Solitary Large Hepatocellular Carcinoma Research Articles

Surgery Versus Transarterial Chemoembolization for Solitary Large Hepatocellular Carcinoma of BCLC Stage A

Background/AimsThe aim of this study was to compare the outcomes of surgery and transarterial chemoembolization (TACE) for a solitary huge hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage A. MethodsOne hundred twenty-three consecutive patients with a solitary large (>5 cm) HCC classified at the BCLC stage A were analyzed. The posttreatment survival outcomes of patients that underwent surgery or TACE were compared. ResultsThe median age was 58 years (range, 29–90 years). The most common cause of HCC is hepatitis B virus infection (61.8 %). Median tumor size was 8.0 cm (range, 5.1–25 cm), and 97 patients (78.9 %) were of Child–Turcotte–Pugh class A. Median posttreatment follow-up duration was 18 months (range, 0.1–136 months). Of the 123 patients, 62 (50.4 %) underwent surgery and 61 (49.6 %) underwent TACE. Cumulative overall survival rates in the surgical group at 1, 3, and 5 years were significantly higher than those in the TACE group (83.2, 75.7, and 65.0 % vs 68.5, 45.0, and 17.5 %, respectively, P < 0.01). In subgroup analysis, the cumulative overall survival in both surgical groups was significantly greater than in corresponding TACE subgroups (P = 0.04 for ≥8-cm subgroup and P < 0.01 for 5- to 8-cm-sized subgroups). Multivariate analysis showed that a larger tumor size (≥8 cm) (hazard ratio [HR] 2.14, P = 0.02) was significantly associated with posttreatment mortality, whereas surgery (HR 0.37, P < 0.01) compared with TACE was inversely associated with posttreatment mortality. ConclusionsSurgery may be the more effective treatment modality than TACE for a solitary large HCC of the BCLC stage A, regardless of tumor size.

SIN1 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial‐mesenchymal transition

Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is essential for early embryonic development and is the key regulator of Akt, which plays an important role in various pathological conditions such as cancer. However, the biological function and clinical significance of SIN1 in hepatocellular carcinoma (HCC) remains unknown. Real-time quantitative reverse-transcriptase polymerase chain reaction analysis, western blot analysis, and immunohistochemical staining were used to test the expression level of SIN1, and its correlation with clinicopathologic parameters as well as the prognosis for patients with HCC were analyzed. In addition, the biological function and molecular mechanisms of SIN1 in HCC were investigated. SIN1 levels were elevated predominantly in HCC tissues, and its level in solitary large HCC was significantly lower than those in nodular HCC (P = .016), but showed no significant differences between solitary large HCC and small HCC (P > .05). Levels of SIN1 were up-regulated in highly metastatic HCC cell lines (HCCLM3 and MHCC97-H), whereas their invasion and migration significantly decreased after depletion of SIN1. High expression of SIN1 was associated with tumor number (P = .012), capsular formation (P = .037), and venous invasion (P = .023) and was an independent risk factor for overall survival (P = .046). Finally, SIN1 was capable of promoting invasion and metastasis of HCC by facilitating epithelial-mesenchymal transition. The current findings suggest that SIN1 plays an important role in HCC invasion and metastasis by facilitating epithelial-mesenchymal transition.

Complete tumor encapsulation on magnetic resonance imaging: A potentially useful imaging biomarker for better survival in solitary large hepatocellular carcinoma

The aim of this study was to determine the prognostic value of complete tumor encapsulation as visualized on magnetic resonance imaging (MRI) in patients with a solitary large hepatocellular carcinoma (HCC) beyond the Milan criteria for liver transplantation (LT). Between December 2000 and March 2011, 57 patients who had a solitary HCC exceeding 5 cm in diameter at the time of initial MRI before any treatment were identified. MRI images of the patients were independently reviewed by 2 experienced readers for the presence of complete tumoral encapsulation. The medical records of the patients were reviewed for an outcome analysis. Thirty of the 57 patients had completely encapsulated HCC according to MRI. There was excellent interobserver agreement between the 2 readers for the assessment of complete encapsulation (κ=0.86). Overall survival was significantly longer for patients with completely encapsulated HCC versus patients with incompletely or nonencapsulated tumors (P<0.001), and this included a subanalysis of 33 patients who received locoregional treatment (LRT; P=0.04). The presence of complete encapsulation was a strong predictor for survival in these patients according to both univariate [hazard ratio (HR)=0.24, 95% confidence interval (CI)=0.12-0.52, P<0.001] and multivariate analyses (HR=0.25, 95% CI=0.07-0.85, P=0.03). The rates of down-staging (P<0.001) and eventual LT (P=0.02) after LRT were also significantly higher in the patients with completely encapsulated tumors. In conclusion, complete tumor encapsulation on MRI is a potentially useful predictor for favorable biology in patients with a solitary large HCC. This new imaging biomarker may have a role in treatment selection for patients whose tumors exceed the Milan criteria size limits.

