Re-Recognizing the Cellular Origin of the Primary Epithelial Tumors of the Liver

Abstract

The primary epithelial tumors of the liver (PETL) are composed of a series of heterogeneous tumors. Although the classification of PETLs has been updated several times by the World Health Organization, the cellular origins of some tumors in this family remain to be precisely depicted. In addition, certain tumors in different categories have similar histology, molecular phenotypes and biological characteristics, suggesting that they may have the same cellular origin. In this work, a narrative review method was adopted to review the relevant papers. By comparing the expression profiles of biomarkers of liver epithelium at different lineages and stages of differentiation, the cells-of-origin of some major members of the PETL family were reassessed. We propose that 1) hepatic adenomas, hepatocellular carcinomas (HCCs) and pure fetal hepatoblastomas (HBs) share the same spectrum in their cellular origin including the hepatocytic-committed progenitors (HCP) and their differentiated descendants. 2) Bile duct adenomas, peribiliary cysts and intrahepatic cholangiocellular carcinomas (ICCs) can share the same spectrum in their cellular origin including the cholangiocytic-committed progenitors (CCP) and their differentiated descendants. 3) The cells-of-origin of embryonal HBs include liver stem cells (LSCs), hepatoblasts, and transitional cells between them. Embryonal HB with small cell element, small cell undifferentiated HB and small cell neuroendocrine carcinoma of the liver can have the same or similar cellsof-origin from LSC. Embryonal HB lacking the small cell component of the LSC phenotype and presenting both hepatocytic and bile duct/ductule components may originate from actual hepatoblasts/hepatic progenitor cells (HPCs) as the combined HCC-ICC does. 4) Teratoid hepatoblastoma and mixed epithelial/mesenchymal HBs can be derived from the LSCs or even less committed extrahepatic pluripotent stem cell. 5) Many members of the PETLs family, including those derived from LSCs, hepatoblasts/HPCs, early HCPs and CCPs, have neuroendocrine potentiality. Except for those primary hepatic neuroendocrine tumor (PHNET) exhibit hepatocytic and/or cholangiocytic phenotypes, other PHNETs subtype may be derived from the descendants of LSC that differentiate towards the upper digestive tract, pancreas or other lineages.

Teratoid Hepatoblastoma—Our Experience

“…This finding illustrates that caution must be used when diagnosing a neuroendocrine component within an HB and the designation should be reserved for those cases in which both morphologic and immunophenotypic neuroendocrine features are present and not on focal expression of neuroendocrine markers alone. Interestingly, previous studies have demonstrated that subsets of hepatoblasts and the more primitive liver stem cells in the developing liver express neuroendocrine markers including NCAM and chromogranin [ 25 ]. We have also noted expression of synaptophysin within embryonal areas of HB.…”

“…We have also noted expression of synaptophysin within embryonal areas of HB. Synaptophysin and chromogranin are also expressed within the developing ductal plate, the site of the development of the intrahepatic bile ducts [ 25 ].…”

“…The liver primordium or liver bud which develops as hepatic cords grow into the mesenchyme of the transverse septum [ 27 ] contains multipotential cells that represent the most primitive stem cells of the liver. These stem cells undergo further differentiation to produce hepatoblasts which demonstrate expression of CK8, CK18, CK7, CK19, AFP, and glypican-3 [ 25 ] as well as MOC-31 and PROX-1 and exhibit bipotential to differentiate into both hepatocytes and cholangiocytes. The origin of hepatic stem cells is still debated, but evidence suggests that they may be derived from the bone marrow as studies in mouse models have demonstrated that purified hematopoietic stem cells have the capability to differentiate into mature hepatocytes [ 28 ].…”

“…The origin of hepatic stem cells is still debated, but evidence suggests that they may be derived from the bone marrow as studies in mouse models have demonstrated that purified hematopoietic stem cells have the capability to differentiate into mature hepatocytes [ 28 ]. Within the adult liver there are a subset of cells termed hepatic progenitor cells with overlapping molecular characteristics with primitive hepatoblasts which may be activated in severe injury to the liver [ 25 ]. More recently, a population of cells was identified within peribiliary glands in adults and infants with overlapping features to the stem cells identified in embryonic development and which were demonstrated to be capable of differentiating into intestinal and pancreatic epithelial cells, fat, bone, cartilage, and endothelial cells [ 25 ].…”

“…Within the adult liver there are a subset of cells termed hepatic progenitor cells with overlapping molecular characteristics with primitive hepatoblasts which may be activated in severe injury to the liver [ 25 ]. More recently, a population of cells was identified within peribiliary glands in adults and infants with overlapping features to the stem cells identified in embryonic development and which were demonstrated to be capable of differentiating into intestinal and pancreatic epithelial cells, fat, bone, cartilage, and endothelial cells [ 25 ]. The presence of stem-like cells in hepatoblastoma, which might explain the presence of teratoid elements, has undergone much investigation.…”