Introduction: Molecular classification of muscle invasive bladder cancer (MIBC) has revealed several subtypes, with luminal and basal as most distinct. A consensus is arising that at IHC level basal cancers can be identified by their CK5+/GATA3- profile, and luminal cancers by CK5-/GATA3+. However a detailed, extensive study using these markers throughout the spectrum of non-MIBC (NMBIC) has not yet been performed. To understand the presentations of the CK5/GATA3 profile and the correlation between tumor grade and basal-luminal subtypes, we studied CK5/GATA3 expression patterns in a large group of pTa NMIBC.
Methods: FFPE tissue slides with papillary pTa BC were obtained from a single-center TURBT series. A panel of IHC markers was used to characterize luminal/epithelial cells: GATA3, CK20; and basal/squamous cells: CK5, P40, P63. Four different patterns of CK5 expression were evaluated (absent, normal, rising, and full-thickness), and a percentage for each pattern was assessed per case. Additionally, percentages of LG vs. HG, GATA3, CK20, P40, and P63 were scored for each specific CK5 pattern. We performed a quantitative polymerase chain reaction (qPCR) based on the results of correlation of CK5 patterns with grading.
Results: 109 TURBT specimens were included with papillary pTa disease. Presence of CK5 patterns was: absent in 41.3%; normal in 72.5%; rising in 84.4%; and full-thickness in 23.9%. Median GATA3 expression was 100% (IQR: 100-100; minimum 80). CK5 expression did not correlate with any of the IHC markers (GATA3, CK20, P40 and P63) for each specific CK5 pattern; but there was a significant inverse correlation between rising CK5 expression and grading (LG vs. HG) (Figure). On qPCR we confirmed that a rising CK5 pattern correlated with upregulation of CK5 mRNA.
Conclusions: Our findings suggest a different applicability and relevance of GATA3/CK5 in classification (luminal-basal) and grading of NMIBC compared to MIBC. Whereas CK5 acts as a basal and poor prognostic marker in MIBC, it does the opposite in pTa NMBIC, with an inverse correlation between amount of CK5 expression and amount of HG disease. Moreover, GATA3+ is omnipresent and does not correlate with any specific tumor feature. If validated in prospective studies with outcome data, CK5 might serve as a beneficial prognostic biomarker to stratify pTa NMBIC. Source of