1. ¹Department of Pathology, Indiana University, Indianapolis, Indiana
2. ²Department of Pathology, Emory University, Atlanta, Georgia
3. ³Department of Pathology, Northwestern University, Chicago, Illinois
4. ⁴Department of Pathology, Tisch Hospital of New York University, New York
5. ⁵Department of Pathology, Montefiore Medical Center, Bronx, New York

Correspondence: Sunil Badve, M.B.B.S., M.D., F.R.C.Path., Department of Surgical Pathology, University Hospital, Room UH-3465, 550 University Boulevard, Indianapolis, IN 46202. fax: 317-274-5346; e-mail: sbadve@iupui.edu

Accepted 16 June 2003.

Abstract

Hepatoblastoma, a childhood tumor of the liver, is composed of epithelial and mesenchymal elements in varying proportions and at various stages of differentiation. The epithelial element recapitulates the stages of hepatocyte development from the primitive blastema through embryonal hepatocytes to fetal hepatocytes. The blastemal or undifferentiated cells have been postulated to represent neoplastic hepatocyte progenitor cells. In this study, we examine the immunophenotype of the various epithelial cells of hepatoblastoma with special emphasis on the small undifferentiated cell component and compare it with that of adult hepatocytes and hepatic stem (oval) cells. Putative stem cells in the liver can express all of the following markers: -feto protein, CK19 (OV-6), chromogranin A, Bcl-2, HepPar-1, and 1 microglobulin. The latter, like -feto protein, is a plasma protein synthesized by hepatocytes. Both 1 microglobulin and HepPar-1 are expressed in fetal liver cells as early as 7 weeks of intrauterine life. They are also expressed in hepatocellular carcinoma and in hepatocytic cell lines derived from normal fetal or adult liver. Formalin-fixed, paraffin-embedded archival tissues from 10 predominantly epithelial hepatoblastomas were immunostained with antibodies directed against CD 34, 1 microglobulin, Bcl-2, HepPar 1, and CK19 using the avidin-biotin-peroxidase method. The undifferentiated small cell component did not express any of the markers studied, namely, Bcl-2, HepPar-1, ₁ microglobulin, CD34, or CK19. Hepatocyte-like cells were 1 microglobulin– and HepPar-1–positive, with the intensity of staining correlating with the degree of hepatocytic differentiation. Bcl-2 expression was restricted to areas of ductular differentiation. CK19 was detected in foci that showed duct formation. The small cells of hepatoblastoma did not express HepPar-1, Bcl-2, CK19, 1 microglobulin, or CD34, markers that characterize the immunophenotype of hepatic stem cells ("oval" cells). Thus, this observation raises the following questions: (1) is "hepatoblastoma" a misnomer? (2) is the expression of tumor antigens dysregulated in hepatoblastoma? (3) does the liver have two different types of progenitor cells, oval cells and blastemal cells, with differing immunophenotypes? and (4) do the blastemal cells, rather than oval cells, represent the more primitive progenitor cells of the liver?