Multicentric occurrence of hepatocellular carcinoma: diagnosis and clinical significance

To evaluate current knowledge on the multicentric occurrence (MO) of hepatocellular carcinoma (HCC) and its clinical significance was the purpose of this review. The criteria for MO of HCC are defined as follows: (1) the recurrent tumor consists of well differentiated HCC occurring in a different hepatic segment from moderately or poorly differentiated preexisting HCC, (2) both the primary and recurrent tumors are well differentiated HCC, (3) the recurrent tumors contain regions of dysplastic nodules in peripheral areas and, (4) multiple HCCs, indicating the "nodule-in-nodule" form, in which nodules consisting of moderately or poorly differentiated HCC cells are contained in a nodule of well differentiated HCC cells. However, these criteria assume rare or no metastasis of well differentiated HCC, and are also not applicable to cases in which some HCCs of multicentric origin are rapidly dedifferentiated, presenting morphologic features of moderately or poorly differentiated tumors. Diagnostic methods, besides histopathologic methods, for determining multicentric origin in multiple HCCs in the liver, or recurrent tumor(s) of HCC, include clonal analysis of the integration pattern of hepatitis B virus (HBV) DNA in HBV carrier patients, and analysis of the p53 mutation patterns or loss of heterozygosity of chromosomal DNA. The prognosis of patients with MO of HCC after curative resection is significantly better than that of patients with intrahepatic HCC metastasis. Moreover, the Liver Cancer Study Group of Japan has reported that patients with hepatic resection for small-sized HCCs showed higher survival rates than a nonsurgical treatment group. Consequently, HCC with MO, whether this is synchronous or metachronous, should be surgically removed as the treatment of first choice.