Twenty-year survivors after resection for hepatocellular carcinoma-analysis of 53 cases.

PURPOSE: To clarify the clinicopathologic features of patients surviving > or =20 years after resection for hepatocellular carcinoma (HCC). METHODS: Between 1961 and 1987, a total of 396 patients underwent hepatic resection for HCC; 53 (13.4%) patients survived > or =20 years, and 343 (86.6%) patients survived <20 years. A comparative study between the two groups was made. RESULTS: By March of 2007, 67.6% (36/53) patients are still alive, disease free; 5.7% (3/53) patients died of tumor recurrence or metastasis; 11.3% (6/53) patients died of liver failure; 5.7% (5/53) patients were lost during follow-up. The longest patient survived 43 years and 2 months. Five young patients got married after resection and have had babies. One patient with a tumor measuring 17 x 13 x 9 cm (largest tumor in this series) survived for 37 years after resection, still alive, free of disease. Reresection for recurrence was done in nine patients, mean survival being 26 years and 11 months. Reresection for solitary pulmonary metastasis was carried out in three patients, mean survival being 29 years and 2 months. In comparison with patients surviving <20 years, patients surviving > or =20 years were significantly younger (P = 0.031), had a higher incidence of asymptomatic tumors (56.6 vs. 34.4%, P = 0.002); lower gamma-glutamyl transpeptidase level (< or =50 U/L, 64.2 vs. 25.9%, P < 0.000), lower proportion of liver cirrhosis (66.0 vs. 83.6%, P = 0.002); higher percentage of small tumors (< or =5 cm, 62.3 vs. 29.9%, P < 0.000), single nodule tumors (90.6 vs. 62.9%, P < 0.000), and well-encapsulated tumors (86.8 vs. 43.6%, P < 0.000); lower proportion of tumor emboli in the portal vein (3.8 vs. 22.5%, P = 0.002), better differentiation of tumor cells (Edmondson grade I, 21.6 vs. 9.1%, P = 0.036), and higher curative resection rate (100 vs. 64.1%, P < 0.000). CONCLUSIONS: Early detection and curative resection are the principal factors improving long-term survival. Long-term follow-up after resection of HCC is very important, and should continue for the remainder of the patient's life. Reresection for recurrence and metastasis is important approach to improve prognosis.

Intrahepatic cholangiocarcinoma: report of 272 patients compared with 5,829 patients with hepatocellular carcinoma.

PURPOSE: To clarify clinicopathologic differences between patients with intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), and identify potential factors influencing survival after hepatectomy for ICC. METHODS: Comparison of clinicopathologic data was made between patients who underwent hepatectomy for ICC (n = 272) and HCC (n = 5,829) during the same period. Twenty-five clinicopathologic variables were selected for univariate and multivariate analyses to evaluate their influence on prognosis of ICC. RESULTS: Compared with patients with HCC, ICC patients were more common in females and more elderly, had a lower proportion of asymptomatic tumors, lower serum alpha-fetoprotein, higher serum carcinoembryonic antigen, carbohydrate antigen 19-9 and alkaline phosphatase levels; lower incidence of hepatitis history, associated cirrhosis and serum hepatitis B surface antigen; lower proportion of small tumors, well-encapsulated tumors and tumor emboli in the portal vein; higher proportion of single tumor, perihila lymph node involvement and poor differentiation; and less frequency of limited resection (all, P < 0.0001). Distant metastasis was less frequent in patients with ICC (P = 0.027). A total of 5-years overall and disease-free survival (in brackets) after resection was 26.4% (13.1%) and 44.5% (33.1%) (P < 0.0001, P < 0.0001) for patients with ICC and HCC, respectively. Factors influencing survival after resection of ICC can be divided mainly into two categories: early detection of asymptomatic ICC (P < 0.0001) and curative resection (P = 0.002). CONCLUSION: ICC Patients have distinct clinicopathologic features as compared with HCC patients. Surgery remains the only effective treatment for ICC. Early detection of asymptomatic ICC and curative resection were the key to achieve optimal survival.

