Staging systems for hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma(HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient’s underlying liver disease and liver functional reserve. Moreover, thereis considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems.     

Inhibitory effect of the angiogenesis inhibitor TNP-470 on tumor growth and metastasis in nude mice bearing human hepatocellular carcinoma

The antitumor and anti-metastatic effects of a potent angiogenesis inhibitor,O-(chloroacetyl-carbamoyl)fumagillol (TNP-470), was investigated in a highly metastatic model of human hepatocellular carcinoma—LCI-D20. Small pieces of LCI-D20 tumor tissue were implanted subcutaneously into the right axillary region of 24 nude mice; the mice were then randomized into two groups. To one group, TNP-470 30 mg/kg was given as a subcutaneous injection every other day from day 1 to day 15 and the mice were sacrificed on day 26. An antitumor effect of TNP-470 was clearly demonstrated by tumor weight (0.97±0.34 g compared to 2.04±0.34 g,P<0.001) and -Fetoprotein value (93±59 g/L compared to 769±282 g/L,P<0.001). There was also an anti-metastatic effect of TNP-470. Lung metastases developed in only 1 of 12 mice in the treated group, while they developed in 6 of mice of the control group. No severe side-effect of TNP-470 was found in this study. In vitro study revealed that the purified hepatoma cells were insensitive to TNP-470 (the 50% inhibitory concentration was 43 g/ml). These results suggest that the angiogenesis inhibitor TNP-470 has both strong antitumor and anti-metastatic effects on a human hepatocellular carcinoma model in nude mice.Abbreviations TNP-470 O-(chloroacetyl-carbamoyl) Fumagillol - MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide This work was partly supported by the CHina Medical Board of New York, grant 93-583, and a Leading Speciality grant of Shanghai Health Bureau     

Metastatic recurrence to a solitary lymph node four years after hepatic lobectomy for primary hepatocellular carcinoma

This report describes a patient that developed recurrent metastatic hepatocellular carcinoma (HCC) to a suprapancreatic lymph node four years after being treated for primary HCC via complete left hepatectomy. Metastatic HCC was proven by pathologic confirmation. The report addresses the role of surgical resection as a treatment modality for recurrent HCC to solitary lymph nodes. The role of biological chemotherapy as adjuvant treatment is also addressed.     

肝细胞癌在血中微小转移的检测

目的 肝细胞癌患者术后复发常是术前不能检出微转移灶或术中癌细胞释放入血之故。建立早期检出肝细胞癌（HCC）血中微小转移的方法并评价其临床意义。方法 采用巢式RT－PCR检测肝细胞特异白蛋白（ALB）mRNA和甲胎蛋白（AFP）mRNA在HCC患者外周血有核细胞成分及组织标本中的表达情况。并以肝癌细胞系HepG2、SMMC7721,乳腺癌细胞MCF－7作为阳性，阴性对照。结果 在肝组织，无论是癌、癌旁还是正常组织，ALB mRNA的表达均为阳性（8／8），而AFP mRNA在癌组织7／8例表达，癌旁5／8例表达。外周血表达的情况为：同一组标本ALB mRNA的阳性率为75.6%（34／45，P＜0．01），AFPmRNA的阳性率为57．8％（26／45，P＜0．01）。在有肝外转移和无肝转移分组中，ALBmRNA和AFPmRNA的表达分别为100．0％，54．2％和29．2％。结论 在HCC患者外周血有核心细胞成分中检测ALBmRNA和AFPmRNA的表达，是预测转移、复发的简捷手段，若ALB与AFP二者联合使用，应用性会更强。     

A proposal of the modified liver damage classification for hepatocellular carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the validity of the two common classifications for assessing liver function; the Child-Pugh classification and the liver damage classification. We also examined the feasibility of the modified liver damage classification. METHODS: A total of 2306 HCC patients diagnosed between 1990 and 2002 were categorized according to the three classifications. The modified liver damage classification is calculated by summation of the scores for five variables (serum bilirubin level, serum albumin level, prothrombin activity, ICG retention rate at 15min, ascites) of the liver damage classification and classified patients into grades A-C in the similar manner as the Child-Pugh classification. The differences in distribution and survival rate of the patients in each group were compared. RESULTS: With respect to the patient distribution, 1787 (77.5%) and 469 (20.3%) patients were categorized into Child-Pugh grades A and B, respectively, whereas 1187 (51.5%) and 962 (41.7%) patients were categorized into liver damage grades A and B, respectively. As a result of this disproportionate distribution, survival rates of Child-Pugh grades A and B were lower than those of the liver damage grades A and B. Furthermore, some discrepancies were found in the distribution of patients between the liver damage classification and the modified liver damage classification. One hundred and forty-one patients of the 1187 liver damage grade A patients were categorized into grade B by the modified liver damage classification and 71 patients of the 962 liver damage grade B patients were categorized into grade C by the modified liver damage classification. The survival rates of these subgroups were similar to those of the liver damage grades B and C, respectively. CONCLUSION: The modified liver damage classification appears to be the best available tool for assessing residual liver function, for estimating the survival of Japanese HCC patients and for making decisions concerning the treatment of these patients.     

Inflammation scores predict survival for hepatitis B virus-related hepatocellular carcinoma patients after transarterial chemoembolization

AIM:To compare the prognostic ability of inflammation scores for patients with hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC)undergoing transarterial chemoembolization(TACE).METHODS:Data of 224 consecutive patients who underwent TACE for unresectable HBV-related HCC from September 2009 to November 2011 were retrieved from a prospective database.The association of inflammation scores with clinicopathologic variables and overall survival(OS)were analyzed,and receiver operating characteristic curves were generated,and the area under the curve(AUC)was calculated to evaluate the discriminatory ability of each inflammation score and staging system,including tumor-node-metastasis,Barcelona Clinic Liver Cancer,and Cancer of the Liver Italian Program(CLIP)scores.RESULTS:The median follow-up period was 390 d,the one-,two-,and three-year OS were 38.4%,18.3%,and 11.1%,respectively,and the median OS was 390d.The Glasgow Prognostic Score(GPS),modifed GPS,neutrophil-lymphocyte ratio,and Prognostic Index were associated with OS.The GPS consistently had a higher AUC value at 6 mo(0.702),12 mo(0.676),and24 mo(0.687)in comparison with other inflammation scores.CLIP consistently had a higher AUC value at6 mo(0.656),12 mo(0.711),and 24 mo(0.721)in comparison with tumor-node-metastasis and Barcelona Clinic Liver Cancer staging systems.Multivariate analysis revealed that alanine aminotransferase,GPS,and CLIP were independent prognostic factors for OS.The combination of GPS and CLIP(AUC=0.777)was superior to CLIP or GPS alone in prognostic ability for OS.CONCLUSION:The prognostic ability of GPS is superior to other inflammation scores for HCC patients undergoing TACE.Combining GPS and CLIP improved the prognostic power for OS.     

Predictive value of gross classification of hepatocellular carcinoma on recurrence and survival after hepatectomy

BACKGROUND/AIM: A new gross classification of hepatocellular carcinoma in which Eggel's nodular type is subclassified into type 1 (single nodular type), type 2 (single nodular type with extranodular growth), and type 3 (contiguous multinodular type) has been widely used in Japan. The aim of the study was to determine whether this classification is correlated with patient outcome. METHODS: Sixty-five resected hepatocellular carcinoma nodules (< or = 5 cm) were classified using this new classification. RESULTS: The 65 tumors were classified into 30 type 1 (46%), 20 type 2 (31%), and 15 type 3 (23%) hepatocellular carcinomas. The rate of microscopic vascular invasion significantly increased from type 1 to type 2, and to type 3 tumors (p=0.03). Kaplan-Meier estimates showed that type 1 was significantly associated with lower recurrence rate (type 1 vs. type 2, p=0.01; type 1 vs. type 3, p=0.004; log-rank test), and higher disease-specific survival (type 1 vs. type 2, p=0.02; type 1 vs. type 3, p=0.002). Cox's proportional-hazards model demonstrated that type 1 was an independent factor for low risk of recurrence (p=0.002) and low risk of disease-specific death (p=0.02). CONCLUSION: The gross classification of hepatocellular carcinoma is of clinical value in predicting patient outcome.     

