Recurrence and metastasis of hepatocellular carcinoma: progress and prospects

Recurrence after resection of hepatocellular carcinoma (HCC) is a major obstacle to improve prognosis. Therefore, further improvement of long-term survival may depend on prevention and treatment of the recurrent tumor.

To evaluate the progress of surgery for HCC, the risk factors for recurrence, and clinical and basic studies on the prevention and management of recurrence and metastasis after resection of HCC.

A review of currently available data in the mentioned areas.

Encouraging changes in the prognostic pattern were observed when the primary liver cancer (PLC) data of 1958-1967 (n=118), 1968-1977 (n=356), 1978-1987 (n=715) and 1988-1997 (n=2038) were compared. The 5-year survival was 2.8%, 7.3%, 27.1% and 52.5%, respectively, and the 10-year survival 2.8%, 4.3%, 19.8% and 39.9%, respectively. Risk factors for recurrence included symptomatic patient, high gamma-glutamyl-peptidase (gamma-PGT), large tumor size, portal vein embolus, advanced tumor stage, etc. Active hepatitis activity in the nontumorous liver and perioperative transfusion enhanced the recurrence. Molecular research into the invasiveness of HCC identified some factors positively related to invasiveness, P16 and P53 mutation, H-ras, c-cerbB2, mdm2, transforming growth factor (TGF), epidermal growth factor receptor (EGF-R), matrix metalloproteinase-2 (MMP-2), urokinasetype plasminogen activator (uPA), its receptor (uPA-R) and inhibitor (PAI-1), intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PD-ECGF), and basic fibroblast growth factor (bFGF). In contrast, some factors were negatively related to HCC invasiveness: nm23-H1, Kai-1, tissue inhibitor of metalloproteinase-2 (TIMP-2), integrin 5, and E-cadherin. Re-resection of subclinical recurrence yielded a 5-year survival of 56.0% calculated from the first resection (n=202). Postoperative transarterial chemoembolization (TACE, n=103), hepatic artery cannulation during operation (n=105), postoperative biotherapy (n=49), and cryohepatectomy (cryosurgery followed by immediate resection of the frozen tumor, n=84) might decrease the recurrence rate, and the 3-year recurrence rate was 7.6%, 18.0%, 11.1%, and 30.1%, respectively. Minimal intraoperative blood loss and transfusion could reduce postoperative recurrence, although the exact mechanism remains to be elucidated.

HCC invasiveness is the major topic to be studied, particularly in the molecular level. Anti-angiogenesis, biotherapy, novel approach based on molecular findings, and multidisciplinary interventions might also be important for HCC.