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.