Distinct molecular pathogenesis in the two most common subtypes of cutaneous squamous cell carcinoma

The Bowenoid subtype of cutaneous squamous cell carcinoma (SCC) has been distinguished from conventional SCC for over a century based on its different histopathologic appearance, clinical features, and biologic potential. While there has been extensive molecular analysis of conventional SCC, there has been comparatively little investigation of Bowenoid SCC. Here we show that loss of RB1 protein expression is a defining feature of Bowenoid SCC and reflects biallelic genetic inactivation which most commonly proceeds through mutation of one RB1 allele and copy number loss of the other allele. Neither RB1 protein loss nor RB1 mutations were seen in conventional SCC. A third, but much less common, form of cutaneous SCC is caused by human papillomavirus (HPV). This subtype showed similar morphologic features to Bowenoid SCC and also showed loss of RB1 protein expression. However, these tumors lacked RB1 mutation and likely inactivate RB1 through HPV's known capacity to promote post-translational degradation of RB1 protein. These data suggest that the two most common subtypes of cutaneous SCC proceed through distinct pathways of molecular pathogenesis and highlight an unexpected relationship between Bowenoid and HPV-associated cutaneous SCC.