Prognostic factors of solitary large hepatocellular carcinoma: The importance of differentiation grade

Aims Solitary large hepatocellular carcinoma (SL-HCC), a novel subtype with relative good prognosis, has recently been defined. However, the concept has not been validated. Besides, prognostic factors of SL-HCC remain unknown. The present study is designed to address the issues. Materials and methods Clinicopatholical variables and survival of consecutive 85 patients with SL-HCC after curative resection are compared with those of 48 patients with small HCC (SHCC). The prognosticators of SL-HCC are also evaluated. Results Disease-free survival of SL-HCC is similar with that of SHCC, whereas significant poorer overall survival is observed in SL-HCC than that in SHCC, accompanied by more frequent vascular invasion, later TNM stage and potentially higher Edmondson–Steiner grade. Vascular invasion, Edmondson–Steiner grade, TNM stage and preoperative AFP level impact overall and/or disease-free survival of SL-HCC, but only Edmondson–Steiner grade is independent. Additionally, differences in both overall and disease-free survival between SL-HCC with Edmondson–Steiner grade I-II and SHCC are all not significant. Conclusions Factors predictive for prognosis of SL-HCC are all tumor-related. The involvement of differentiation grade might be helpful for further distinguishing a particularly good outcome in SL-HCC.

Solitary Large Hepatocellular Carcinoma

To evaluate and compare the clinical and pathologic characteristics and outcomes after hepatic resection of large hepatocellular carcinoma (SLHCC), small HCC (SHCC), and nodular HCC (NHCC). Traditional viewpoint insists that the classification and prognosis of HCC are determined by the size of HCC. As a result, large HCC is often considered as advanced and unresectable. However, we have observed a unique type of HCC-SLHCC, which is large in size but exhibits good clinical, pathologic, and molecular biologic characteristics as well as prognosis. From January 1992 to December 2002, a total of 481 consecutive patients were diagnosed with HCC and received hepatic resection. In this series of patients, the clinical and pathologic data, surgical outcome, and long-term survival of patients with SLHCC (group A, n = 260) were analyzed retrospectively and compared with patients who had SHCC (group B, n = 135) or NHCC (group C, n = 86). Postresection prognostic factors of HCC were also evaluated by univariate and multivariate analysis using Cox's proportional hazards model. The clinical and pathologic characteristics of SLHCC and SHCC were similar except for tumor necrosis and tumor size. Patients of SLHCC had significantly longer operative time, higher intraoperative blood loss, higher intraoperative blood transfusion, and higher postoperative morbidity than SHCC. However, the 2 groups were similar in duration of hospital stay and overall morbidity. Overall survival and disease-free survival in group A and group B were similar and significantly better than those in group C. Multivariate analysis revealed that large amount of intraoperative blood transfusion and vein invasion were independently significant factors for overall survival of patients with HCC. The clinical and pathologic characteristics and the outcome after hepatic resection of SLHCC are similar to that of SHCC, but significantly better than NHCC. We propose SLHCC as a specific subtype of HCC and hepatic resection as its choice of standard treatment.

Role of a hepatectomy for the treatment of large hepatocellular carcinomas measuring 10 cm or larger in diameter

A curative hepatectomy is the mainstay of effective treatment for small hepatocellular carcinoma (HCC), but the treatment of large HCC remains challenging. The possible prognostic factors were retrospectively analyzed in 85 patients with large HCC (> or = 10.0 cm) who all underwent a hepatectomy for HCC between 1988 and 2004. A survival analysis was made by classifying the tumors into four spreading patterns according to the number of tumors and the presence of macroscopic tumor thrombus. A positive hepatitis B antigen, the earlier period of hepatectomy, a non-curative hepatectomy, multiple tumors, and portal vein invasion were identified as independent predictors of a poor prognosis. The median survival term and 5-year survival rate of patients with a solitary large HCC without a macroscopic tumor thrombus was 9.8 years and 69.8%, respectively. The tumor spreading patterns according to the number of tumors and the presence of a macroscopic tumor thrombus were statistically associated with a non-curative hepatectomy (p < 0.001). There was a statistical difference among 33 patients with large HCC undergoing a non-curative hepatectomy based on the presence of a macroscopic portal vein invasion (p = 0.0089). A hepatectomy could yield an excellent long-term survival in patients with a solitary large HCC without a macroscopic tumor thrombus. Even if a curative hepatectomy could not be achieved, a hepatectomy might provide better survival in large HCC patients without a macroscopic tumor thrombus compared in those with macroscopic tumor thrombus.