Focal nodular hyperplasia of the liver in 86 patients.

BACKGROUND: Focal nodular hyperplasia (FNH), the second most common benign hepatic tumor after hemangioma, is characterized by a stellate central scar and hyperplastic nodules. Although some large FNH may be associated with significant symptoms, more frequently they are discovered incidentally on physical examination or the work-up of unrelated symptoms. Since its nature and pathogenesis are still controversial, accurate diagnosis of FNH based on clinical presentation and radiographic studies is difficult. The purpose of this study was to explore the diagnosis and treatment of FNH. METHODS: Eighty-six FNH patients confirmed pathologically were treated at the Liver Cancer Institute in our hospital from 1996 to 2006. Their clinical manifestations, imaging presentation, pathological findings, and surgical results were analyzed retrospectively. RESULTS: Of the 86 patients with 99 foci, 54 were male and 32 female, with a mean age of 37 years. Eighty patients had a single solitary focus and 6 had multiple foci. Tumor diameter was less than 5 cm in 69 patients, 5-10 cm in 15, and more than 10 cm in 2. The overall rate of correct preoperative diagnosis was 59.3% (51/86) including 32.9% (26/79) by color Doppler flow imaging (CDFI), 60.3% (35/58) by CT, and 77.4% (24/31) by MRI. All the 86 patients underwent resection with good curative effect. CONCLUSIONS: CT and MRI are important diagnostic methods for FNH but it is difficult to make a definite preoperative diagnosis for partial classical and all non-classical FNH patients. We suggest that patients with clinical symptoms or with indefinite diagnosis should accept surgical removal.

Factors influencing survival in hepatocellular carcinoma patients with macroscopic portal vein tumor thrombosis after surgery, with special reference to time dependency: a single-center experience of 381 cases.

BACKGROUND/AIMS: The prognosis ofhepatocellular carcinoma with macroscopic portal vein tumor thrombosis is extremely poor. The risk factors may differ at different postoperative intervals. This study was undertaken to clarify the surgical outcome and time dependency of factors influencing survival in these patients. METHODOLOGY: We analyzed clinicopathological variables of 381 hepatocellular carcinoma patients with macroscopic portal vein tumor thrombosis who underwent hepatic resection. Survival rates were calculated using Kaplan-Meier method. The stratified Cox models were used to identify factors independently influencing short- and long-term survival, respectively. RESULTS: The cumulative 1-, 2-, 3-, 5-, and 10-year survival rates in 381 patients were 47%, 23%, 16%, 12%, 6%, respectively. The 1-, 3-, and 5-year survival rates calculated from time of re-resection were 36%, 14% and 0% in patients undergoing re-resection for intrahepatic recurrence within 2 years after first operation, and 85%, 53% and 32% in those more than 2 years after first operation (P<0.05). Multivariate analysis showed that portal vein infusion chemotherapy, serum alpha-fetoprotein > 20 mg/L and positive surgical margin were significant prognostic factors within 2 years after operation. In contrast, alanine aminotransferase > 80 U/L was the only significant factor beyond 2 years after operation. CONCLUSIONS: The survival of hepatocellular carcinoma patients with macroscopic portal vein tumor thrombosis was poor, but the prognosis of patients who had tumor recurrence more than 2 years after operation was much better than those with tumor recurrence within 2 years. Evaluation of time-dependency of risk factors may have important clinical implication in determining the therapeutic strategy.

Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial.

