Fig. 2

Tumor formation in situ and metastasis by p53^−/− hepatoblasts. a Images of livers explanted from wild-type CCl₄-primed mice that receipted trans-splenic injection of p53^−/− hepatoblasts are shown in upper panel. Metastases in abdominal cavity and left back are also shown. Tumor regions are highlighted by dash lines. b Hematoxylin–eosin staining of areas of tumor show hepatocellular (HCC-like area, upper left) or cholangiocellular differentiation (CC-like area, lower left). Briefly, HCC-like cells were poorly differentiated with compact trabecular pattern. The tumor cells show a “pushing-border” invading into adjacent normal hepatic tissue. Representative HCC-like area without obvious mucus production is shown in upper right panel. Within CC-like area shown, the invasive adenocarcinoma was moderately differentiated with glandular growth pattern. Mucus production is highlighted by Periodic Acid-Schiff staining within irregular lumens in the lower right panel. Images were from mouse no. 266. c Hematoxylin–eosin staining of two metastases from the abdominal cavity separated by fibrous capsule shows heterogeneous histology (mouse no. 263). Higher magnifications of the boxes highlight the well differentiated neoplastic hepatocytes with clusters of small tumor cells around (upper) and moderately differentiated HCC (lower). The hepatic origin of the metastases is confirmed by albumin staining. Corresponding human tumor samples (patient no. 5) are shown for comparison. In the lower panels, focal small tumor cells, poorly differentiated tumor cells, and well-differentiated adenocarcinomas explanted from recipient mice are highlighted by CK19 staining. d Histologic profiles of subcutaneous metastasis are shown (mouse no. 266). Hematoxylin–eosin staining of the margin area of one metastasis shows ill-defined glandular structure embedded in broad desmoplastic stroma. In the center area of metastasis, well-moderately differentiated adenocarcinoma highlighted by CK19 staining is associated with less fibrous stroma. The corresponding histologic appearances of CC-like areas in human tumors are presented for comparison (patient no. 8). e Representative splenic tumors (mouse no. 266) mimic the multicentric occurrence features of human combined hepatocellular-cholangiocarcinoma (patient no. 8). Higher magnifications of the boxes show striking similarity to ductular reactions with hepatocyte regeneration in well differentiated HCC areas of CK19 staining sections from both human and mice