Staging, workup, neoadjuvant/adjuvant therapy, and treatment options for cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide and represents a growing source of morbidity and mortality. Incidence continues to rise globally, driven by an aging population, cumulative ultraviolet exposure, and increasing prevalence of high-risk patient populations. While most cSCCs follow an indolent course, a clinically meaningful subset can demonstrate aggressive behavior, highlighting the need for accurate risk stratification and individualized management strategies. This narrative review synthesizes contemporary evidence regarding the clinical presentation, tumor biology, diagnostic evaluation, staging systems, and treatment paradigms for cSCC with emphasis on emerging prognostic tools shaping future care. We summarize key clinical and histopathologic features associated with adverse outcomes, including depth of invasion, differentiation, and perineural involvement, and review current imaging and nodal assessment strategies. Staging frameworks, including American Joint Committee on Cancer (AJCC), Brigham and Women's Hospital (BWH), and evolving stages of the National Comprehensive Cancer Network (NCCN) systems, are discussed alongside newer models such as risk-integrated squamous cell carcinoma staging, which aim to improve outcome discrimination. Treatment approaches encompassing surgery, radiation therapy, and systemic immunotherapy are reviewed, with particular attention to risk-adapted use of Mohs micrographic surgery, adjuvant radiation therapy (ART), and neoadjuvant or definitive programmed cell death protein-1 (PD-1) blockade for advanced disease. Finally, we examine emerging molecular prognostic assays, including gene expression profiling (GEP), that offer biologic insight beyond traditional clinicopathologic factors and may refine decisions regarding surveillance and treatment escalation. As the burden of cSCC continues to expand, integrated frameworks incorporating clinical, histopathologic, and molecular data will be essential for optimizing outcomes while minimizing patient and system-level burdens, particularly for identifying tumors requiring treatment escalation.