BACKGROUND/AIMS: Recurrence after resection of hepatocellular carcinoma (HCC) is a frequent event. This study evaluated the effect of postoperative interferon alpha (IFN alpha) treatment on recurrence and survival in patients with hepatitis B virus (HBV)-related HCC. METHOD: Two hundred and thirty six patients were randomized after resection into IFN alpha treatment (5 micro i.m. tiw for 18 months) and control groups. Treatment was terminated if recurrence was diagnosed, and recurrence was managed the same way in both groups. Statistical analysis was based on the method of intent-to-treat. RESULTS: The two groups were comparable in all clinicopathological parameters. The median overall survival was 63.8 months in the treatment group and 38.8 months in the control group (P=0.0003); the median disease-free survival period was 31.2 versus 17.7 months (P=0.142). Fever, leucocytopenia, and thrombocytopenia were adverse effects in the treatment group, but were mostly manageable. CONCLUSIONS: IFN alpha treatment improved the overall survival of patients with HBV-related HCC after curative resection, probably by postponing recurrence.

[Time dependency of factors influencing survival of hepatocellular carcinoma patients with portal vein tumor thrombosis after surgery].

OBJECTIVE: To investigate the surgical outcome of the hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) after surgery and the time-dependency of the factors influencing survival. METHODS: The clinicopathological data of 382 HCC patients with macroscopic PVTT who had undergone resection of HCC were analyzed. The survival rte was calculated using Kaplan-Meier method. Stratified Cox model was used to identify the factors independently influencing the short- and long-term survival rates. RESULTS: The 1-, 2-, 3-, 5-, and 10-year survival rates of the 382 patients were 47%, 23%, 16%, 12%, and 6% respectively. The 1-, 3-, and 5-year survival rates re-calculated from the time of re-resection because of recurrence within 2 years after the first operation were 36%, 14%, and 0% 1 respectively. However, the 1-, 3-, and 5-year survival rates re-calculated from the time of re-resection because of recurrence 2 years after the first operation were 85%, 53%, and 32%, all significantly higher than those re-calculated from the time of re-resection within 2 years after the first operation (all P < 0.05). Multivariate analysis showed that portal infusion chemotherapy, serum alpha-fetoprotein < 20 microg/L and negative surgical margin were significant favorable prognostic factors within 2 years after operation. Alanine aminotransferase > 80 U/L was the only significant unfavorable factor beyond 2 years after operation. CONCLUSION: The prognosis of the patients with macroscopic PVTT who suffer from liver tumor recurrence occurring more than 2 years after the first operation is much better than those with the recurrence occurring within 2 years. Evaluation of the time-dependency of risk factors may have important clinical implication in determining the therapeutic strategy.

[The effects of portal vein microscopic and macroscopic tumor thrombi on post-operation patients with hepatocellular carcinoma].

OBJECTIVE: To evaluate the effects of portal vein microscopic and macroscopic tumor thrombi on post-operation patients with hepatocellular carcinoma (HCC). METHODS: Three thousand three hundred and forty eight HCC patients were retrospectively reviewed, which were divided into no portal vein tumor thrombi (PVTT), microscopic PVTT and macroscopic PVTT groups according to the pathology, effects of portal vein microscopic and macroscopic tumor thrombi on post-operation patients's survival were studied by univariate analysis and overall survival was evaluated in each group. RESULTS: Hazard ratio (HR) of portal vein microscopic tumor thrombi and macroscopic tumor thrombi was 1.421 and 3.136 respectively; The overall 1-, 3-, 5- and 10-year cumulative survival rate was 85.97%, 62.78%, 49.88% and 35.42% respectively, and mean time for survival was 59.7 months in group without PVTT, while 74.42%, 51.66%, 39.25% and 27.28% respectively and mean time for survival 39.1 months in group with microscopic PVTT, 52.59%, 25.97%, 20.42% and 11.33% respectively and mean time for survival 13.5 months in group with macroscopic PVTT. CONCLUSIONS: PVTT was an important prognostic factor for survival in post-operation patients with HCC while macroscopic PVTT was more danger than microscopic PVTT. The period of microscopic PVTT was the landmark affecting post-operation survival.

[Cryohepatectomy for liver cancer: preliminary evaluation of reducing postoperative recurrence].

