Combined Hepatocellular-cholangiocarcinoma: from Genesis to Molecular Pathways and Therapeutic Strategies

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver cancers. Little is known about the combined hepatocellular-cholangiocarcinoma (cHCC-ICC) variant and the proper therapeutic strategies. Out of over 1200 available studies about cHCC-ICC, we selected the most representative ones that reflected updated information with application to individualized therapy. Based on literature data and own experience, we hypothesize that two molecular groups of cHCC-ICC can be identified. The proposed division might have a significant therapeutic role. Most cases develop, like HCC, on a background of cirrhosis and hepatitis and share characteristics with HCC; thus, they are named HCC-type cHCC-ICC and therapeutic strategies might be like those for HCC. This review also highlights a new carcinogenic perspective and identifies, based on literature data and the own experience, a second variant of cHCC-ICC called ICC-type cHCC-ICC. Contrary to HCC, these cases show a tendency for lymph node metastases and ICC components in the metastatic tissues. No guidelines have been established yet for such cases. Individualized therapy should be, however, oriented toward the immunoprofile of the primary tumor and metastatic cells, and different therapeutic strategies should be used in patients with HCC- versus ICC-type cHCC-ICC.