Expression and significance of ADAM17 mRNA in solitary large hepatocellular carcinoma

目的 探讨ADAM17(a disintegrin and metalloproteinase 17, ADAM17)mRNA在孤立性大肝癌(SLHCC)中的表达及其与病理特征的关系.方法采用逆转录多聚酶链式反应(RT-PCR)半定量检测8例SLHCC、12例小肝癌(SHCC),11例结节性肝癌(NHCC)以及相应癌旁肝组织中ADAM17 mRNA的表达.结果 NHCC的静脉浸润(83.3%)明显多于SLHCC和SHCC,其分化程度也较SLHCC和SHCC差(P<0.05),而比较SLHCC和SHCC的病理特征未见明显差异.77.4%的肝癌组织中可见ADAM17 mRNA表达,明显高于癌旁肝组织(35.5%).NHCC中ADAM17 mRNA的表达高于SLHCC和SHCC(P<0.05).分化较差的肝癌中ADAM17 mRNA表达高于分化较好的肝癌(P<0.05).结论 ADAM17 mRNA的表达与肝癌的分化程度密切相关.而SLHCC表达ADAM17 mRNA相对较低可能与SLHCC相对良好的分子病理特征有关。

Clinical analysis of the risk factors for recurrence of HCC and its relationship with HBV

To comprehend the risk factors of recurrence of hepatocellular carcinoma (HCC) and its relationship with the infection patterns of hepatitis B virus (HBV). All materials of 270 cases of postoperative HCC were statistically analyzed by SPSS software. Recurrence and metastasis were classified into early (< or =2 years) and late phase (>2 years). Risk factors for recurrence and metastasis after surgery in each group were analyzed. Out of 270 cases of HCC, 162 cases were followed up in which recurrence and metastasis occurred in 136 cases. There were a lot of risk factors related to recurrence and metastasis of HCC; risk factors contributing to early phase recurrence were serum AFP level, vascular invasion, incisal margin and operative transfusion, gross tumor classification and number of intrahepatic node to late phase recurrence. The HBV infective rate of recurrent HCC was 94.1%, in which "HBsAg, HBeAb, HbcAb" positive pattern reached 45.6%. The proportion of HBV infection in solitary large hepatocellular carcinoma (SLHCC) evidently decreased compared to nodular hepatocellular carcinoma (NHCC) (P<0.05). The early and late recurrence and metastasis after hepatectomy of HCC were associated with different risk factors. The early recurrence may be mediated by vascular invasion and remnant lesion, the late recurrence by tumor's clinical pathology propert, as multicentric carcinogenesis or intrahepatic carcinoma de novo. HBV replication takes a great role in this process. From this study, we found that SLHCC has more satisfactory neoplasm biological behavior than NHCC.

Genomic analysis reveals RhoC as a potential marker in hepatocellular carcinoma with poor prognosis.

Hepatocellular carcinoma (HCC) is one of the most malignant human tumours because of its high incidence of metastasis. The mechanisms underlying the metastasis of HCC, however, remain poorly understood. In this study, we performed cDNA microarray analysis to profile gene expression patterns in two subtypes of HCC, solitary large HCC (SLHCC) and nodular HCC (NHCC), which differ significantly in the incidence of metastasis. Among 668 genes that were differentially expressed, we focused on RhoC, whose expression was significantly decreased in SLHCC compared to NHCC. The expression of RhoC in HCC and pericarcinomatous liver tissues (PCLT) was analysed at both the mRNA and protein levels by reverse transcription–polymerase chain reaction (RT–PCR) and Western blotting. In addition, immunohistochemistry was also performed on 94 cases of HCC with follow-up information. Collectively, our data indicate that the expression of RhoC significantly increased in HCC compared to PCLT; extrahepatic metastatic lesions expressed significantly higher levels of RhoC than the corresponding intrahepatic HCC tissues. There is a highly significant correlation of the RhoC expression levels with tumour vein invasion, number of tumour nodes and the status of differentiation. Significantly, the HCC patients with RhoC-positive expression had shorter survival than those with RhoC-negative expression. Together, our findings suggest a strong correlation between the expression of RhoC and HCC metastasis, implicating RhoC as a potential prognosis marker and therapeutic target for HCC.