OBJECTIVE: To determine whether cryohepatectomy is potentially beneficial in reducing the recurrence and prolonging survival for hepatocellular carcinoma (HCC). METHODS: The study included 84 patients who underwent cryohepatectomy, cryosurgery with liquid nitrogen (-196 degrees C) followed by the resection of the frozen tumor by conventional technique, for HCC and were closely follow-up after surgery. Recurrence and survival rates were calculated by the life-table method. RESULTS: The postoperative course of cryohepatectomy in all of the 84 patients was uneventful, there being no operative mortality or severe complications. The 1-, 3-, and 5-year survival rates after cryohepatectomy were 98.7%, 83.9% and 64.0%, respectively. The 1-, 3-, and 5-year recurrence rates after cryohepatectomy were 15.1%, 30.1% and 39.0%, respectively. CONCLUSIONS: Cryohepatectomy for HCC is a safe procedure and may be potentially beneficial in reducing recurrence and prolonging survival. More time is needed to further define whether this procedure will improve long-term survival as compared with conventional resection.

The prognostic factor for outcome following second resection for intrahepatic recurrence of hepatocellular carcinoma with a hepatitis B virus infection background.

PURPOSE: Second resection has been proved to be a safe and effective treatment for patients with intrahepatic recurrent HCC after primary resection; however, preoperative prognostic factors for outcome following second resection in patients with a hepatitis B virus (HBV) infection background remains to be clarified. METHODS: Fifty-seven patients with intrahepatic recurrent an HCC and HBV infection background received second resection from 1997 to 2003 in our institute. All of them were negative for anti-hepatitis C virus (HCV) and positive regarding HBV profile. Patient and tumor factors were analyzed. RESULTS: At the time of preparing this paper, 31 had re-recurrence and 21 patients had died. No postoperative mortality was noted. The 1-, 3-, and 5-year overall survival after second resection were 69.9%, 61.2%, and 30.6%, respectively. Univariate and multivariate analysis showed that vascular invasion and time to recurrence were the independent prognostic factors for overall survival following second resection. The 3- and 4-year overall survival after second resection were 57.7% and 46.6% in patients with the presence of any of two risk factors (n = 46), and 100% and 100% in those with absence of both risk factors (n = 11, P = 0.008). CONCLUSIONS: Vascular invasion and time to recurrence were the prognostic factors for overall survival following second resection of intrahepatic recurrent HCC.

Downstaging followed by resection plays a role in improving prognosis of unresectable hepatocellular carcinoma.

BACKGROUND: Curable outcome of unresectable hepatocellular carcinoma (HCC) was seldom encountered in the past. This study was designed to assess the role of downstaging followed by resection (downstaging-resection) in the improvement of prognosis of unresectable HCC. METHODS: During the period of 1958-2003, a total of 1085 patients were verified surgically to be unresectable. Of these patients, 139 received downstaging-resection, with a rate of 84.2% for coexisting cirrhosis and a median tumor diameter of 11.1 cm. Resection of the right lobe, hepatic hilum and bilateral cancer accounted for 97.8% of the patients. Downstaging including hepatic artery ligation (HAL)+hepatic artery chemo-infusion (HAI) was performed in 65.5% of the patients, HAL+HAI+radiotherapy/radioimmunotherapy in 29.5%, and HAL or HAI alone in 5.0%. Retrospective analysis was made of the survival of patients with unresectable HCC, downstaging-resection rate and treatment pattern. RESULTS: In the 139 patients with downstaging-resection, the median interval between the first and second operation was 7.2 months and the 5-year survival rate calculated from the first operation was 48.7%. In the 1085 patients with unresectable HCC, their 5-year survival was 0% in the period of 1958-1973, 11.5% in the period of 1974-1988 and 19.3% in the period of 1989-2003. These figures were correlated with the increasing downstaging-resection rate from 0%, 9.0% to 15.6%, and the increasing percentage of triple or double combination treatment from 32.2%, 60.4% to 69.7%. The 5-year survival in triple treatment group was 24.9%, double treatment 15.2%, and single treatment only 10.9%, which was also correlated with the downstaging-resection rate of 34.6%, 16.2% and 1.8% respectively. CONCLUSIONS: Downstaging-resection plays a role in improving prognosis of unresectable HCC. Triple and double treatments provide a higher downstaging-resection rate and may result in better prognosis.

