Toyohito Iwata

Usefulness of monoclonal antibody Ki-67 as a prognostic factor of hepatocellular carcinoma

Abstract We studied the proliferative activity of hepatocellular carcinoma (HCC) by immunohistochemical staining with Ki-67, a monoclonal antibody to nuclear protein observed in the proliferative period of the cell cycle, and evaluated the usefulness of Ki-67 as a prognostic factor. Of the patients who underwent hepatectomy for HCC at our department, 56 cases in which pathological studies for the tumor showed no degeneration or necrosis were selected. Immunohistochemical staining was performed according to the method of Shi et al., using MIB-1 monoclonal antibody (Immunotech, SA) as a primary antibody. Ki-67 L.I. was significantly higher in chronic hepatitis (CH) and liver cirrhosis (LC) than in normal liver, and the L.I. was also significantly higher in non-cancerous tissue of the patients with HCC than in tissues with other liver diseases. In patients with a history of portal hypertension, the L.I. in non-cancerous liver tissue was significantly lower at the previous operation for portal hypertension without HCC than that at the subsequent operation for HCC. The L.I. was significantly higher in patients who showed a high serum AFP level and in those who had intrahepatic metastasis. It also tended to be higher in patients with vessel invasion, infiltration to capsule, aneuploidy tumor cells, and poor differentiation. The cumulative survival rate was significantly lower in patients with the L.I. of 10% or higher than in those with the L.I. of less than 10% in cancerous region. Recurrence was observed earlier after hepatectomy in patients with higher L.I. and the L.I. was significantly higher in those who had recurrence within 12 months. In the patients who could be followed up, the L.I. was significantly higher in those who had multiple recurrence after hepatectomy than in those who had single-lesion recurrence. The incidence of HCC was higher in patients with CH or LC in which the proliferative activity was abnormally enhanced for a prolonged period, suggesting that hepatocyte hyperproliferation triggers hepatic carcinogenesis. In addition, long-term survival was expected even in patients with advanced HCC if the L.I. in preoperative biopsy specimens was low, while in patients with high L.I., postoperative recurrence and distant metastasis may occur more frequently, and postoperative supplementary therapies may be necessary, even when the tumor is completely resectable. In conclusion, Ki-67 staining is considered to be useful for evaluation of the malignant potential of HCC.

Clinicalpathological analysis of risk factors for the development of hepatocellular carcinoma after surgery for esophageal varices due to underlying cirrhosis or pre-cirrhosis in the 397 patients

Risk factors for the development of hepatocellular carcinoma (HCC) were investigated in 397 patients who underwent non-shunt operation for esophageal varices due to underlying cirrhosis or pre-cirrhosis between September 1979 and May 1995. Ninety-five of these patients developed HCC. The clinical characteristics of patients at the time of surgery for varices, stages (F0-F4) of the progression of fibrosis, and grades (A0-A3) of necroinflammatory activity in liver biopsy tissue obtained at surgery in 170 patients based on the New Inuyama Classification (Int. Hepatol. Commun. 6 (1996) 112), were analyzed to investigate their relationship with the development of HCC. In addition, the levels of AST and ALT were followed every 3 months after surgery in 116 patients, and were divided into 2 groups at 80 IU/ml to compare the level of risk for the development of HCC. In liver biopsy tissue, group F4 (n=68/152, 45%) showed a significantly higher (P=0.0224) rate of appearance of HCC than group F3 (n=3/18, 17%). Group F4 also tended to show a higher cumulative HCC appearance rate of 55% compared with 37% for group F3 at 10 years after surgery (P=0.097). In regard to activity, the appearance rate of HCC in group A2+A3 (n=52/112, 51%) was significantly higher (P=0.0008) than that of HCC in group A1 (n=14/58, 25%). The cumulative appearance rate (60%) of HCC in group A2+A3 was significantly higher than that (31%) in group A1 at 10 years after surgery (P=0.0003). The appearance rate of HCC was significantly higher in the group (n=33/44, 75%) with a mean AST level >/=80 IU/ml than in the group (n=41/72, 57%) with a mean AST level <80 IU/ml (P=0.0496). A multivariate analysis of the risk factors for the development of HCC showed that necroinflammatory activity was a risk factor. These results suggested that the histopathologic classification (the New Inuyama Classification) of liver biopsy tissue from patients who underwent non-shunt operation for esophageal varices due to underlying cirrhosis or pre-cirrhosis is useful for predicting the development of HCC, to which the grades of necroinflammatory activity in particular are more closely related.