MVD and expression of integrin αv subunit and MMP-2 in solitary large hepatocellular carcinoma and their clinical significance

目的 研究单结节原发性大肝癌的病理特征及与侵袭转移相关的分子标志物表达情况,以探讨其生物学特征.方法比较20例单结节大肝癌与13例小肝癌、10例多结节肝癌的病理特征,用免疫组化方法检测并比较这三组肝癌中整合素αv亚基、基质金属蛋白酶2(matrix metalloproteinase-2, MMP-2)的表达及肿瘤微血管密度(microvessel density, MVD).结果单结节大肝癌的肝硬化、细胞分化程度明显较多结节肝癌轻和好(P＜0.05),而癌组织坏死较小肝癌明显(P＜0.05).整合素αv亚基、MMP-2的表达及MVD值在单结节肝癌中比在多结节肝癌中弱或低(P＜0.05).结论单结节大肝癌比多结节者有相对良好的生物学行为特征,而与小肝癌相近。

ADAM17 mRNA expression and pathological features of hepatocellular carcinoma.

To study the expression of a disintegrin and metalloproteinase 17 (ADAM17) mRNA in hepatocellular carcinoma (HCC) and to evaluate the relationship between ADAM17 mRNA expression and clinicopathological features of HCC. Hepatocellular carcinomas (HCC) from 31 cases were divided into small HCC (SHCC), nodular HCC (NHCC) and solitary large HCC (SLHCC) according to tumor diameter and the number of nodes. ADAM17 mRNA expressions were compared among those groups by means of semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The relationship between ADAM17 mRNA expression level and clinicopathological features of HCC was evaluated. NHCC had lower differentiation and was more frequently of microvascular invasion (10/12) than SHCC (3/11) and SLHCC (3/8) (P<0.05), but no statistical difference was observed between SHCC and SLHCC comparing their clinicopathological features. ADAM17 mRNA expression was detected in 77.4% (24/31) of HCC tissues and was significantly higher than that in paired non-cancerous liver tissues in which only 35.5% (11/31) of the samples were detected of the expression (P<0.05). The expression of ADAM17 mRNA was much higher in NHCC than in SHCC and SLHCC (P<0.05), while no significant difference was discovered between SHCC and SLHCC. The quantities of ADAM17 mRNA were significantly higher in poorly differentiated HCC than in well or moderately differentiated HCC, but no statistical difference was found concerning liver cirrhosis, tumor capsule formation or microvascular invasion of the cancer. The increased expression of ADAM17 may play a key role in the development of HCC. The expression levels of ADAM17 mRNA varied among different pathological types of HCC. Lower mRNA expression of ADAM17 mRNA in SLHCC may be associated with the better molecular pathological features of SLHCC.

Expressions of cysteine-rich61, connective tissue growth factor and Nov genes in hepatocellular carcinoma and their clinical significance

To investigate the expression of cysteine-rich61 (Cyr61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed gene (Nov) in hepatocellular carcinoma (HCC), and to evaluate the relationship between Cyr61, CTGF and Nov genes expression with invasion and metastasis of HCC. Thirty-one HCC specimens were divided into small hepatocellular carcinoma (SHCC), nodular hepatocellular carcinoma (NHCC), solitary large hepatocellular carcinoma (SLHCC) according to their diameter and number of nodes. Reverse transcription polymerse chain reaction (RT-PCR) was used to detect the mRNA expression levels of Cyr61, CTGF and Nov genes in 31 resected specimens of hepatocellular carcinoma and para-cancerous normal liver tissues semi-quantitatively and the relation between their expression levels and clinical pathological parameters were compared. The expressions of Cyr61 and CTGF mRNA in carcinoma tissues were significantly higher than those in para-cancerous normal liver tissues (P<0.01). The expressions of Cyr61 and CTGF mRNA in HCC with venous invasion were higher than those in HCC without venous invasion. CTGF expression in HCC Edmondson's grade III-IV was significantly higher than that in HCC Edmondson's grade I-II (P = 0.022). There was no obvious correlation between Nov mRNA and clinical-pathological features. Compared to NHCC, SLHCC had better cell differentiation, easier capsule formation, less microscopic venous invasion, milder liver cirrhosis. The expressions of Cyr61 and CTGF mRNA in NHCC were significantly higher than those in SLHCC and SHCC. Cyr61 and CTGF genes may play an important role in hepatocellular carcinogenesis and correlate with recurrence and metastasis of hepatocellular carcinoma. SLHCC has better biological behaviors than NHCC.