类胰岛素生长因子与肝癌

肝癌是常见的恶性肿瘤之一,其病程快且预后很差.其发生是一个多因素多步骤协同的复杂过程.近来的研究报道,肝癌发生分子机制与类胰岛素生长因子体系信号通路异常相关,类胰岛素生长因子是一种多功能细胞增殖调控因子,他在胚胎发育、中枢神经系统发育及肿瘤细胞增殖等方面具有重要的生物学功能.类胰岛素生长因子的生物学活性受到包括类胰岛素...     

The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma

We aimed to evaluate the prognostic value of preoperative plasma osteopontin (OPN) levels in 101 patients with hepatocellular carcinoma (HCC) who underwent liver resection. Plasma OPN levels were detected by ELISA. The association of plasma OPN levels of patients with clinicopathological characteristics, tumor recurrence, and survival was analyzed. The median plasma OPN level of patients was 176.90 ng/ml (range 13.73–780.00 ng/ml), which was significantly higher than that of 24 healthy volunteers (63.74 ng/ml, range 12.20–122.32 ng/ml). Plasma OPN levels were significantly different in patients with different numbers of tumor nodules (168.18 and 217.11 ng/ml for single and multiple nodules, respectively; P = 0.002), different Edmondson’s grades (201.24, 168.36, and 503.58 ng/ml for grades I, II, and III/IV, respectively; P = 0.015), and different TNM stages (168.16, 167.54, and 216.18 ng/ml for stages I, II, and III/IV, respectively; P = 0.016). Significantly higher plasma OPN levels were found in patients with a recurrence of HCC after resection, compared with those without recurrence (213.55 versus 153.70 ng/ml; P = 0.0013). A higher plasma OPN level was a leading independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in univariate and multivariate Cox models. This suggests that the preoperative plasma OPN level can be used as a predictive marker for HCC recurrence and may be helpful to assess the prognosis of patients with HCC after surgery.     

肝细胞癌四种临床分期系统预后判断和治疗指导价值的比较

目的 比较4个分期系统[巴塞罗那临床肝癌分期标准(BCLC)、日本综合分期积分(JIS)、意大利肝癌评分(CLIP)和国内分期]对中国肝癌患者预后判断和对治疗方案选择的指导意义.方法 回顾性分析2001年至2002年复旦大学附属中山医院收治的861例初发肝细胞癌患者的临床资料,分别按4个分期系统分期或评分,比较各期患者的生存情况以及不同治疗方案对其生存的影响.结果 在判断预后方面,BCLC、JIS和国内分期系统的各分期间生存率差异均有统计学意义;而在CLIP分期的一些评分间的生存率差异无统计学意义.在指导治疗方面,BCLC C期,CLIP 3、4分以及国内分期ⅢA期的患者接受手术治疗与接受肝动脉化学治疗栓塞(TACE)和(或)肝动脉栓塞(TAE)治疗的生存率差异无统计学意义;而比这些更早期的患者接受手术治疗的生存率优于接受TACE和(或)TAE治疗的生存率.结论 BCLC、JIS和国内分期系统在判断预后方面适用于中国患者;但仅国内分期和BCLC分期同时兼备了判断预后和指导治疗两方面的作用.     

碱性成纤维细胞生长因子在肝细胞癌中的表达及意义

目的 探讨bFGF在肝细胞癌中的表达及其临床病理意义。方法 使用免疫组化SABC法检测41例肝细胞癌手术切除标本及5例外伤性肝破裂肝切取标本。结果 正常对照组bFGF均为阴性。肝细胞癌组bFGF阳性率为70．7％（29／41）。bFGF表达与患者年龄、性别、AFP是否阳性、HBsAg是否阳性无关（P＞0．05）；而与肝癌分化程度、有无癌栓、包膜是否完整有关。在高侵袭转移组与低侵袭转移组间，bFGF阳性率分别为86．4％和52．6％，差异具有显著性（P＜0．05）。结论 bFGF在肝细胞癌中高表达，可以作为判断肝癌恶性程度及转移潜能的参考指标。     