Postoperative adjuvant arterial chemoembolization improves survival of hepatocellular carcinoma patients with risk factors for residual tumor: a retrospective control study.

AIM: To evaluate the effect of postoperative adjuvant transcatheter arterial chemoembolization (TACE) on the prognosis of hepatocellular carcinoma (HCC) patients with or without risk factors for the residual tumor. METHODS: From January 1995 to December 1998, 549 consecutive HCC patients undergoing surgical resection were included in this research. There were 185 patients who underwent surgical resection with adjuvant TACE and 364 patients who underwent surgical resection only. Tumors with a diameter more than 5 cm, multiple nodules, and vascular invasion were defined as risk factors for residual tumor and used for patient stratification. Kaplan-Meier method was used to analyze survival curve and Cox proportional hazard model was used to evaluate the prognostic significance of adjuvant TACE. RESULTS: In the patients without any risk factors for the residual tumor, the 1-, 3-, 5-year survival rates were 93.48%, 75.85%, 62.39% in the control group and 97.39%, 70.37%, 50.85% in the adjuvant TACE group, respectively. There was no significant difference in the survival between two groups (P = 0.3956). However, in the patients with risk factors for residual tumor, postoperative adjuvant TACE significantly prolonged the patients' survival. There was a statistically significant difference in survival between two groups (P = 0.0216). The 1-, 3-, 5-year survival rates were 69.95%, 49.86%, 37.40% in the control group and 89.67%, 61.28%, 44.36% in the adjuvant TACE group, respectively. Cox proportional hazard model showed that tumor diameter and cirrhosis, but not the adjuvant TACE, were the significantly independent prognostic factors in the patients without risk factors for residual tumor. However, in the patients with risk factors for residual tumor adjuvant TACE, and also tumor diameter, AFP level, vascular invasion, were the significantly independent factors associated with the decreasing risk for patients' death from HCC. CONCLUSION: Postoperative adjuvant TACE can prolong the survival of patients with risk factors for residual tumor, but can not prolong the survival of patients without risk factors for residual tumor.

Diagnosis and surgical treatments of hepatocellular carcinoma with tumor thrombosis in bile duct: experience of 34 patients.

AIM: Hepatocellular carcinoma (HCC) with bile duct tumor thrombosis (BDT) is a rare event. The prognosis of this type of patients is very dismal. The aim of this study was to share the experience in the diagnosis and treatment of HCC with BDT, to further improve the prognosis of these patients. METHODS: Thirty-four patients of HCC with BDT received surgical treatment in authors' institute from July 1987 to January 2003 were reviewed retrospectively. The experience in the diagnosis and treatment, and the outcome of this type of HCC patients were summarized. RESULTS: Thirty of the 34 patients (88.2%) were positive for alpha-fetoprotein (AFP) (>20 microg/L), and 12 patients (35.3%) were found having obstructive jaundice before operation, 18 cases were suspected of "obstruction of bile duct" preoperatively. The primary tumors were frequently located at the left medial (13 cases) or right anterior lobe (14 cases). Thirty-one patients received liver resections and removal of BDT, while the other 3 patients received removal of BDT combined with hepatic artery ligation and cannulation (HAL+HAI), or only removal of BDT because their liver function reservation and general condition could not tolerate the primary tumor resection. The 1-year survival rate was 71.4%(20/28). The longest disease-free survival was over 15 years. The intrahepatic tumor recurrence within 1 year after operation was found in 14 patients (14/28, 50.0%). CONCLUSION: Surgical removal of primary tumors and BDT is safe and beneficial to the HCC patients with BDT. Early detection, diagnosis, and surgical treatment are the key points to prolong the survival time of patients.

