Liquid biopsy, the analysis of tumor-derived material in blood, saliva, and other body fluids, is increasingly explored for the diagnosis, surveillance, and molecular characterization of head and neck squamous cell carcinoma (HNSCC). Its performance, however, is not uniform across the disease, and the reason is fundamentally molecular. human papillomavirus (HPV)-positive oropharyngeal cancers carry viral oncogenes that are absent from the host genome and therefore provide a near ideal, tumor specific circulating marker, whereas HPV-negative tumors are driven by a heterogeneous somatic landscape that offers no single universal target. In this narrative review, we adopt a molecular perspective. We first examine the biological origin of circulating tumor DNA and of the other analytes that liquid biopsy can interrogate including circulating tumor HPV DNA, viral transcripts, microRNAs, extracellular vesicles, and methylation signatures. We then consider how analytical platforms, from droplet digital PCR to next generation and ultrasensitive whole-genome sequencing, translate these molecules into measurements. Only afterward do we discuss the clinical questions, organized by clinical objective rather than by individual study: diagnosis and early detection, prognosis and risk stratification, treatment response monitoring, minimal residual disease and surveillance, and biomarker guided de-escalation in HPV-positive disease. Twelve registered clinical trials, involving approximately 1183 patients, are presented as illustrations of these questions. We close on the biological and technical gaps that still separate promising signals from clinical practice, and on the multi analyte and dynamic strategies most likely to bridge them. At present, liquid biopsy should be regarded as a complementary tool rather than as a replacement for established clinicopathological assessment.

This narrative review explores the potential role of the oral microbiota and dysbiosis in upper aerodigestive tract (UADT) carcinogenesis. The localized accumulation of acetaldehyde (ACH) derived from microbial ethanol metabolism has emerged as a notable, modifiable risk factor under investigation. Specific resident microorganisms, including Neisseria subflava, Streptococcus mitis, Rothia spp., and Candida albicans, exhibit alcohol dehydrogenase activity in vitro, combined with a near-complete lack of local detoxification capacity. This biochemical imbalance turns saliva into a potential reservoir for mutagenic metabolites that could theoretically promote DNA damage. However, robust clinical evidence supporting a definitive connection between these in vitro findings and human carcinogenesis remains limited. Current data are largely observational and prone to confounding from lifestyle factors like tobacco and alcohol use. Similarly, emerging concepts regarding endogenous ACH production through carbohydrate fermentation lack strong clinical confirmation. Nevertheless, these findings open promising new avenues for research. The accessibility of the oral cavity positions the microbiota as a compelling candidate for non-invasive biomarker development and targeted preventive strategies. While longitudinal trials are required to establish definitive causality, exploring these microbiome-mediated pathways offers an encouraging framework to enhance future personalized risk assessment in UADT oncology.

Background: Bacteria colonizing the nasal cavity contribute to mucosal homeostasis, and altered sinonasal bacterial communities have been associated with chronic rhinosinusitis with nasal polyps (CRSwNP). Whether routine, culture-based microbiology can distinguish the cultivable bacterial profile of CRSwNP patients from that of controls remains unclear. Methods: In this single-center observational pilot study, middle-meatus swabs from 30 patients with CRSwNP and 30 controls were cultured on four media, and isolates were identified with the VITEK 2 system. For each species, presence or absence per subject was compared between groups using Fisher’s exact test with Benjamini–Hochberg correction for multiple comparisons; the number of cultivable species per subject was compared with the Mann–Whitney test. Results: The two groups were comparable in age and sex. Patients yielded more cultivable bacterial species per subject than controls (mean 4.4 vs. 2.9; Mann–Whitney p < 0.001). Several species were numerically more frequent in patients (e.g., Staphylococcus hominis, S. lugdunensis) and others in controls (e.g., S. epidermidis, S. aureus), but no individual species difference remained significant after correction. Conclusions: Using routine culture, CRSwNP was characterized chiefly by a higher number of cultivable bacterial species, whereas individual species differences were not statistically robust. These hypothesis-generating findings warrant confirmation in larger, sequencing-based studies.