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.

During the past decade, a vast number of studies were dedicated to unravelling the obscurities of non-coding RNAs in all fields of the medical sciences. A great amount of data has been accumulated, and consequently a natural need for organization and classification in all subfields arises. The aim of this review is to summarize all reports on microRNAs that were delineated as prognostic biomarkers in laryngeal carcinoma. Additionally, we attempt to allocate and organize these molecules according to their association with key pathways and oncogenes affected in laryngeal carcinoma. Finally, we critically analyze the common shortcomings and biases of the methodologies in some of the published papers in this area of research. A literature search was performed using the PubMed and MEDLINE databases with the keywords “laryngeal carcinoma” OR “laryngeal cancer” AND “microRNA” OR “miRNA” AND “prognostic marker” OR “prognosis”. Only research articles written in English were included, without any specific restrictions on study type. We have found 43 articles that report 39 microRNAs with prognostic value associated with laryngeal carcinoma, and all of them are summarized along with the major characteristics and methodology of the respective studies. A second layer of the review is structural analysis of the outlined microRNAs and their association with oncogenes and pathways connected with the cell cycle (p53, CCND1, CDKN2A/p16, E2F1), RTK/RAS/PI3K cascades (EGFR, PI3K, PTEN), cell differentiation (NOTCH, p63, FAT1), and cell death (FADD, TRAF3). Finally, we critically review common shortcomings in the methodology of the papers and their possible effect on their results.

Representative hematoxylin and eosin and IHC staining from two cases. Case 3: (A1.1) hematoxylin and eosin of tumor surface, (A1.2) VEGF-A IHC at tumor surface, (A2.1) hematoxylin and eosin of tumor depth, and (A2.2) VEGF-A IHC at tumor depth, showing no qualitative differences between regions. Case 5: (B1.1) hematoxylin and eosin of tumor surface, (B1.2) VEGF-A IHC at tumor surface, (B2.1) hematoxylin and eosin of tumor depth, and (B2.2) VEGF-A IHC at tumor depth, with a slight tendency toward stronger expression in the depth.

Clinicopathologic characteristics of the study cohort.

Paired analysis demonstrated significantly higher VEGF-A mRNA expression at tumor depth compared with surface (Wilcoxon z = −2.219; P = 0.026).

High expression of miR-93-5p, miR-210-3p, and miR-144-3p was associated with significantly reduced RFS [χ2(2) = 4.68, log-rank P = 0.03; χ2(2) = 4.53, log-rank P = 0.03; and χ2(2) = 4.53, log-rank P = 0.03, respectively]. Previously published in ref. 4.