[Effect of postoperative transcatheter arterial chemoembolization on hepatocellular carcinoma patients with residual tumor].

OBJECTIVE: To evaluate the effect of postoperative adjuvant transcatheter arterial chemoembolization (TACE) on hepatocellular carcinoma (HCC) patients with residual tumor. METHODS: The patients were classified into intervention group (with adjuvant TACE) and control group (without adjuvant TACE) who were further stratified to those with high risk (patients with single tumor > 5 cm in diameter, or with multiple tumors, invasion to blood vessels), and low risk factors. Univariate analysis and Cox model were used to analyse prognostic factors. RESULTS: In low risk patients with residual tumor, the 1-, 2-, 3-, 4-year survival rate was 97.2%, 78.0%, 66.5% and 66.5% in the intervention group, and 91.2%, 81.4%, 70.3% and 54.4% in the control group, respectively. There was no statistical difference between the two groups in survival (log-rank P = 0.7667). Comparing with the control group, the 1-, 2-, 3-, 4-year survival rate was 89.5%, 73.4%, 59.2% and 53.8% in the intervention group, and 70.5%, 61.9%, 46.8% and 46.8% in the control group, respectively. Postoperative adjuvant TACE significantly prolonged the survival in high risk patients with residual tumor (P = 0.0029). Cox model revealed that the benefit of adjuvant TACE was significantly increased by the high risk factors in HCC patients with residual tumor. CONCLUSION: The beneficial effect of postoperative TACE was only observed in high risk patients with residual tumor but not in the low risk patients with residual tumor.

[Three-grade criteria of curative resection for primary liver cancer].

OBJECTIVE: To clarify three-grade criteria of curative resection for primary liver cancer (PLC) and evaluate their clinical significance. METHODS: Criteria of curative resection of PLC were summed up to three grades. Grade I: complete removal of all gross tumors with no residual tumor at the excision margin. Grade II: on the basis of Grade I, there was no extrahepatic metastasis, no hilar lymph node metastasis, no tumor thrombus in the main trunks and their primary tributaries of the portal vein, common hepatic duct, hepatic vein and vena cava inferior, and the tumor was not more than two in number. Grade III: in addition to the above criteria, AFP dropped to normal level (in patients with elevated AFP before surgery) within 2 months after operation, and no residual tumor upon diagnostic imaging. A total of 354 cases with PLC who had their liver resected was reviewed. Patients in each grade were divided into two portions depending on whether the treatment was curative or palliative. RESULTS: The survival of patients receiving curative treatment was better than those receiving palliative treatment (P < 0.01). This was true for patients whose treatment belonged to anyone of the three-grade criteria. The survival was improved along with the promotion of curative criteria used. The 5-year survival rate of Grade I, II and III patients undergone curative resection was 43.2%, 51.2% and 64.4%, respectively (P < 0.01). CONCLUSION: 1. The three-grade criteria may be used for judging the radicality of tumor resection for PLC. 2. The more stringent the criteria used, the better the survival would be. 3. Adopting high-grade criteria to select cases, to guide operation and postoperative follow-up would improve the results of liver resection for PLC.

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.

Loss of heterozygosity at D14S62 and D14S51 detected by a simple and non-radioactive method in plasma DNA is a potential marker of metastasis and recurrence after curative hepatic resection in hepatocellular carcinoma.