Safety of hepatectomy for elderly patients with hepatocellular carcinoma

The number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. Characteristics of elderly HCC patients are a higher proportion of females, a lower rate of positive hepatitis B surface antigen, and a higher rate of positive hepatitis C antibodies. Careful patient selection is vital for performing hepatectomy safely in elderly HCC patients. Treatment strategy should be decided by not only considering tumor stage and hepatic functional reserve, but also physiological status, including comorbid disease. Various assessment tools have been applied to predict the risk of hepatectomy. The reported mortality and morbidity rates after hepatectomy in elderly HCC patients ranged from 0% to 42.9% and from 9% to 51%, respectively. Overall survival rate after hepatectomy in elderly HCC patients at 5 years ranged from 26% to 75.9%. Both short-term and long-term results after hepatectomy for strictly selected elderly HCC patients are almost the same as those for younger patients. However, considering physiological characteristics and the high prevalence of comorbid disease in elderly patients, it is important to assess patients more meticulously and to select them strictly if scheduled to undergo major hepatectomy.     

Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma

ABM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100 patients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469,P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P=0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.     

Metastatic hepatocellular carcinoma of the external auditory canal

This report describes a rare case of metastatic hepatocellular carcinoma (HCC) presenting a huge mass in the left external auditory canal (EAC). The patient was a 55-year-old man with hepatitis B virus-related HCC. He presented to our department with a three-month history of increasing left otalgia,and hearing loss with recent fresh aural bleeding. Histopathologic examination indicated that the tumor was secondary to HCC. Although external irradiation was not effective,the tumor was treated with surgical debulking and high dose rate 192 Ir remote afterloading system (RALS) for postoperative intracavitary irradiation. A review of the literature revealed only five other cases of HCC metastasis to the temporal bone,all of which mainly metastasized in the internal acoustic meatus. The present case is the first report of HCC metastasis to the EAC.     

Chest wall metastasis from unknown primary site of hepatocellular carcinoma

Previous reports of a solitary metastatic hepatocellular carcinoma have been rare. Because this tumor has a different treatment modality and prognosis, an accurate differential diagnosis is essential. Here we report a rare case of a solitary chest wall metastasis from unknown primary site of hepatocellular carcinoma. It involves a 51-year-old man who was admitted to our hospital because of a palpable left upper chest wall mass. The mass was resected and pathologic examination confirmed a diagnosis of metastatic hepatocellular carcinoma. Despite our investigation, no evidence was found that indicated the primary origin of the hepatocellular carcinoma. Four months later, the patient was admitted again because of spinal cord compression at the third and fourth thoracic vertebrae. Emergent decompressive laminectomy was performed and microscopic features revealed the same pathology as the initial chest wall mass resected 4 months earlier. After one year, a follow-up abdominal computed tomography (CT) still revealed no evidence of primary hepatocellular carcinoma.     

