillomavirus- and Epstein-Barr virus-driven malignancies, where viral kinetics serve as sensitive biomarkers for recurrence. Furthermore, we explore the utility of "Saliva-Exosomics," suggesting that salivary exosomes may offer high sensitivity for early-stage oral cavity lesions due to anatomical proximity. The review also synthesizes data on novel RNA species, such as tumor-educated platelets and circular RNAs, which act as stable systemic biosensors. Despite promising results, significant heterogeneity in isolation protocols and detection platforms (e.g., next-generation sequencing vs. digital PCR) remains a barrier to widespread clinical implementation. We conclude that integrating multianalyte liquid biopsies into clinical practice holds the potential to personalize therapeutic strategies, improve survival outcomes, and redefine the standard of care in head and neck oncology.