Zhi-Ying Lin

A decade’s studies on metastasis of hepatocellular carcinoma

Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. This paper summarized a decade’s studies on HCC metastasis at the Liver Cancer Institute of Fudan University. We have established a stepwise metastatic human HCC model system, which included a metastatic HCC model in nude mice (LCI-D20), a HCC cell line with high metastatic potential (MHCC97), a relatively low metastatic potential cell clone (MHCC97L) and several stepwise high metastatic potential cell clones (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 tumors, and the biological characteristics of small HCC were only slightly better than that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarray, and 2-dimensional gel electrophoresis, we obtained some interesting results. In particular, in collaboration with the National Institute of Health (NIH) in the United States, we generated a molecular signature that can classify metastatic HCC patients, identified osteopontin 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. Experimental 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 primary tumor is a multigene-involved, multistep, and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basis for the prediction and prevention of the metastatic recurrence of HCC.

Surgery of small hepatocellular carcinoma. Analysis of 144 cases

A long‐term follow‐up study of 144 cases with surgically and pathologically proved small hepatocellular carcinoma (±5 cm) from 1967 to 1987 is reported. One hundred eight cases (75.0%) were detected by alpha‐fetoprotein serosurvey and/or ultrasonography mainly in a high‐risk population; 129 cases (89.6%) coexisted with cirrhosis. Resection was done in 132 cases (91.7%) with three (2.3%) operative deaths; cryosurgery, laser vaporization, and hepatic arterial chemotherapy were used in the rest. Limited resection was done in 67.4% of resections. Reresection of subclinical recurrence or solitary pulmonary metastasis was done in 21 cases. The 5‐year and 10‐year survival rates were 67.9% and 53.4% in the resection group but zero in the nonresection group. Survival was correlated negatively with tumor size, 5‐year survival after resection was 84.6% in tumors < 2 cm but 59.5% in tumors of 4.1 to 5 cm. The increase of resectability and reresection resulted in marked improved of 5‐year survival from 43.5% in 1973 to 1977 to 63.3% in 1978 to 1982 in the entire series. No significant difference was found between survival of limited resection and lobectomy. Resection may be the modality of choice for treatment of small hepatocellular carcinomas with compensated liver function. Limited resection instead of lobectomy was the key to increased resectability and decreased operative mortality in cirrhotic livers. Reresection of subclinical recurrence was important to prolong survival further.

Recurrence after resection of alpha-fetoprotein-positive hepatocellular carcinoma.

The long-term prognosis of surgery for hepatocellular carcinoma (HCC) is not yet satisfactory, the main reason being the high recurrence rate. The authors report the results of a long-term follow-up of 308 patients with HCC who became α-fetoprotein-(AFP)-negative after resection between 1975 and 1991. By March 1992, there was recurrence in 134 patients (43.5%). The 1-, 3-, 5- and 10-year recurrence rates were 9.2%, 38.8%, 54.9% and 85.0%, respectively. The 5-year survival rate was 49.7% for patients who had undergone a second hepatic resection (n=48). Analysis of factors influencing postoperative recurrence indicated that patients subjected to mass survey, with a lower γ-glutamyltransferase level, at an early stage of TNM classification, with a tumour of less than 5 cm, without tumour embolus, and with postoperative immunotherapy had a lower incidence of recurrence. It is concluded that the earlier the disease is diagnosed, the less the recurrence rate; adjuvant immunotherapy may reduce postoperative recurrence, and the early detection and resection of a recurrent tumour are important to prolonging survival further after curative resection of HCC.

Solitary minute hepatocellular carcinoma. A study of 14 patients

Fourteen patients with clinical Stage I hepatocellular carcinoma (T1NOMO) were studied. All patients were asymptomatic, and their conditions were detected by alpha‐fetoprotein (AFP) serosurvey and/or ultrasonography (US) either in the natural population in the early years of the study or in the high‐risk population in the later years of the study. Cirrhosis was present in all patients. Radical resection was performed in all patients. There were no operative deaths or hospital deaths in this series. The 5‐year survival rate after resection was 100%. There were seven long‐term survivors in this series (14.2 years (alive), 11.3 years (alive), 8.8 years (alive), 8.8 years, 7.9 years, 7.6 years (alive), and 7.2 years after resection). The authors discuss aspects concerning early diagnosis, treatment, and prognosis of hepatocellular carcinoma (HCC).

Long-term results of surgery for small primary liver cancer in 514 adults

During 1958–1993, 2030 patients with pathologically proven primary liver cancer (PLC) were retrospectively reviewed. Comparison between small PLC (<-5 cm,n=514) and large PLC (>5 cm,n=1516) revealed that small PLC had a higher resection rate (92.4% versus 49.1%), lower operative mortality (1.7% versus 5.2%), a higher percentage of single tumour nodules (78.0% versus 53.4%), a higher percentage of well encapsulated tumour (74.5% versus 35.8%) and higher survival rates after resection (5-year, 63.8% versus 36.6%; 10-year, 46.8% versus 28.5%). No significant difference was found between survival following limited resection (n=440) and lobectomy (n=34) in patients with small PLC. Re-resection of any subclinical recurrence or solitary pulmonary metastasis after small PLC resection was done in 70 cases. These results indicate that resection is still the modality of choice for treatment of small PLC; limited resection instead of lobectomy was the key to increasing resectability and decreasing operative mortality; re-resection of subclinical recurrence was important to prolong survival further.

