The second pathway, the dysplasia pathway, is less frequent and is responsible for the formation of approximately 20 % of urothelial carcinomas . This pathway leads to high-grade urothelial tumors. It starts with dysplasia, which progresses either to the formation of a high-grade papillary tumor or, in a smaller percentage of cases, to flat urothelial carcinoma (carcinoma in situ). HGUC is also associated with a high recurrence rate but, most importantly, has a high risk of progression to muscle-invasive, stage T2, T3, and T4 tumors with lymph node and systemic metastases. This pathway is genetically unstable and is associated with a number of additional mutations; the most significant of them are inactivating mutations of TP53, which are seen in approximately 60 % of these tumors.

What is of significance is that the key molecular abnormalities associated with the dysplasia pathway, especially the TP53 mutations, which are strongly associated with high-grade and high-stage urothelial carcinomas, are essentially mutually exclusive with the molecular abnormalities characterizing the hyperplasia pathway [13].

It was historically believed that at some point of the hyperplasia pathway, LGUC will acquire more mutations, particularly RAS mutations, and will progress to HGUC [15]. In general, the accepted rate of progression was about 10 %. However, there are recent studies demonstrating that noninvasive LGUC (Ta) has a very low risk of progression (less than 1–5 %) [16]. In addition, RAS (HRAS and KRAS) mutations, that were believed to be necessary for the progression to high-grade tumors, are mutually exclusive with the FGFR3 mutations that are characteristic for the low-grade pathway [12]. This could potentially indicate that these two pathways are completely separate from each other. If that would prove to be right, low-grade carcinoma and high-grade carcinoma may represent two entirely different diseases. This finding would potentially be of great clinical significance, considering that there are already opinions that low-grade tumors originating from the hyperplasia pathway should not even be called “carcinoma”. All these pathogenetic considerations aside, truly clinically significant urothelial neoplasms are the ones that have the ability to invade deep muscle; these are HGUC.

Therefore, the guiding principle for The Paris System is to detect HGUC. In line with this principle, the negative category includes reactive changes, infectious and nonneoplastic conditions, as well as cases that may have some cytologic features of low-grade urothelial neoplasms, but are negative for HGUC. Therefore, the proposed diagnostic category is “Negative for High-Grade Urothelial Carcinoma” (NHGUC) . Despite the fact that we strive to detect all high-grade urothelial tumors, we recognize that there will be cases where the definite diagnosis cannot be made. Therefore, in The Paris System we include the categories of “Atypical Urothelial Cells” (AUC) and “Suspicious for High-Grade Urothelial Carcinoma” (SHGUC) . Of importance is the understanding that the difference between the two categories, suspicious for HGUC and positive for HGUC, are quantitative since the diagnostic features for these two categories are based on similar morphologic findings.

Although the diagnosis of LGUC is not the main goal of this system, a separate diagnostic category has been included to define those circumstances where cytologic features of low-grade urothelial neoplasms (LGUN) are present (see Chap. 7). We recognize that the cytologic diagnosis of LGUC can be rarely made, and should be based only on the presence of well-defined fibrovascular cores in the absence of cellular atypia. Otherwise, if there is a high cytologic suspicion for a low-grade lesion and/or there is a papillary lesion present on cystoscopy and/or biopsy, a diagnosis of LGUN can be included in the overall Negative for HGUC category with a secondary diagnosis of LGUN.