MOLECULAR CHARACTERISTICS OF THE HETEROGENEITY OF NON-INVASIVE PAPILLARY UROTHELIAL CARCINOMAS AND THE MARKERS OF THEIR RECURRENCE.

Urothelial carcinoma represents the most common type of bladder cancer (>90%) and is the most frequent malignancy of the urinary tract. Most of the urothelial carcinomas are non-invasive at the time of diagnosis, however they are characterised with the risk of recurrence after surgical treatment. The aim of our study was to investigate the characteristics of tumor heterogeneity and markers of its progression in urothelial papillary carcinomas. Study included following groups: normal urothelial epithelium, urothelial papilloma, urothelial neoplasms with low malignant potential (PUNLM), non-invasive low grade papillary urothelial carcinomas (LGPUC) and non-invasive high grade papillary urothelial carcinomas (HGPUC). In addition, study included relapsed cases of non-invasive LGPUC and HGPUC. Nuclear features and mitotic counts was assessed using digital pathology software QuPath in standard H&E stained specimens. In addition, the presence of mitosis was detected as PHH3 labelled cells by immunohistochemistry. Proliferation was measured as Ki67 labelling index by immunohistochemistry. Tumor heterogeneity was investigated by the differential expression pattern of CK5, CK7 and CK20 by immunohistochemistry. Study results showed, that Nuclear features, as well as the number of mitosis, proliferation index and intratumoral heterogeneity significantly correlate with the presence of higher grade non-invasive urothelial lesions. In addition, it is possible to distinguish two major groups of non-invasive LGPUC and HGPUC, based on nuclear and phenotypic heterogeneity and mitotic and proliferative activity, I group which is characterised with higher intratumoral heterogeneity, higher mitotic count and higher proliferative activity, represents the high risk group of non-invasive LGPUC and HGPUC recurrence.