Cutaneous squamous cell carcinoma (cSCC) is recognized as the second most common skin cancer, with studies estimating increases in incidence of between 50% and 200% over the past 30 years.

Current methods for risk assessment in cSCC are heterogenous, relying on the incorporation of high-risk tumor characteristics, as defined by current staging systems.

Identification of novel biomarkers to improve the prognosis of cSCC and incorporation of risk prognostication methods may significantly contribute to the development of more precisely targeted therapies and serve as a potential opportunity to improve upon and help standardize the treatment of cSCC.

This article will review over 10 years of the most relevant literature assessing the following risk factors currently relied upon in clinical practice to guide patient management: perineural invasion, differentiation, depth of invasion, size, and location, along with reviewing staging systems used in the USA, and evaluating the potential for molecular tools to enhance current risk assessment for cSCC patients.