Atypical large well-differentiated hepatocellular carcinoma with benign nature: a new clinical entity

Based on intranodular hemodynamic studies of nodular lesions associated with liver cirrhosis using computed tomography (CT) during arteriography, CT during arterial portography (CTAP) and angiography under ultrasonography, relatively large hepatocellular nodules with portal perfusion have been depicted. We report 17 such nodules in a total of 663 patients who underwent CTAP. Large well-differentiated hepatocellular carcinomas (HCCs) are characterized by the presence of intranodular portal perfusion even if they measure more than 2.5 cm in diameter. Such nodules display a benign nature clinically as well as pathologically. These nodules, called 'atypical large well-differentiated HCC or dysplastic nodules', show extremely slow growth. Pathological study showed extremely peculiar findings; the nodules consisted of homogeneously hyperplastic or well-differentiated HCC without the component of moderately or poorly differentiated HCC, and without fibrous capsules, vessel invasion or intrahepatic metastasis, all of which are commonly found in typical overt HCC. The incidence of such nodules is not rare; it was 2.6% (17/663) in our HCC patients who underwent CTAP over a period of 7 years. During the 7-year observation period, none of 10 such nodules developed into arterial supply-dominant overt HCC. The recognition of these benign-nature nodules (or large low-grade malignant nodules) is extremely important for the following three reasons. First, the knowledge that such large atypical nodular lesions exist is important for clinicians. Second, regarding the treatment strategy for such nodular lesions, it should be kept in mind that these nodules show a benign nature, and rarely cause death. Finally, considering the etiology and clinical significance of such atypical large benign-nature nodules, the recognition of these nodules provides an important suggestion regarding the pathogenesis of progression from dysplastic nodule to early HCC and finally to overt HCC during multistep human hepatocarcinogenesis. These atypical large benign-nature nodules do not seem to be the nodules in a sequence of multistep progression. The early step of hepatocarcinogenesis includes mainly hyperplastic change, whereas the late step includes mainly an angiogenic process. Although the detailed molecular pathogenesis of both the early and late steps of hepatocarcinogenesis is not clear, it is speculated that these atypical benign-nature nodules do not undergo the phenotypic change of late-step hepatocarcinogenesis. In that sense, these atypical benign-nature nodules are suggestive for the clarification of the mechanism of multistep human hepatocarcinogenesis based on the intranodular vascular supply or hemodynamics. From the viewpoint of clinical practice as well as pathogenesis of human hepatocarcinogenesis, these nodular lesions should be managed as a different disease from overt HCCs; atypical large HCCs or dysplastic nodules with benign nature should be regarded as a new clinical entity.