Subclinical hepatocellular carcinoma (SCHCC) is defined as HCC without obvious HCC symptoms and signs. During 1958-1991, 391 patients with SCHCC were analyzed. In the entire series, 1) 67.3% was detected by natural population sereening using alpha-fetoprotein (AFP) serosurvey, while the others were discovered by high-risk population screening or regular health checkup using AFP and/or ultrasonography (US); 2) AFP>20 ug/L was found in 77.6% of patients; 3) serum hepatitis B surface antigen (HBsAg) was positive in 68.9; 4) associated liver cirrho-sis occurred in 89.1%; 5) the median tumor size was 5 cm, and limited resection was performed in the majority (71.3%); 7) re-resection for sub-clinical recurrence was done in 44 patients; and 8) cytoreduction and sequential resection was carried out in 13 patients with unresectable SCHCC. Comparison between SCHCC and clinical HCC (n=1, 251) revealed higher resectability(81.4% vs, 46.8%), lower operative mortality (1.9% vs. 6.0%), and higher 5-year survival (entire series; 50.7% vs. 20.6%; resection: 60.5% vs. 36.8%). It is concluded that the study of SCHCC has resulted in marked improvement of ultimate outcome of HCC; screening in high-risk populations using AFP and/or US, limited resection, and re-resection for subclinical recurrence are some of the key features.

In the 1950s, hepatic lobectomy for huge hepatocellular carcinoma (HCC) has benfited 5-10% of HCC patients; in the 1970s, limited resection for small HCC and reresection for recurrence have benefited another 5-10% HCC patients. Cytoreduction and sequential resection for unresectable HCC might be of benefit to a further 5-10% HCC patients in the 1990s. Analysis of 1,642 patients with pathologically proven HCC in 1959-1991 demonstrated that the series 5-year survival has increased from 3.0%(n=136) in the 1960s, to 12.2% (n=440) in the 1970s, to 40.2% (n=1,066) in the 1980s, which was correlated to the increasing number of limited resections for small HCC, re-resections for subclinical recurrence, and cytoreductions and sequen-tial resections for portions of unresectable HCC. With the advances in early detection, multimodality treatment, and changing concepts in early detection, multimodality treatment, and changing concepts in surgical oncology, the role of surgery in the treatment of HCC has increased.

Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally con-quered. This paper summarized a decade's studies on HCC metawstasis at the Liver Cancer Institute of Fudan University. We have established a sptepwise metastatic human HCC model system, which included a metastatic HCC model in nude mice (LCI-D20), a HCC cell line with hgh metastatic potential (MHCC97), a relatively low metastatic potential cell clone (MHCC97L) and several stepwise high metastatic potential cellclones (MHCC97H, HCCLM3, and HCCLM6) from their parent MHCC97 cell. Endeavors have been made for searching human HCC metastasis-related chromosomes/proteins/genes. Monogene-based studies revealed that HCC invasion/metastasis was similar to that of other solid tumorsa, and the biological characteristics of small HCC were only slightly better that that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarray, and 2-dimensional gel electrophore-sis, we obtained some interesting results. In particular, in collaboration with the National Institute of Health (NIH) in the United Staters, we generated a molecular signature that can classify metastatic HCC patients, identified ostewopntin as a lead gene in the signature, and found that genes favoring metastasis progression were initiated in the primary tumors. We also found that chromosome 8p deletion, particularly in the region of 8p23, was associated with HCC metastasis. Cytokeratin 19 was identified as one of the proteins, which was found in MHCC97H, but not in MHCC97L cells. Experi-mental interventions using the high metastatic nude mice model have provided clues for the prevention of HCC metastasis. Translation from workbench to bedside demonstrated that serum VEGF, microvessel density, and p53 scoring may be of value for the prediction of postoperative metastatic recurrence. Interferon alpha proved effective for the prevention of recurrence both experimentally and clinically. In conclusion, HCC metastasis that probably initiated in the prim,ary tumor is a multigene-involved, multistep, and changing is a multigene-involved, multistep, and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basos for the prediction and prevention of the metastatic recurrence of HCC.

Hepatocellular carcinoma(HCC) is one of the most common and aggressive human malignan-cies. Its high mortality rate is mainly a result of intra-hepatic metastases. We analyzed the ex-pression profiles of HCC samples without or with intra-hepatic metastases. Using a supervised machine-learning algorithm, we generated for the first time a molecular signature that can clas-sify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival. We found that the gene expression signature of primary HCCS with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes fa-voring metastasis progression were initiated in the primary tumors. Osteopontin, which was identified as a lead gene in the signature, was over-expressed in metastatic HCC; an osteopon-tin-specific antibody effectively blocked HCC cell invasion in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC.