Programmed death ligand 1 protein expression, histological tumour differentiation and intratumoural heterogeneity in pulmonary adenocarcinoma.

Intratumoural heterogeneity of pulmonary adenocarcinoma challenges the accurate interpretation of programmed death ligand 1 (PD-L1) immunohistochemistry, which is the only validated predictive marker for successful anti-PD-1/PD-L1 immunotherapy. The aim of this study was to determine whether PD-L1 expression is related to adenocarcinoma histological differentiation in a retrospective analysis of tumour biopsies with intratumoural histological heterogeneity. Adenocarcinomas with high intratumoural heterogeneity were categorised as 'mixed adenocarcinomas'. PD-L1 expression was determined immunohistochemically using tumour proportion scores (TPS). In 'mixed adenocarcinomas' PD-L1 scores were assessed across tumour areas with specific histological patterns. Comparisons were performed between histologically distinct differentiated tumours and/or histological areas. Poorly differentiated adenocarcinomas, represented by predominantly solid or micropapillary histological patterns, showed significantly higher expression of PD-L1 than other subtypes (p<0.001). Differentiation of intra-adenocarcinoma components was inversely correlated with PD-L1 expression: there were more PD-L1 positive cells in poorly differentiated areas than less differentiated (p<0.001), or than well differentiated areas (p<0.001), and in less differentiated more than well differentiated areas (p=0.001). In conclusion, PD-L1 expression is associated with poorly differentiated morphology in adenocarcinomas with intratumoural histological heterogeneity. Consequently, a TPS approach may not account for the contribution of more aggressive tumour components with higher levels of PD-L1 expression in within the tumour. Performing spectral analyses of PD-L1 expression across tumours is likely to be more accurate.