Cytological and histological changes in the urothelium produced by electromotive drug administration (EMDA) and by the combination of intravescical hyperthermia and chemotherapy (thermochemotherapy).

The treatment of non muscle-invasive bladder cancer (NMIBC) encompasses a range of different procedures. Electromotive drug administration (EMDA) and chemo-hyperthermia (C-HT; Synergo) represent a minimally-invasive methods of intravesical instillation of therapeutic agents as mitomycin C (MMC). We selected patients with high grade NMIBC, BCG non responder, treated with EMDA/MMC and C-HT/MMC and we also examined the morphological changes in urine cytology samples. During the period from 2012 to 2014, 110 patients with high grade NMIBC, BCG refractory were selected. All cases examined were classified according to The Paris System Classification as negative for high urothelial carcinoma (NHGUC) or atypical urothelial cells (AUC) with a mean of follow-up of 15 months and the cytological diagnosis were confirmed by histological biopsies. In particular 50 patients were treated with EMDA/MMC and 60 patients underwent to C-HT/MMC. The morphological changes were evaluated in urine samples processed by Thin Prep method. In the 50 patients treated with EMDA/MMC, 35 samples were classified as NHGUC and 15 cases were classified as AUC, while in the 60 patients treated with C-HT/MMC, 43 samples were NHGUC and 17 cases were classified AUC. The increase of cellularity and nuclear size with the alteration of nuclear/cytoplasmatic ratio (N/C) were common in patients treated with EMDA/MMC and C-HT/MMC without clinical and histological evidence of recurrence of neoplasia. The hyperchromasia and irregular nuclear chromatin were rarely observed. The irregular nuclear membrane rarely identified in urine cytology after EMDA/MMC treatment, is a feature present in patients C-HT/MMC treated.

Emerging Immunotargets in Bladder Cancer.

Bladder cancer treatment, namely systemic therapy, was dominated in the last three decades due to the absence of newer therapeutic options other than chemotherapy regimens. Chemotherapy, by itself, both in first and second-line seems to have achieved the modest plateau of its possibilities at the cost of non-negligible toxicity. Targeted therapies, which changed the therapy of many different tumors, seem rather ineffective in bladder cancer. More recently, a new generation of Immunotherapy based regimens represent the most promising avenue for the future systemic treatment of bladder cancer. Checkpoint inhibition, namely PD1/PD-L1 pathway inhibition, showed impressive results in many other tumor types and are expected to become a major player in the treatment of bladder cancer. Other immunotherapy strategies such as fusion proteins represent distant, although promising, options. A brief overview of the current status of bladder cancer immunotherapy is presented.

Rare entities in urinary bladder pathology.

Bladder carcinoma with variant histology is a subject of recent interest, with data suggesting more aggressive behavior when compared with conventional urothelial carcinoma. The timely identification and recognition of these histological variants should avoid their misinterpretation as benign lesions. We emphasize the need to recognize these peculiar morphologic features since some of them may require a different/specific therapeutic approach. Other rare entities such as bladder polyps and myofibroblastic proliferations tend to occur at a younger age and represent specific problems in the differential diagnosis. We describe the salient clinicopathologic features of representative rare entities arising in the urinary bladder.

Dysplasia and carcinoma in situ of the urinary bladder.

Urothelial dysplasia (low-grade intraurothelial neoplasia) is recognized as a premalignant urothelial lesion in the 2004 World Health Organization (WHO) classification system. Although clarification of the diagnostic criteria of urothelial dysplasia has improved in recent years, there is still a lack of interobserver reproducibility. Active clinical follow-up is mandatory in patients with a diagnosis of urothelial dysplasia since it constitutes a marker of urothelial instability, and disease progression, in up to 19% of cases. The differential diagnosis of urothelial dysplasia is with other flat urothelial lesions with atypia, including flat urothelial hyperplasia, reactive urothelial atypia, urothelial atypia of unknown significance, and urothelial carcinoma in situ (high-grade intraurothelial neoplasia). In most cases, especially when small amounts of tissue are available, morphologic features alone may not be sufficient for diagnosis. Immunohistochemistry can be of help in selected cases, and a panel of cytokeratin 20, p53, and CD44 may help in the diagnosis. The use of HER2, p16, and Racemase remains as an option pending validation. Herein, we present the pathologic features and clinical significance of urothelial dysplasia and carcinoma in situ with emphasis on differential diagnosis from common flat lesions with atypia.