Cell proliferation and cell loss in nodule-in-nodule hepatocellular carcinoma

BACKGROUND/AIMS: In order to clarify the significance of the balance between cell proliferation and cell loss during the progression of hepatocellular carcinoma, 16 operative specimens of nodule-in-nodule hepatocellular carcinoma were investigated. METHODOLOGY: In 16 specimens, cell proliferation was evaluated by the expression of Ki-67 nuclear antigen, and cell loss was also examined by the method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). The expressions of p53 protein, bcl-2 protein and Fas antigen were also investigated to clarify the relationship between their expression and cell kinetics. RESULTS: The Ki-67 labeling index of the inner nodules was higher than that for the outer nodules (18.9% vs. 7.2%; p<0.05) and the TUNEL labeling index of the inner nodules was also higher than that for the outer nodules (12.8% vs. 6.6%; p<0.05). The increasing rate of the Ki-67 labeling index from Edmondson's grade I to II was 3.9+/-3.0, that from grade II to III was 3.9+/-2.4, while the increasing rate of the TUNEL labeling index from grade I to II was 2.7+/-0.3 and that from grade II to III was 1.7+/-10.2 (p<0.05). p53 Protein was observed in 5 cases, while bcl-2 protein was found in 4 cases in the border area of the inner nodule. However, Fas antigen was found in none of the examined cases. Regarding the Ki-67 positive rate in the inner nodule, the Ki-67 positive rate in the p53 protein positive cases was significantly higher than that in the negative cases (30.3+/-15.4 vs. 11.9+/-9.2; p<0.05). However, the TUNEL labeling index was not affected by the expression of those proteins. CONCLUSIONS: This study suggested that tumor progression depends on a disturbance in the cell kinetic balance caused not by a decrease in the absolute amount of cell loss but in the chaotic balance between cell loss and cell proliferation.