Molecular Markers of Occult Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma (HNSCC) Patients
Authors: Meliante Piero Giuseppe , Pizzolante Sofia , Perna Luca , Filippi Chiara , Bandiera Giorgio , Barbato Christian , Minni Antonio , de Vincentiis Marco , Covelli Edoardo 
Published: February 2025

The accurate diagnosis of regional lymph node metastasis is critical for guiding treatment decisions in head and neck cancer patients. Despite advances in imaging techniques, detecting nodal metastasis using radiology remains challenging, leading to potential undertreatment or overtreatment. This review aims to identify molecular markers associated with occult metastasis in head and neck squamous cell carcinoma (HNSCC) patients. We divided the results by subsite for markers: lymph node analysis (microRNAs, myosin-5a (MYO5A), ring finger protein 145 (RNF145), F-box only protein 32 (FBXO32), CTONG2002744, cytokeratin 14 (CK14), eukaryotic initiation factor 4E (eIF4E), desmoglein-3 (DSG3), microsatellite D9S171, squamous cell carcinoma antigen, cytokeratin, tumor budding score, human papillomavirus-DNA (HPV-DNA), tumor infiltrating lymphocytes, sentinel lymph node analysis techniques, single fiber reflectance spectroscopy, radiological techniques), tumor tissue analysis (activin A, carcinoma-associated fibroblasts, cyclins, β-catenin, histopathology, genetic amplifications, DNA methylation, ecotropic viral integration site 1, CC-chemokine receptor 7, melanoma associated-A antigens, vascular endothelial growth factor-C (VEGF-C), panitumumab, epidermal growth factor receptor (EGFR), cornulin, total protein analysis, CD133, NANOG homeobox, neurogenic locus notch homolog protein 1 (NOTCH1), metastasis-associated protein 1, 14-3-3-zeta, E-cadherin, focal adhesion kinase, p-epithelial-mesenchymal transition (EMT), small proline rich protein 1B (SPRR1B), transcription factor NKX3-1, DNA copy number aberrations, microfibril-associated protein 5 (MFAP5), troponin C1, slow skeletal and cardiac type (TNNC1), matrix Gla protein (MGP), fibroblast growth factor binding protein 1 (FBFBP1), F-box protein 32 (FBXO32), fatty acid binding protein 5, B cell-specific Moloney murine leukemia virus integration site 1, podoplanin, p53, Bcl-2, epidermal growth factor receptor (EGFR), Ki67, cyclin D1, cox-2, semaphorin-3F, neuropilin-2, histologic features, cellular dissociation grade, prospero homeobox protein 1, radiologic features, Ki-67, poly (ADP-ribose) polymerase (PARP), Bcl-2 associated agonist of cell death (BAD), caspase-9, vascular endothelial growth factor A (VEGF-A), HPV, p16, methylation status of long interspersed element 1 (LINE-1) and Alu elements, mesenchymal-epithelial transition (MET), gene expression analyses, molecular subtypes) and blood markers (standard blood analysis indexes and ratios, circulating tumor cells, HPV-DNA, CD-31, bone marrow analysis). Several promising markers were identified, including miR-205, desmoglein 3 (DSG3), pan-cytokeratin (CK) AE1/AE3, HPV-16, activin-A, cyclin D1, E-cadherin, and neural progenitor lineage (NPL) that demonstrated effectiveness across multiple studies. Future research should focus on exploring combination scoring systems to improve diagnostic precision and optimize treatment selection in HNSCC patients.