Characteristics and prognosis of primary liver cancer in young patients in China

To investigate the clinicopathologic characteristics of primary liver cancer (PLC) in young adults, 77 patients aged 35 or younger were compared with 603 patients older than 35 years during the same period. In the young patients, PLC showed: (1) a low incidence detected at mass survey (young 15.6% vs older 28.7%,P<0.05); (2) a low level of history of hepatitis (young 36.8% vs older 66.3%,P<0.01); (3) a high incidence of positivity for hepatitis B surface antigen (HBsAg) (young 79.2% vs older 67.6%,P<0.05); (4) a relatively low incidence of associated cirrhosis (young 64.9% vs older 90.7%,P<0.01); (5) larger tumor size (PLC>5 cm; young 87.0% vs older 73.0%,P<0.01); and (6) a more advanced stage of the disease according to the TNM classification (stage III; young 29.9% vs older 18.2%,P<0.05). It is suggested that hepatitis B virus (HBV) may play an important role in the development of PLC without associated liver cirrhosis in young patients. Close periodic surveillance of young adults who are positive for HBsAg is important to detect PLC at an early stage.

mRNA levels of nm23 in murine ascites hepatoma (H22) clones with different lymphatic metastatic potential

Levels of expression of the nm23 gene inversely correlated with metastatic potential in several rodent tumor model systems and human breast carcinoma. In the present study, we examined nm23 mRNA levels in two murine ascites hepatoma models (H22-16A3-F and H22-A2-P) with different metastatic potentials. Metastatic H22-16A3-F (80% metastatic rate) and non-metastatic H22-A2-P clones were both derived from murine ascites hepatoma (H22). We found that a 0.8-kb nm23 transcript was expressed in both cell clones. The nm23 gene was expressed at a higher level in non-metastatic H22-A2-P: approximately 8.6-fold higher than in metastatic H22-16A3-F. The present data suggest that the expression of nm23 mRNA might be associated with metastasis of murine ascites hepatoma (H22), though heterogeneity of nm23 steady-state expression levels among the H22 clones remains to be investigated.

Treatment of hepatocellular carcinoma: A summary of 33 years' experience

Hepatocellular carcinoma (HCC), the most common type (90-95%) of primary liver cancer (PLC), causes 100,000 deaths every year in China. However, based on various strategies aimed at controlling this neoplasm, HCC has become “partly curable” instead of “incurable.” In China, hepatectomy for HCC started in the 1950s, liver cancer cell lines were established in the 1960s, field work in high risk areas, including epidemiology, etiology, and screening, have been conducted from the 1970s [1,2], and small HCC resection became an important clinical feature in the 1970s and 1980s [3–7]. During the past ten years, substantial progress has been made in the field of basic liver cancer research, studies have focused on the relation between hepatitis B virus (HBV) and HCC, a set of protooncogenes and HCC-related genes have been studied, and cytoreduction and sequential resection for unresectable HCC have become new trends [8].

Multimodality treatment of hepatocellular carcinoma

Abstract By 1996, 2898 patients with pathologically proven hepatocellular carcinoma (HCC) had been treated at the Liver Cancer Institute of Shanghai Medical University. The 5 year survival in the entire series was 36.2%, being increased from 4.8% in 1958–70, 12.2% in 1971–83, to 50.5% in 1984–96 and 274 patients had survived more than 5 years. The increase in the survival rate could be attributed to the decreasing mean tumour diameter (11.7, 10.5 and 9.5 cm, respectively) and multimodality treatment. In addition to small HCC resection (5 year survival 64.9%, n = 735) and large HCC resection (5 year survival 37.4%, n = 1050), the following deserves to be mentioned. First, the 5 year survival of unresectable HCC treated by palliative surgery increased from 0% to 7.2% to 20.0%, which was related to the increase in use of multimodality treatment, particularly in those followed by second‐stage resection. Second, cytoreduction and sequential resection is a new field with a significant potential in the treatment of localized unresectable HCC in a cirrhotic liver. Cytoreduction can be achieved by surgery, such as hepatic artery ligation, cannulation, cryosurgery and their combination, and followed by intrahepatic arterial chemoembolization, targeting therapy or regional radiotherapy. Ninety of 647 patients with unresectable HCC so treated had marked shrinkage of tumour and received second‐stage resection; the 5 year survival was 71.4%. Third, non‐surgical cytoreduction was mainly achieved by transcatheter arterial chemoembolization (TACE); for 70 patients with second‐stage resection following TACE, the 5 year survival was 56.0%. Finally, re‐resection of subclinical recurrence of tumour after curative HCC resection was performed in 155 patients; the 5 year survival calculated from the first resection was 50.9%, which played an important role in increasing the 5 year survival in the resection group (from 13.0% to 29.5% to 56.2%). It is concluded that multimodality treatment with combined and sequential use of different modalities and repeated use of some modalities is of substantial benefit for localized unresectable HCC.

Evaluation of Early Detection and Treatment of Hepatocellular Carcinoma

During 1972–1991, 1443 patients with hepatocellular carcinoma (HCC) were studied. Comparison between screening (n=522) and nonscreening (n=921) groups revealed higher small HCC percentage (49.4% vs. 12.4%), higher resection rate (75.10% vs 45.9%) higher 5-year survival (42.1% vs. 24.8%) and bigger number of 5-year survivors (71 vs. 53). The increase of series 5-year survival (11.5% in 1970s to 43.4% in 1980s) coincided to the increase of screening in the series (25.3% to 41.2%). The increase of 5-year survival in screening group (29.0% in 1970s to 47.4% in 1980s) was a result of increasing resectability. The 5-year survival of 391 patients with subclinical HCC after resection was as high as 60.5%. It is concluded that screening using AFP and/or ultrasonography in high risk population and treated with resection is of proved merit to improve survival of patients with HCC.