HRAS and in situ carcinoma: In the papillary pathway of superficial or low-grade lesions (80% of cases), there is activation of proliferative factors (FGFR3 and HRAS), whereas in the non-papillary pathway (20% of cases), including carcinoma in situ (CIS) and infiltrating carcinomas, there is a loss of p53 or RB1 function.