BACKGROUND/AIMS: Recurrence and metastasis in hepatocellular carcinoma remains a major challenge to further improve survival. High frequency of loss of heterozygosity at D14S62 and D14S51 in tumor tissue has been shown to be closely related to metastasis and recurrence in breast cancer. But, loss of heterozygosity on 14q in plasma and tumor tissue DNA of hepatocellular carcinoma patients has not been investigated. To establish a way to predict metastasis and recurrence after curative hepatic resection, we analyzed loss of heterozygosity on 14 q in plasma and tumor tissue DNA of hepatocellular carcinoma patients with curative resection. METHODOLOGY: We used a simple, rapid and non-radioactive method to analyze loss of heterozygosity at D14S62 and D14S51 in paired plasma, lymphocyte and tumor tissue DNA of 85 hepatocellular carcinoma patients with curative resection. RESULTS: From 79 cases informative for D14S62 and 78 cases informative for D14S51 of 85 hepatocellular carcinoma tissue DNA, loss of heterozygosity at D14S62 and D14S51 was present in 45 (57.0%) and 41 (52.6%) cases respectively. And in 96.0% of the tissues which showed loss of heterozygosity we were able to detect loss of heterozygosity in their matched plasma. In matched 85 cases of hepatocellular carcinoma plasma DNA, we detected loss of heterozygosity at D14S62 in 55.7% and at D14S51 in 50.0% of the respective informative DNA samples. The loss of heterozygosity patterns of plasma DNA were almost identical to their corresponding tumor tissues. A comparison of these genetic changes with clinicopathological data of these checked hepatocellular carcinoma patients showed that loss of heterozygosity at D14S62 and D14S51 was adversely correlated significantly with the presence of tumor size, with 35.4% at both the D14S62 and D14S51 locus in the HTMR (high-tendency to metastasis and recurrence) group compared with 72.9% and 59.4% in the LTMR (low-tendency to metastasis and recurrence) group at D14S62 and D14S51, respectively (P = 0.001 and P = 0.027, respectively). CONCLUSION: Our results suggest that loss of heterozygosity at D14S62 and D14S51 plays an important role in the metastasis and recurrence of hepatocellular carcinoma patients following curative resection. Loss of heterozygosity at D14S62 and D14S51 in the plasma DNA of hepatocellular carcinoma patients detected by a simple and non-radioactive method has great potentials to be clinically used to predicate metastasis and recurrence after curative hepatic resection.

Surgery for large primary liver cancer more than 10 cm in diameter.

PURPOSE: Large primary liver cancer (PLC) more than 10 cm in diameter is not infrequently encountered in clinical practice. This study evaluated the clinicopathological features and long-term results after surgery for large PLC. METHODS: Comparison of clinicopathological data between patients with PLC >/=10 cm ( n=1,227) and PLC <10 cm ( n=2,349) during the same period. RESULTS: In comparison with patients with PLC <10 cm, patients with PLC >/=10 cm were significantly younger ( P<0.01), had a lower incidence of asymptomatic tumors (9.1% vs 39.5%, P<0.001), higher alpha-fetoprotein levels ( >400 ng/ml, 78.3% vs 49.2%, P<0.001), higher gamma-glutamyl transpeptidase levels ( >6U, 87.7% vs 70.5%, P<0.001), a lower incidence of a history of hepatitis (45.0% vs 61.4%, P<0.001) and associated macronodular cirrhosis (cirrhotic nodules >/=0.3 cm, 59.8% vs 66.6%, P<0.001), poor differentiation of tumor cells (Edmondson grade 3-4, 24.3% vs 19.7%, P<0.01), a lower percentage of single nodule tumors (59.9% vs 75.4%, P<0.001) and well-encapsulated tumors (28.5% vs 62.1%, P<0.001), a higher proportion of tumor emboli in the portal vein (20.5% vs 9.0%, P<0.001), a lower resection rate (50.6% vs 86.8%, P<0.001), a lower curative resection rate (54.8% vs 78.3%, P<0.001), a higher operative mortality rate (4.5% vs 2.3%, P<0.001), and less local resection (52.5% vs 80.2%, P<0.001). The 5- and 10-year survival rates after resection were 26.2% and 17.5%, respectively, for patients with PLC >/=10 cm ( n=621), and 54.3% and 39.5%, respectively, for patients with PLC <10 cm ( n=2039) ( P<0.01). CONCLUSIONS: Large PLC had specific clinicopathological features. Surgery is the first choice of treatment. In selected patients, resection is safe and offers the chance of long-term survival. Large PLC does not exclude the possibility of cure.

