PD-L1 immunoexpression and molecular characterization of histological subtypes in urothelial carcinoma

Urothelial carcinoma (UC) has histological subtypes whose phenotype reflects their molecular diversity, behavior and response to conventional therapy. Immune checkpoint inhibitors (ICIs) have improved the management of UC by evaluation of PD-L1. In the case of PD-L1 22C3, the initiation of ICI is considered from a combined positive score (CPS) greater than 10. However, UC subtypes with absent PD-L1 22C3 expression in cases with CPS>10 may not respond to these treatments. This study aims to establish a correlation between the PD-L1 immunoexpression and molecular alterations in divergent differentiation and histological subtypes of UC (UC-s).

Twenty-six samples of UC were detected from a total of 24 patients. Two pathologists performed separately an assessment of UC-s on hematoxylin-eosin as well as PD-L1 expression. Molecular study of each case was performed by next generation sequencing (NGS). A descriptive analysis of the variables included was conducted.

Nine cases (34.61%) showed a CPS>10, some with negative PD-L1 immunoexpression in aggressive UC-s. The molecular study revealed alterations in genes belonging to the p53/cell cycle control, RAS, and DNA repair pathways, among others. None of the alterations were exclusive to any histological subtype.

Special attention should be paid to CPS>10 cases that include histological subtypes of UC with divergent expression for PD-L1 as they may not respond to treatment with ICI. We recommend examining the proportion and PD-L1 status of each subtype, especially if it has aggressive behavior.