Utility of Cytokeratin 5/6, Cytokeratin 20, and p16 in the Diagnosis of Reactive Urothelial Atypia and Noninvasive Component of Urothelial Neoplasia

Background: The utility of cytokeratin (CK)5/6 in distinguishing reactive urothelial atypia (RA) from urothelial carcinoma in situ (CIS) and from noninvasive component of high-grade papillary urothelial carcinoma (PUC) is unknown. Design: Twenty RA with or without papillary hyperplasia and 90 noninvasive components of neoplastic urothelial lesions were submitted for immunostaining with CK5/6, CK20, and p16. Results: Diffuse and strong reactivity involving the full or nearly full thickness of urothelium was observed with CK5/6 in 90% of RA cases. CK20 and p16 were negative in 90% and 85% of the RA cases, respectively. For CIS and noninvasive components of high-grade PUC without squamous differentiation, there was no CK5/6 staining or reactivity in the basal layer only. CK20 and p16 showed strong positivity in full thickness of urothelium in 75% to 85% of cases. CIS with weak/focal or negative reactivity for p16 or CK20 exhibited moderate cytologic atypia. Low-grade PUC displayed variable reactivity for CK5/6, CK20, and p16. Urothelial lesions with squamoid or basaloid features showed positive reactivity for CK5/6. Urothelial lesions with glandular differentiation showed negative reactivity for CK5/6. Conclusions: Diffuse CK5/6 reactivity in RA and negative CK5/6 reactivity in CIS and PUC may be helpful in distinguishing between these 2 entities.