Intravesical immunotherapy, chemotherapy, and neoadjuvant systemic chemotherapy 
are among the most frequent therapeutic procedures to treat malignancies of the 
urinary bladder. These treatment modalities produce reactive morphologic changes 
in the urothelium that can mimic urothelial carcinoma in situ, urothelial 
dysplasia or true invasive urothelial neoplasia. Mitomycin C used after 
transurethral resection of bladder tumor to reduce recurrences, BCG intravesical 
immunotherapy to treat high risk non-muscle invasive bladder cancer and 
urothelial carcinoma in situ, and platinum-based systemic chemotherapy to 
improve post-cystectomy disease-specific survival some of the causes of therapy 
related atypia in urinary bladder. In addition, a number of systemic drugs in 
use to treat other systemic diseases, such as cyclophosphamide used to treat 
certain auto-immune disorders or hematologic malignancies, or the anesthetics 
ketamine increasingly used as illegal recreational drug, may produce similarly 
relevant atypical changes in the urothelium, and therefore, need to be 
differentiated from intraepithelial neoplasia. Immunohistochemical approach to 
reactive urothelium from CIS using CK20, p53, and CD44 may also be of utility in 
the pos-therapy scenario.