Pathology of Combined Hepatocellular Carcinoma-Cholangiocarcinoma: An Update

Simple Summary Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare tumor with its origin in the liver, risk factors comparable to hepatocellular carcinoma and poor prognosis. This review describes its histomorphological classification and diagnosis over time and outlines the molecular foundation for potential prospective therapeutic approaches. Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that is composed of both hepatocellular and cholangiocellular differentiated cells. It is slightly more common in men and among Asian and Pacific islanders. Overall, risk factors are similar to classic risk factors of hepatocellular carcinoma (HCC). The classification has significantly evolved over time. The last WHO classification (2019) mainly emphasized diagnosis on morphological basis with routine stainings, discarded previously recognized classifications with carcinomas with stem cell features, introduced intermediate cell carcinoma as a specific subtype and considered cholangiolocarcinoma as a subtype of cholangiocellular carcinoma. Immunohistochemical markers may be applied for further specification but have limited value for diagnosis. Recent discoveries in molecular pathway regulation may pioneer new therapeutic approaches for this poor prognostic and challenging diagnosis.