A four-antibody immunohistochemical panel can distinguish clinico-pathological clusters of urothelial carcinoma and reveals high concordance between primary tumor and lymph node metastases

Urothelial carcinoma of the bladder (UC) has a poor prognosis, partly because of chemotherapy resistance. Molecular classifications have shown their interest and can help to offer personalized treatment. In this study, we evaluated the feasibility of an immunohistochemical study to divide advanced UC into clinico-pathological-molecular subgroups and evaluate phenotypic correspondence between primary UC and matched lymph node metastases (LMN). An eight-antibody immunohistochemical panel was performed on UC and matched LMN from patients treated with radical cystectomy. One hundred eighty-seven UCs (100 pN0 tumor and 87 pN+ tumor) were tested. Multiple correspondence analysis showed that UC expressing GATA3 also expressed FOXA1 (p = 0.010) and did not stain for CK5/6 (p = 0.031) nor CK14 (p = 0.003). UC expressing CK14 coexpressed CK5/6 (p < 0.0001), had high Ki67 (p = 0.010) and no GATA3 (p = 0.003) nor FOXA1 (p = 0.011) expression. Loss of expression of STAG2 was associated with high Ki67 (p = 0.001). Sixty-seven percent of [CK5/6 CK14]+ [GATA3 FOAXA1]- patients had high Ki67 expression vs 37% of [GATA3 FOXA1]+ [CK5/6 CK14]- patients (p = 0.024). The majority of [CK5/6 CK14]+ [GATA3 FOAXA1]- patients (92%) had advanced disease (pT3-pT4) whilst 86% of pT1-T2 cases were [GATA3 FOXA1]+ [CK5/6 CK14]- (p = 0.041). Differential antigen expression between 63 pN+ primary tumors and their corresponding LNM showed the following concordance percentages: p53 (76%), p63 (75%), CK5/6 (65%), CK14 (89%), GATA3 (75%), FOXA1 (68%), STAG2 (65%), and Ki-67 (71%). These results support the interest of immunohistochemistry for subtype profiling in metastatic UC, using CK5/6, CK14, GATA3, and FOXA1, highlighting also few phenotypical modifications when tumor spreads to lymph nodes.