Heterogeneity-analysis of molecular subtypes of muscle-invasive bladder cancer and their precursor lesions in multiregion mapped whole-organ bladders

Abstract

In the recent years, molecular subtypes of urothelial bladder cancer have been described which seem to have a predictive effect for the efficacy of chemotherapy regimens and therefore are now under clinical investigation. Due to this clinical implication and possible decision guidance, the aim of our study is to characterize in which extent precursor lesions and tumors exhibit a heterogeneity of molecular subtypes, which possibly could influence response to chemotherapy regimens. 23 positions of three whole-organ mapped bladder specimens were histomorphologically reviewed for classifying location of normal urothelium, precursor lesions and different areas of the tumor. Immunohistochemical analysis of luminal (CK20, GATA3, FOXA1) and basal markers (CD44, CK14 and CK5/6) was carried out in selected precursor lesions and tumors to map the distribution of luminal and basal subtypes across the different positions/lesions. Out of three analyzed multiregion mapped bladder tumors, one showed a heterogenous luminal and double-negative molecular subtype in multiple tumor positions as well as a mixed morphology including conventional urothelial and neuroendocrine areas. Moreover, among the second analyzed bladder tumor, all tumor positions showed a high expression of basal markers whereas the included Carcinoma in situ demonstrated a luminal subtype with almost total absence of basal markers. The third analyzed mapped bladder tumor demonstrated a homogenous luminal molecular subtype in all precursor and tumorous lesions. This first analysis of three multiregion mapped bladder tumors shows divergent results of subtype distribution: Heterogeneity of subtypes can be observed, but other tumors and associated precursor lesions show a homogenous distribution of subtypes. To further elucidate how often subtype heterogeneity occurs in whole multiregion mapped bladder tumors, data of further bladder specimens will be presented at the meeting.