Pathology and DNA cytophotometry of small hepatocellular carcinoma with a nodule-in-nodule appearance--evidence for stepwise progression of hepatocellular carcinoma.

Among 92 surgically resected human hepatocellular carcinomas (HCCs) < or = 3 cm in diameter, 23 tumors (25%) grossly showed a nodule-in-nodule appearance indicating stepwise progression of HCC. The central nodules showed destructive growth of HCC, which was less differentiated than the surrounding area histologically, while the surrounding area showed growth of very-well-differentiated HCC with no, or only minimal, destruction of the underlying liver structures. Previously, we proposed the term "early HCC" for HCCs without definite destructive growth, and the nodule-in-nodule lesions described here are considered to be in the transitional stage from early HCC to advanced HCC, and are therefore named early advanced HCC (eAd HCC). DNA cytophotometry was performed in 12 cases of eAd HCC, in which the early HCC component, advanced HCC component and non-tumorous liver tissue showing chronic hepatitis or cirrhosis were analyzed separately. The early HCC component showed a diploid pattern in eight of the 12 cases. The advanced HCC component showed an aneuploid peak in seven cases, and in three of these the peak was detected only in the advanced HCC component and not in the early HCC component. The mean nuclear DNA content was significantly increased from non-tumorous liver to the early HCC component and from the early HCC component to the advanced HCC component. Polyploid cells containing more than 4.8C DNA were exceptional in non-tumorous liver, but were detectable in the early HCC component and increased in number in the advanced HCC component. These findings suggest that DNA instability may have an important role to play in the subclonal progression of human HCC.