Nucleolar organizer regions in small nodular lesions representing early stages of human hepatocarcinogenesis

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Abstract
Background. It is believed that in the early stages of hepatocarcinogenesis, some adenomatous hyperplasias (AH) progress to early hepatocellular carcinoma (eHCC), and that many eHCC develop into overt hepatocellular carcinoma (HCC) through nodule‐in‐nodule formation. However, the proliferative activity of these small nodular lesions has not been fully investigated. Methods. Cell proliferative activity was assessed by counting nucleolar organizer region‐associated proteins (Ag‐NOR) in paraffin sections of 12 AH nodules, 25 eHCC nodules, and 8 nodule‐in‐nodule lesions. In nodule‐in‐nodule lesions, an area of well‐differentiated HCC corresponding to eHCC and a discrete inner nodule area composed of obvious HCC were examined. Results. Mean Ag‐NOR numbers of extranodular parenchyma, AH, and eHCC were 1.35, 1.35, and 1.75 (P < 0.01), respectively. With regard to the relative Ag‐NOR number compared with that of parenchyma, there was no overlap between AH and eHCC with a border of 1.1‐fold except in one specimen. In nodule‐in‐nodule lesions, the mean Ag‐NOR number (2.53) in the inner nodular area was much higher (P < 0.01) than that of the area of eHCC (mean, 1.88). Conclusions. A stepwise increment of Ag‐NOR number was demonstrated in accordance with the multistep of the AH to eHCC to nodule‐in‐nodule lesion sequence of hepatocarcinogenesis. Thus, it was proposed that the Ag‐NOR count may be a practical and objective parameter for assessing the malignant potential of hepatocellular neoplasms histopathologically.