Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma

Nagasue, Naofumi; Uchida, Masaaki; Makino, Yoshinari; Takemoto, Yoshinari; Yamanoi, Akira; Hayashi, Takafumi; Chang, Yu‐Chung; Kohno, Hitoshi; Nakamura, Teruhisa; Yukaya, Hirofumi

doi:10.1016/0016-5085(93)90724-q

Cited by 365 publications

(297 citation statements)

References 26 publications

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“…prognosis and improved survival of patients with HCC compared with nonencapsulated tumors. [30][31][32][33] Our data give new insights into this concept. Indeed, we show that nonencapsulated HCC had the highest expression of MMP2, MT1-MMP, TIMP2, and collagen I compared with encapsulated HCC.…”

Section: Discussionmentioning

confidence: 99%

Increased Extracellular Matrix Remodeling Is Associated With Tumor Progression in Human Hepatocellular Carcinomas

Théret¹

2001

Hepatology

184

128

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Matrix metalloproteinase-2 (MMP2) is a key enzyme in the process of extracellular matrix remodeling involved in tumor invasion and metastasis. The activation of MMP2 involves interplay with the membrane type-matrix metalloproteinase-1 (MT1-MMP) and the tissue inhibitor of metalloproteinase-2 (TIMP2). In vitro, activated hepatic stellate cells are a main source of MMP2 and collagen I induces MMP2 activation. The steady-state mRNA levels of MMP2, MT1-MMP, TIMP2, collagen I, collagen IV, and laminin ␥1 were compared with MMP2 activity in 55 hepatocellular carcinomas, 47 matching nontumor biopsies and 19 histologically normal livers. In hepatocellular carcinomas, increased collagen I mRNA levels were strongly associated with those of MMP2 (Spearman R ‫؍‬ .74, P < .001), MT1-MMP (R ‫؍‬ .65, P < .001) and TIMP2 (R ‫؍‬ 0.61, P < .001). MMP2 activity was correlated with the mRNA expression of collagen I (R ‫؍‬ .45 P < .01), collagen IV (R ‫؍‬ .40, P < .01) and laminin ␥1 (R ‫؍‬ .33, P < .05). Unlike collagen IV and laminin ␥1 mRNAs, MMP2, MT1-MMP, TIMP2, collagen I mRNA levels were increased in nonencapsulated compared with encapsulated tumors (P < .05). In addition, MMP2 activity was fourfold higher (P < .01) in tumors arising in cirrhotic livers than in those arising in noncirrhotic livers. Moreover, tumor recurrence was associated with 4.6-and 2.8-fold (P < .05) higher collagen I and MMP2 mRNA levels, respectively, in hepatocellular carcinomas arising in cirrhotic livers. Thus, a high extracellular matrix remodeling favors tumor progression in hepatocellular carcinomas. (HEPATOLOGY 2001;34:82-88.)Tumor progression depends on the interplay between transformed cells and their micro-environment, particularly the surrounding extracellular matrix (ECM). 1 The balance between synthesis and degradation of ECM components is indeed a key modulator of tumor growth and metastasis. Among the proteases involved in the turnover of ECM, matrix metalloproteinase 2 (MMP2), the type IV collagenase/gelatinase, was shown to specifically act in the process of basementmembrane remodeling related to tumor progression. 2 MMP2 is secreted as a proenzyme and the critical step of MMP2 activation occurs at the cell surface through the formation of a molecular complex involving MMP2, the membrane-type matrix metalloproteinase MT1-MMP 3 and the tissue inhibitor of MMP2, TIMP2, which promotes the binding of MT1-MMP to MMP2. 4 Thus, TIMP2 plays a dual role by acting at a high concentration as a specific inhibitor of MMP2 activation and at a low concentration as a trigger of MMP2 and MT1-MMP clustering. 5 In human livers, fibrogenesis underlies the development of HCC in at least 90% of cases and HCC is an ominous complication of cirrhosis in 30% of the patients. 6,7 However, direct relationships between fibrosis and the progression of HCC were not shown, so far. Increased expression of MMP2, tissue inhibitors of metalloproteinase (TIMP1 and TIMP2), and MT1-MMP by nonparenchymal cells were reported in fibrosis 8-9 and in HCC. [10][11][12] Indeed, hep...

