PD-L1 expression across urothelial carcinoma subtypes: A multicenter comparison of 22C3 and SP142 for clinical decision-making in the immunotherapy era.

BACKGROUND

Urothelial carcinoma with histological subtypes (UC-s) presents diverse biological behaviours and therapeutic responses. PD-L1 immunoexpression has become a key biomarker for guiding immune checkpoint inhibitor therapy in advanced UC. However, the role of PD-L1 across UC-s remains limited characterized, with discrepancies reported between assays.

OBJECTIVE

This multicenter retrospective study aimed to assess PD-L1 expression patterns in 169 UC-s cases using two assays (22C3 and SP142), with analysis of tumor cells (TC), immune cells (IC), combined positive score (CPS), interobserver variability, and to assess their diagnostic relevance.

METHODS

Samples were obtained from five Spanish hospitals. Whole-slide immunohistochemistry was performed using both PD-L1 assays. Positivity thresholds were CPS ≥ 10 (22C3) and IC ≥ 5 % (SP142). Histological subtypes were subclassified and scoring was performed by four trained pathologists.

RESULTS

PD-L1 expression varied widely among UC-s subtypes. Squamous and sarcomatoid subtypes showed the highest PD-L1 expression with both assays. A greater number of UC-s were positive with SP142, especially in IC, while 22C3 showed higher TC expression. Discordant cases highlighted the influence of assay and cellular compartment on PD-L1 status. Interobserver agreement was high. Notably, 27 cases were SP142-positive but 22C3-negative for IC, suggesting potential therapeutic implications.

CONCLUSION

The 22C3 and SP142 assays show analytical concordance for overall PD-L1 status but significant variability in IC scoring. Given the variability in PD-L1 expression across UC-s, precise characterization of both TC and IC staining per assay is crucial. These findings support incorporating UC-s subtype and assay-specific PD-L1 profiles into routine diagnostics to optimize immunotherapy decisions.