Keratin 19-expressing hepatocellular carcinoma and small-duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features

Aims The present study aimed to systematically compare clinicopathological and genetic features between keratin 19 (K19)-expressing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Methods and results Consecutive cases of HCC (n = 430) were classified into K19(+) and K19(-) using immunohistochemistry. ICCA cases were also separated into small-(S-iCCA; n = 36) and large-duct types (n = 22) based on recently proposed criteria, with the former being used in the present study. Mutational hot-spots in TERT, CTNNB1, KRAS and IDH1 were sequenced. Twenty-six cases (6%) of HCC expressed K19. K19(+) HCC was more strongly associated with chronic hepatitis B than K19(-) HCC and S-iCCA (46% versus 17% and 6%; both P < 0.001). Lymph node metastasis was observed in K19(+) HCC (8%) and S-iCCA (22%), but was exceptional in K19(-) HCC (1%). K19(+) HCC had TERT promoter mutations less frequently than K19(-) HCC (31% versus 59%; P = 0.022), and lacked alterations in KRAS and IDH1. CTNNB1 mutations were similarly observed in K19(+) and K19(-) HCC (23% and 19%, respectively), but rare in S-iCCA (3%). The postoperative survival curve of K19(+) HCC was almost identical to that of S-iCCA in the first 5 years (approximately 50% at 5 years), and significantly worse than that of K19(-) HCC (P = 0.040). Extrahepatic recurrence was more common in K19(+) HCC (50%) and S-iCCA (35%) than in K19(-) HCC (15%) (P = 0.001). Conclusions Although K19(+) HCC and S-iCCA showed similar biological behaviours, they did not share any driver gene mutations, suggesting the possible involvement of epigenetic alterations in the iCCA-like features of K19(+) HCC.