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Section: Discussionmentioning

confidence: 99%

Increased Extracellular Matrix Remodeling Is Associated With Tumor Progression in Human Hepatocellular Carcinomas

Théret¹

2001

Hepatology

184

128

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“…1) There have been many studies concerning factors related to recurrence and outcome after resection of HCC. [2][3][4][5][6][7][8][9][10][11][12][13] In some of these reports, hepatitis viral status was not evaluated. In others, hepatitis C virus (HCV) infection was determined by whether the patients had anti-HCV antibodies in their sera before the operation.…”

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confidence: 99%

Effects of Continuous Hepatitis with Persistent Hepatitis C Viremia on Outcome after Resection of Hepatocellular Carcinoma

Kubo¹,

Nishiguchi

Shuto³

et al. 1999

Japanese Journal of Cancer Research

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The effect of persistent hepatitis C viremia on the outcome after resection of hepatocellular carcinoma (HCC) was investigated in 59 consecutive patients with a single small HCC (≤ ≤ ≤ ≤3.0 cm in diameter). The presence of serum hepatitis C virus (HCV) RNA was evaluated using a reverse transcription polymerase chain reaction method as well as a branched DNA probe method. Clinicopathologic findings were compared between patients with and without viremia and the risk factors for poor outcome were evaluated. Hepatitis C virus (HCV) RNA was not detected in the sera from 7 patients (group 1), but was detected in the sera from the other 52 patients (group 2). Alanine aminotransferase (ALT) activity was significantly higher in group 2 than in group 1. The proportion of patients with active hepatitis was significantly higher in group 2. In group 2, new HCC often developed after the operation and four patients died of liver dysfunction. HCV viremia, high ALT activity, high concentration of total bilirubin, and liver cirrhosis were related to recurrence after the operation. Multivariate analysis indicated that HCV viremia and high ALT activity were independent risk factors for recurrence of HCC. Continuous hepatitis with persistent HCV viremia worsened the outcome after the resection of HCC by causing new development of HCC and deterioration of liver function. In patients with HCV-related HCC, but without HCV viremia, satisfactory results can be expected after liver resection.Key words: Hepatocellular carcinoma -Hepatitis C virus -Chronic hepatitis C -Liver resection -Histologic activity indexDespite improvements in medical imaging, surgical techniques, and perioperative management, outcomes after liver resection for hepatocellular carcinoma (HCC) still are unsatisfactory because of a high recurrence rate. 1)There have been many studies concerning factors related to recurrence and outcome after resection of HCC. [2][3][4][5][6][7][8][9][10][11][12][13] In some of these reports, hepatitis viral status was not evaluated. In others, hepatitis C virus (HCV) infection was determined by whether the patients had anti-HCV antibodies in their sera before the operation. The subjects in these studies thus might have included patients without HCV viremia at the time of or after the operation.In patients infected with HCV, cirrhosis with chronic inflammation, liver cell necrosis and regeneration, and extensive fibrosis are important in the development of HCC.14-18) HCC tends to develop or to become detectable when DNA synthesis increases in patients with HCVassociated cirrhosis. Increased DNA synthesis in hepatocytes also appears to accelerate recurrence after resection for HCC in patients with HCV-associated cirrhosis. 19) We have found that a high spermidine/spermine ratio, which is closely related to cell proliferation, in the noncancerous hepatic tissue is a risk factor for recurrence after liver resection for HCC.20) It has also been reported that the sustained elevation of the serum alanine aminotransferase (ALT) activity in HCV...

