Genetic re-classification of combined hepatocellular-cholangiocarcinoma and small duct type intrahepatic cholangiocarcinoma.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) shares various features with small duct type intrahepatic cholangiocarcinoma (SmD-iCCA) and sometimes histological diagnosis may be difficult.

Methods: We examined genetic alterations such as hTERT promoter (hTERT), p53, and fibroblast growth factor receptor 2 (FGFR2) in 103 PLCs diagnosed as cHCC-CCA or SmD-iCCA. A cluster analysis was performed on the R software for re-classification of PLCs including cHCC-CCA and SmD-iCCA.

Results: The primary liver carcinomas (PLCs) were divided into 5 clusters; 19 tumors (18 %) in Cluster-1 (with alterations in hTERT and/or p53), 24 (23 %) in Cluster-2 (FGFR2 and/or p53), 13 (13 %) in Cluster-3 (IDH2 or null), 19 (18 %) in Cluster-4 (MTAP and/or FGFR2), 28 (27 %) in Cluster-5 (ARID1A and/or PBRM1), being based on genetic alterations. Cluster-1 and Clusters-2 to- 5 formed distinct 2 groups. Cluster-1 was characterized by significantly bigger size, rich and higher histological grade of HCC component, significantly less cholangiolocellular carcinoma (CLC)-component, ductal plate malformation pattern and bile duct adenoma in the background livers. No SmD-iCCA was included in Cluster-1, whereas SmD-iCCA distributed evenly in Clusters 2-5. Cluster-4 was characterized by higher prevalence of hepatitis B and higher histological diversity scores.

Conclusions: PLCs diagnosed as cHCC-CCA or SmD-iCCAs could be divided into 5 clusters based on genetic alterations. Cluster-1 was HCC-like cluster characterized by hTERT alteration, rich and higher grade of HCC and bigger size. Clusters-2-5 may be iCCA-like clusters characterized by different genetic alterations. cHCC-CCA in Cluster-1 and Clusters-2-5 may be handled separately for further analysis and treatment.