A handful of therapeutic procedures are used to treat malignancies of the 
urinary tract, most frequently intravesical immunotherapy or chemotherapy, but 
also neoadjuvant systemic chemotherapy. These treatment modalities produce 
morphological changes in the urothelium that can be mistaken for carcinoma; in 
particular, these therapies frequently mimic urothelial carcinoma in situ (CIS) 
urothelial dysplasia or true invasive neoplasia. Drugs such as mitomycin C used 
after transurethral resection of bladder tumour to reduce recurrences, bacillus 
Calmette-Guérin (BCG) intravesical immunotherapy to treat high-risk 
non-muscle-invasive bladder cancer and urothelial CIS and platin-based systemic 
chemotherapy to improve postcystectomy disease-specific survival are examples of 
therapy-related atypia seen in the urinary tract. To complicate the 
pathologist's life, a number of systemic drugs in use to treat other diseases, 
such cyclophosphamide, used to treat some autoimmune disorders or certain 
haematological malignancies or, in the case of anaesthetics, ketamine, used 
increasingly as an illegal recreational drug, may produce similarly relevant 
atypical changes in the urothelium, and therefore need to be differentiated from 
intraepithelial neoplasia. Other less frequent procedures, such as photodynamic 
and laser therapy or the newer gene therapy to treat urothelial neoplasia, 
remain experimental. An immunohistochemical approach to reactive urothelium 
versus carcinoma in situ using p53, cytokeratin 20 and CD44 is also valid in the 
post-therapy setting. The pathologist should be aware of these novelties, as he 
or she plays a crucial role in evaluating treatment efficacy, but at the same 
time needs to avoid misdiagnosing secondary atypia as intraepithelial neoplasia.