Assessment of KL-6 as a tumor marker in patients with hepatocellular carcinoma

AIM: To investigate the clinical significance of KL-6 as a tumor marker of HCC in two different ethnic groups with chronic liver disease consecutively encountered at outpatient clinics. METHODS: Serum KL-6 was measured by the sandwich enzyme immunoassay method using the KL-6 antibody (Ab) as both the capture and tracer Ab according to the manufacturer's instructions (Eisai, Tokyo, Japan). Assessment of alpha fetoprotein (AFP) and protein induced vitamin K deficiency or absence (PIVKA-Ⅱ) was performed in both groups using commercially available kits. RESULTS: A significantly higher mean serum KL-6 (556±467 U/L) was found in HCC in comparison with non-HCC groups either with (391±176 U/L; P<0.001) or without (361±161 U/L; P<0.001) liver cirrhosis (LC). Serum KL-6 level did not correlate with either AFP or PIVKA-Ⅱ serU/Levels. Using receiver operating curve analysis for KL-6 as a predictor for HCC showed that the area under the curve was 0.574 (95%CI = 0.50-0.64) and the KL-6 level that gave the best sensitivity (61%) was found to be 334 U/L but according to the manufacturer's instructions; a cut-off point of 500 U/L was used that showed the highest specificity (80%) in comparison with AFP and PIVKA-Ⅱ (78% vs 72% respectively). Combining the values of the three markers improved specificity of AFP for HCC diagnosis from 78% for AFP alone; 93% for AFP plus PIVKA-Ⅱ to 99% for both plus KL-6 value (P<0.001). Mean serum alkaline phosphatase level was significantly higher in KL-6 positive (564±475) in comparison with KL-6 negative (505±469) HCC patients (P = 0.021), but such a difference was not found among non-HCC corresponding groups. CONCLUSION: KL-6 is suggested as a tumor for HCC. Its positivity may reflect HCC-associated cholestasis and/ or local tumor invasion.     

肝细胞癌的非手术治疗

肝细胞癌（HCC）是原发性肝癌的最主要类型。肝切除术可根治 HCC,使患者长期生存,但肝切除术受到一定的限制,主要在于：（1）肿瘤细胞恶性程度高、病情进展快,极易发生播散和转移;（2）HCC 患者多存在严重的肝硬化基础,因为肝功能失代偿而无法手术;（3）大部分肿瘤为多中心发生,很难切除完全。因此,切除率低和复发率高乃是制约手术治疗 HCC 患者的主要障碍。联合应用手术治疗与各种非手术治疗,多种方案的优化组合将成为综合治疗 HCC 患者的优先选择,提高疗效[1,2]。目前,常用的非手术治疗方法主要有肝动脉化疗栓塞（TACE）、局部消融、放射治疗、系统化疗和分子靶向治疗等。     

High level of intercellular adhesion molecule-1 affects prognosis of patients with hepatocellular carcinoma

AIM: To determine the cut-off value of intercellular adhesion molecule-1 (ICAM-1) and assess the correlation of ICAM-1 with clinicopathological features and the prognosis of hepatocellular carcinoma (HCC) patients who underwent surgical resection.METHODS: We prospectively collected clinicopathological data from 236 HCC patients who had undergone successful hepatectomy. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value of ICAM-1. Enzyme-linked immunosorbent assay was used to measure the concentration of ICAM-1 in 236 serum samples isolated from HCC patients and the stratified analysis was used to compare the serum level of ICAM-1 in different HCC subgroups. Immunohistochemistry was performed to test the expression level of the ICAM-1 protein in 76 cases of HCC tissues and their adjacent normal liver tissues (ANLT). The survival probability of HCC patients was estimated using Kaplan-Meier plots and differences between the groups were obtained using the log-rank test. Furthermore, independent indicators of the prognosis were acquired using a stepwise Cox proportional hazard model to analyze a series of predictors that were associated with disease-free survival (DFS) and overall survival (OS) in HCC patients.RESULTS: Our findings suggested that ICAM-1 promotes HCC metastasis and high serum ICAM-1 is significantly associated with alpha-fetoprotein (AFP) (P = 0.022), clinical tumor-node-metastasis stage (P < 0.001), portal vein tumor thrombus (P = 0.005), distant metastasis (P = 0.016) and recurrence (P = 0.034). We further detected the ICAM-1 protein in HCC specimens and found that 56 of 76 (73.7%) HCC tissues had ICAM-1 positive staining while only 23 of 76 (30.3%) ANLT were positively stained (P < 0.0001). Survival analysis indicated that HCC patients with increased ICAM-1 concentrations had significantly shorter DFS and OS after resection. A multivariate analysis showed that ICAM-1 > 684 ng/mL was an independent factor for DFS (HR = 1.643; 95%CI: 1.125-2.401; P = 0.010) and OS (HR = 1.692; 95%CI: 1.152-2.486; P = 0.007).CONCLUSION: ICAM-1 may be a promising serological biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection and may provide a useful reference for the prediction of intra- and extrahepatic metastasis.