Abstract
According to current predictions, one-fifth of all Americans will develop skin cancer during their lifetime. Cutaneous squamous cell carcinoma (cSCC) most commonly occurs in the head and neck region, which is the area of the body with the highest level of sun exposure. High-risk head and neck cSCC (HNcSCC) is a broad category with numerous high-risk factors that are associated with unfavorable results. In cSCC staging systems, clinical and tumor traits that are likely to result in poor outcomes are identified. Metastasis occurs in ~2.5% of patients with cSCC, most often in the local lymph nodes, and there is some indication that lymph node metastasis has a distinct pattern based on the tumor site. Current findings on tumor molecular targets have suggested the use of systemic treatments, particularly immunotherapy (such as cemiplimab, pembrolizumab and nivolumab), over radiotherapy or chemotherapy for this type of metastasis. However, when used simultaneously with immunotherapy, radiotherapy may be beneficial in the treatment of metastatic HNcSCC by improving the efficacy of immunotherapy. The present review aims to assess the existing literature on metastatic HNcSCC pathways and treatment options, in order to define current and future directions. Notably, there is an urgent need to identify patients who may benefit from local or systemic cancer treatments. The treatment of lymph node metastasis presents a therapeutic challenge and requires comprehensive management.