Insights into metastatic roadmap of head and neck cancer squamous cell carcinoma based on clinical, histopathological and molecular profiles.

The incidence of head and neck cancer (HNC), constituting approximately one in ten cancer cases worldwide, affects approximately 644,000 individuals annually. Managing this complex disease involves various treatment modalities such as systemic therapy, radiation, and surgery, particularly for patients with locally advanced disease. HNC treatment necessitates a multidisciplinary approach due to alterations in patients' genomes affecting their functionality. Predominantly, squamous cell carcinomas (SCCs), the majority of HNCs, arise from the upper aerodigestive tract epithelium. The epidemiology, staging, diagnosis, and management techniques of head and neck squamous cell carcinoma (HNSCC), encompassing clinical, image-based, histopathological and molecular profiling, have been extensively reviewed. Lymph node metastasis (LNM) is a well-known predictive factor for HNSCC that initiates metastasis and significantly impacts HNSCC prognosis. Distant metastasis (DM) in HNSCC has been correlated to aberrant expression of cancer cell-derived cytokines and growth factors triggering abnormal activation of several signaling pathways that boost cancer cell aggressiveness. Recent advances in genetic profiling, understanding tumor microenvironment, oligometastatic disease, and immunotherapy have revolutionized treatment strategies and disease control. Future research may leverage genomics and proteomics to identify biomarkers aiding individualized HNSCC treatment. Understanding the molecular basis, genetic landscape, atypical signaling pathways, and tumor microenvironment have enhanced the comprehension of HNSCC molecular etiology. This critical review sheds light on regional and distant metastases in HNSCC, presenting major clinical and laboratory features, predictive biomarkers, and available therapeutic approaches.