Heterogeneity of Proliferative Activity in Nodule‐in‐Nodule Lesions of Small Hepatocellular Carcinoma

Surgically resected small hepatocellular carcinomas showing “nodule‐in‐nodule’formation were analyzed in terms of cell proliferative activity. The analysis was achieved by successful immunohistochemical demonstration of proliferating cell nuclear antigen in formalin‐fixed paraffin‐embedded tissue sections. Eight nodules (up to 3 cm in diameter) examined were either atypical adenomatous hyperplasia or hepatocellular carcinoma of low histologic grade, containing a discrete inner nodular area composed of obvious hepatocellular carcinoma of higher histologic grade. In all cases, the proliferating cell nuclear antigen labeling index of the latter area was much higher than that of the former, which in turn was slightly higher than that of the non‐cancerous liver of the patient in 6 cases. The data presented here provide supporting evidence that the successive emergence and expansion of a more rapidly proliferating subclone within a nodule result in the stepwise progression of malignancy of human hepatocellular carcinoma.