Biomarkers of Common Molecular Dysregulation in Tumor Tissue and Peritumor Mucosa in Head and Neck SCC: Insights into Field Cancerization

Field cancerization is a fundamental paradigm in tumorigenesis, emphasizing that carcinogenesis begins long before the appearance of clinically detectable lesions and often precedes recognizable premalignant changes. A direct manifestation of this process is the molecular dysregulation observed in the peritumoral mucosa-histologically normal-appearing tissue that nonetheless exhibits genetic and epigenetic alterations similar to those of the adjacent tumor. This review summarizes current evidence on the molecular alterations shared between tumor tissue and peritumoral mucosa in HNSCC and evaluates their potential as biomarkers for defining molecular margins and improving surgical precision. A literature search was conducted in PubMed using combinations of the keywords "peritumor," "laryngeal", "HNSCC," and "field cancerization." Studies were included if they directly compared tumor tissue with peritumoral mucosa and, preferably, a third set of distant normal control samples. Only nine studies met the inclusion criteria, highlighting the scarcity of focused research in this area. Reported biomarkers exhibiting comparable dysregulation in both tumor and peritumor tissues include MDM2, E2F2, CDKN2A/p16, ETS-1, MGMT, and multiple microRNAs (e.g., miR-21, miR-96-5p, miR-145-5p). These molecular signatures demonstrate the presence of a biologically altered field extending beyond histologically defined tumor margins. Peritumoral mucosal dysregulation, as a consequence of field cancerization, underscores the need to redefine surgical margins at the molecular level. The identification and validation of biomarkers reflecting this continuum could enable the establishment of molecular margins-improving risk assessment, reducing local recurrence, and advancing personalized oncologic surgery in HNSCC. Standardizing definitions and sampling protocols for "normal adjacent tissue" remains essential for future translational research.