FIGURE 2.

Field cancerisation in the setting of HPV infection. The progression from IEN to SCC formation is characterized by the clonal selection, acquisition of mutations, and loss of HPV replication. Skin is used here as a HPV susceptible tissue, as we have previously shown that clonal expansion occurs from the hair follicle junctional zone. In mild IEN there are many clones, which in the case of p53 mutation susceptible tissues, may harbor individual distinct mutations as shown (circles with different colors). Progression of IEN is characterized by the selection and expansion of individual clones that have gained a proliferative advantage from additional mutations, culminating in severe IEN with full thickness epidermal dysplasia that is genetically uniform. With increasing mutational load, epidermal dysplasia increases and HPV episomes are lost. In the case of β-HPV types, the entire viral infection is lost, which accounts for the “hit and run” mechanism of transformation. From within the severe IEN, foci of SCC develop as shown, resulting in invasion into the underlying tissue.