Allelic imbalance regions on chromosomes 8p, 17p and 19p related to metastasis of hepatocellular carcinoma: comparison between matched primary and metastatic lesions in 22 patients by genome-wide microsatellite analysis.

To understand the molecular mechanisms of metastasis in hepatocellular carcinoma (HCC), it is necessary to identify the accumulating genetic alterations during its progression as well as those responsible for the acquisition of metastatic potential in cancer cells. In our previous study, using comparative genomic hybridization (CGH), we found that loss on chromosome 8p is more frequent in metastatic lesions than in matched primary tumors of HCC. Thus, 8p deletion might contribute to HCC metastasis. To narrow the location of metastasis-related alteration regions, we analyzed 22 primary and matched metastatic lesions of HCC by genome-wide microsatellite analysis. Common regions with high levels of allelic imbalance (AI) were identified on 17p, 8p11-cen, 8p21-23, 4q32-qter, 4q13-23, 16q, and 1p33. Regions with increased AI in metastatic lesions were 8p23.3, 8p11.2, 17p11.2-13.3, 4q21-22, 4q32-qter, 8q24.1, 9p11, 9q31, 11q23.1, 13q14.1-31, 13q32-qter, 16p13.3, 16q13, 16q22, and 19p13.1, and these were considered to be related to the metastasis phenotype. Among them, loss on 8p was again proved to be related to progression and metastasis of HCC, and 8p23.3 and 8p11.2 were two likely regions harboring metastasis-related genes. It was also shown for the first time in HCC that AI of 19p13.1 might also be related to metastatic potential. These results provide some candidate regions for further study to identify putative genes suppressing metastasis of HCC.

Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning.

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies. Its high mortality rate is mainly a result of intra-hepatic metastases. We analyzed the expression 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 classify 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 favoring 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 osteopontin-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.

P53 immunohistochemical scoring: an independent prognostic marker for patients after hepatocellular carcinoma resection.

AIM: To confirm if p53 mutation could be a routine predictive marker for the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: Two hundreds and forty-four formalin-fixed paraffin-embedded tumor samples of the patients with HCC receiving liver resection were detected for nuclear accumulation of p53. The percent of P53 immunoreactive tumor cells was scored as 0 to 3+ in P53 positive region (<10% -, 10-30% +, 31-50% ++, >50% +++). Proliferating cell nuclear antigen (PCNA) and some clinicopathological characteristics, including patients' sex, preoperative serum AFP level, tumor size, capsule, vascular invasion (both visual and microscopic), and Edmondson grade were also evaluated. RESULTS: In univariate COX harzard regression model analysis, tumor size, capsule status, vascular invasion, and p53 expression were independent factors that were closely related to the overall survival (OS) rates of HCC patients. The survival rates of patients with 3+ for P53 expression were much lower than those with 2+ or + for P53 expression. Only vascular invasion (P<0.05) and capsule (P<0.01) were closely related to the disease-free survival (DFS) of HCC patients. In multivariate analysis, p53 overexpression (RI 0.5456, P<0.01) was the most significant factor associated with the OS rates of patients after HCC resection, while tumor size (RI 0.5209, P<0.01), vascular invasion (RI 0.5271, P<0.01) and capsule (RI-0.8691, P<0.01) were also related to the OS. However, only tumor capsular status was an independent predictive factor (P<0.05) for the DFS. No significant prognostic value was found in PCNA-LI, Edmondson's grade, patients' sex and preoperative serum AFP level. CONCLUSION: Accumulation of p53 expression, as well as tumor size, capsule and vascular invasion, could be valuable markers for predicting the prognosis of HCC patients after resection. The quantitative immunohistochemical scoring for P53 nuclear accumulation might be more valuable for predicting prognosis of patients after HCC resection than the common qualitative analysis.