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“…One of the major reasons for this poor prognosis is the high rate of recurrence, which is 20% to 40% within 1 year, and about 80% in 5 years after curative operation in Japan. [2][3][4][5] HCC recurrence may be the result of intrahepatic metastasis (IM) or independent multicentric occurrence (MO). Discrimination between the two is important not only for the study of hepatocarcinogenesis, but also for determination of therapeutic strategies.…”

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Determination of the Clonal Origin of Multiple Human Hepatocellular Carcinomas by Cloning and Polymerase Chain Reaction of the Integrated Hepatitis B Virus Dna

et al. 1999

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The poor prognosis of hepatocellular carcinoma (HCC) is partly the result of the high rate of recurrence that is caused either by intrahepatic metastasis (IM) or independent multicentric occurrence (MO). For convenience, discrimination of IM and MO is based on pathological findings, but reliable parameters are not sufficiently established. In the case of hepatitis B virus (HBV)-associated HCC, molecular discrimination of IM from MO can be achieved by comparison of integrated HBV DNAs. However, Southern blotting cannot be used for this purpose when one tumor is saved in frozen form and the other is in paraffin-embedded form. To solve this problem, we employed polymerase chain reaction (PCR) assays to confirm the clonality of primary and recurrent tumors. From the frozen tissue, we determined the junction between the integrated HBV and flanking genomic DNA by molecular cloning, and checked the existence of an identical junction in the DNA of paraffinembedded tissue by PCR. Using this method, as well as Southern blotting, we proved in 6 of 8 patients that two nodular HCC lesions resected metachronously or simultaneously were caused by MO, while the remaining 2 cases were caused by IM. In 1 IM case, band patterns between two HCCs detected by Southern blotting were not identical. (HEPATOLOGY 1999;29:1446-1452.) Hepatocellular carcinoma (HCC), one of the most common cancers in many parts of the world, is the third-leading cause of death from malignancy in Japan. In 1995, HCC was responsible for about 30,000 deaths, and the number of deaths continues to increase in Japan. 1 Improvement in imaging modalities and strict follow-up of patients with hepatitis B virus (HBV) or hepatitis C virus, including measurement of serum tumor markers, allows early detection of HCCs. In spite of technical advances in the treatment of HCC, such as surgical resection, percutaneous ethanol injection therapy, and microwave coagulation therapy, the longterm survival rate is still low. One of the major reasons for this poor prognosis is the high rate of recurrence, which is 20% to 40% within 1 year, and about 80% in 5 years after curative operation in Japan. 2-5 HCC recurrence may be the result of intrahepatic metastasis (IM) or independent multicentric occurrence (MO). Discrimination between the two is important not only for the study of hepatocarcinogenesis, but also for determination of therapeutic strategies. Some groups have reported that HCC with IM recurs earlier and has a poorer prognosis than its MO counterpart. 2,6 Aggressive therapy may not be warranted in cases with widespread metastatic dissemination, but in cases with MO, intervention should be taken within the limits of liver functional reserve. The diagnosis of IM or MO is mainly based on pathological findings as reported by the Liver Cancer Study Group of Japan 7 with modifications, 6,[8][9][10][11] or on the analysis of HBV-DNA integration by Southern blotting in cases of HBV-associated HCC. 8,[12][13][14][15][16][17][18] The pathological criteria for MO reflect the multiste...

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Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma

Cited by 365 publications

References 26 publications

Increased Extracellular Matrix Remodeling Is Associated With Tumor Progression in Human Hepatocellular Carcinomas

Increased Extracellular Matrix Remodeling Is Associated With Tumor Progression in Human Hepatocellular Carcinomas

Effects of Continuous Hepatitis with Persistent Hepatitis C Viremia on Outcome after Resection of Hepatocellular Carcinoma

Determination of the Clonal Origin of Multiple Human Hepatocellular Carcinomas by Cloning and Polymerase Chain Reaction of the Integrated Hepatitis B Virus Dna

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