Differentially expressed genes between solitary large hepatocellular carcinoma and nodular hepatocellular carcinoma

To study the difference in gene expression between solitary large hepatocellular carcinoma (SLHCC) and nodular hepatocellular carcinoma (NHCC). Polymerase chain reaction (PCR) products of 8464 human genes were spotted on a chip in array. DNAs were then fixed on a glass plate. Total RNA was isolated from freshly excised human SLHCC (n = 7) and NHCC (n = 15) tissues, and was reversely transcribed to cDNAs with the incorporation of fluorescent dUTP for preparation of hybridization probes. The mixed probes were then hybridized to the cDNA microarray. After highly stringent washing, cDNA microarray was scanned for the fluorescent signals to display the difference between the two kinds of HCC. In addition, the expression of RhoC and protocadherin LKC was also detected with the reverse transcriptase polymerase chain reaction (RT-PCR) method. Among the 8464 human genes, 668 (7.89%) genes were expressed differentially at the mRNA levels between SLHCC and NHCC. Three hundred and fifty five (4.19%) genes, including protocadherin LKC, were up-regulated, whereas 313 (3.70%) genes, including RhoC, were down-regulated. The mRNA expression levels of RhoC and protocadherin LKC were confirmed by RT-PCR. Analysis of differentially expressed genes confirmed that our molecular data obtained by cDNA microarray were consistent with the published biochemical and clinical observations of SLHCC and NHCC. cDNA microarray is an effective technique in screening the difference in gene expression between SLHCC and NHCC. Many of these differentially expressed genes are involved in the invasion and metastasis of HCC. Further analysis of these genes will help to understand the different molecular mechanisms of SLHCC and NHCC.

Hepatocellular carcinoma: long-term results of combined treatment with laser thermal ablation and transcatheter arterial chemoembolization.

To determine the potential long-term effectiveness of laser thermal ablation (LTA) followed by transcatheter arterial chemoembolization (TACE) in the percutaneous ablation of large hepatocellular carcinoma (HCC). Thirty large HCCs 3.5-9.6 cm in diameter (mean diameter, 5.2 cm) and 15 small HCCs 0.8-3.0 cm (mean diameter, 1.9 cm) were treated with ultrasonographically guided LTA with TACE and with LTA alone, respectively, in 30 patients: 19 with a solitary large HCC, and 11 with one to three additional synchronous small HCCS: A 1.064-microm neodymium yttrium-aluminium-garnet (Nd-YAG) laser at a power of 5.0 W was coupled with one to four quartz optic fibers that were advanced through 21-gauge needles. Segmental TACE was performed 30-90 days after LTA. All lesions were evaluated for change in size at computed tomography (CT), alpha-fetoprotein (AFP) levels, recurrence rates, and cumulative survival rates. No major complications occurred in 127 LTA sessions. CT showed complete tumor necrosis in 27 (90%) of 30 large HCCS: Twenty-eight patients were followed up for 6-41 months (mean, 17.1 months). In 25 patients, all lesions appeared stable or smaller at CT. AFP levels decreased to the normal range in all patients with high pretreatment values. The 1-, 2-, and 3-year local recurrence rate was 7% in large HCCS: Complete tumor necrosis was achieved in all 15 (100%) small HCCs; none of them recurred locally. The 1-, 2-, and 3-year cumulative survival rates were 92%, 68%, and 40%, respectively. LTA followed by TACE is an effective palliative therapy in treating large HCCS:

Hepatocellular carcinoma: treatment with percutaneous ethanol injection and transcatheter arterial embolization.

The therapeutic effectiveness of a new combination therapy--pretreatment with transcatheter arterial embolization (TAE) and subsequent percutaneous ethanol injection (PEI)--for solitary large (> 3.0 cm in diameter) primary hepatocellular carcinoma lesions was compared with that of TAE alone. With TAE alone, a partial response of the tumor was seen in only 10% of the patients, and the 1-, 2-, and 3-year survival rates were calculated to be 68%, 37%, and 0%, respectively. Histologic examination of specimens obtained at hepatectomy showed that TAE alone caused complete necrosis in only 20% of the tumors. In contrast, PEI combined with TAE significantly (P < .05) increased the partial response rate (45%) and significantly (P < .01) prolonged the 1-, 2-, and 3-year survival rates (100%, 85%, and 85%, respectively). Combination therapy caused complete histologic necrosis in 83% of the tumors. It also was significantly (P < .05) better than TAE alone in terms of rate of primary tumor recurrence during follow-up.