CD44 + p53 + CK20 can be used to differentiate urothelial reactive atypia from CIS (carcinoma in situ) in bladders. In normal urothelium, superficial umbrella cell layer shows reactivity for CK20 only, whereas CD44 staining is limited to the basal and parabasal urothelial cells and p53 nuclear staining is absent to focal. For urothelium with reactive atypia, particularly in cases with marked atypia, CD44 shows increased reactivity in all layers of the urothelium and is often absent in neoplastic cells. CK20 and p53 staining remain identical to those seen in normal urothelium. In cases of CIS, diffuse, strong cytoplasmic reactivity for CK20 and diffuse nuclear reactivity for p53 is observed throughout the urothelium.