This chapter will give a general overview on the molecular mechanisms at the basis of the occurrence of cutaneous squamous cell cancer (cSCC) and their implications on histopathological classification, treatment, and prognosis. We will describe the main epidemiologic characteristics of cSCC in detail. Moreover, we will discuss the etiopathogenetic mechanisms of this tumor underlining the involvement of the exposure to ultraviolet (UV) rays and to high- and low-risk human papillomaviruses (HPV). The molecular mechanism of transformation will be also described with a special focus to Fas and its ligand, the p53 family proteins (especially p63), and lymphatic vessel proteins such as podoplanin. These molecular markers will be also discussed as potential predictors of survival and response to therapy together with the conventional histopathological factors and to the proteins belonging to the epidermal growth factor receptor family. We will also illustrate the main surgical and medical therapeutic strategies available for the treatment of either local or invasive/metastatic cSCC. In this view, the conventional standard treatments will be described together with the strategies based upon the use of new molecularly target-based agents (MTAs) including cetuximab and erlotinib. Some MTAs used in the treatment of another cutaneous tumor (melanoma) can, in turn, induce the occurrence of cSCC. This is the case of Raf kinase inhibitors, and we will discuss the related hypothetical mechanisms of induction. Finally, we will propose therapeutic strategies designed to overcome the resistance of SCC to the antiproliferative effects of anticancer agents such as interferon alpha (IFN-α).
