Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma

Abstract Background & Aims Intrahepatic cholangiocarcinoma ( iCCA ) is a heterogeneous entity with diverse aetiologies, morphologies and clinical outcomes. Recently, histopathological distinction of cholangiolocellular differentiation ( CD ) of iCCA has been suggested. However, its genome‐wide molecular features and clinical significance remain unclear. Methods Based on CD status, we stratified iCCA s into iCCA with CD (n=20) and iCCA without CD (n=102), and performed an integrative analysis using transcriptomic and clinicopathological profiles. Results iCCA with CD revealed less aggressive histopathological features compared to iCCA without CD , and iCCA with CD showed favourable clinical outcomes of overall survival and time to recurrence than iCCA without CD ( P <.05 for all). Transcriptomic profiling revealed that iCCA with CD resembled an inflammation‐related subtype, while iCCA without CD resembled a proliferation subtype. In addition, we identified a CD signature that can predict prognostic outcomes of iCCA ( CD _ UP , n=486 and CD _ DOWN , n=308). iCCA s were subgrouped into G1 (positivity for CRP and CDH 2, 7%), G3 (positivity for S100P and TFF 1, 32%) and G2 (the others, 61%). Prognostic outcomes for overall survival ( P =.001) and time to recurrence ( P =.017) were the most favourable in G1‐ iCCA s, intermediate in G2‐ iCCA s and the worst in G3‐ iCCA s. Similar result was confirmed in the iCCA set from GSE26566 (n=68). Conclusions CD signature was identified to predict the prognosis of iCCA . The combined evaluation of histology of CD and protein expression status of CRP , CDH 2, TFF 1 and S100P might help subtyping and predicting clinical outcomes of iCCA .