Liver Cancer Study Group Of Japan Research Articles

Tumor budding may be a promising prognostic indicator in intrahepatic cholangiocarcinoma: A multicenter retrospective study.

This retrospective study evaluated our hypothesis that high tumor budding (≥10 buds) may help determine the appropriate T category for more accurate staging of intrahepatic cholangiocarcinoma (ICC). We analyzed the clinical and histopathologic data of 235 consecutive patients with histologically confirmed ICC following hepatectomy at five university hospitals in the Kansai region of Japan between January 2009 and December 2020. ICC staging was based on the Liver Cancer Study Group of Japan (LCSGJ) staging system, 6th edition. Patients with ICC with high budding showed significantly shorter disease-specific survival (DSS) and disease-free survival (DFS) than patients with low/intermediate budding. Cox proportional hazards regression analysis showed a hazard ratio of 2.2-2.3 (P < 0.05) for high budding. Based on these results, we modified the T category of ICC in the LCSGJ staging system by adding severity of tumor budding as a fourth determinant. This proposed staging system for ICC has significantly improved the prognostic accuracy for both DSS and DFS (both: P < 0.05). High tumor budding is a new candidate for an additional determinant of the T category in staging ICC. An LCSGJ staging system containing an additional evaluation of tumor budding may lead to improved staging accuracy.

The Impact of a Preoperative Staging System on Accurate Prediction of Prognosis in Intrahepatic Cholangiocarcinoma.

Simple SummaryNon-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. A newly invented PRE-Stage was developed using a CRP–albumin–lymphocyte index < 3, central tumor location, and CA19-9 level > 40 U/mL, and it was able to significantly predict DSS and DFS when the patients were stratified into four stages (p < 0.05). The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the Liver Cancer Study Group of Japan stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making.Background: Non-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. Methods: The clinical data of 227 consecutive patients with histologically confirmed ICC following hepatectomy at five university hospitals were analyzed. Results: Cox proportional hazards regression analysis of survival revealed that a CRP–albumin–lymphocyte index < 3, central tumor location, and CA19-9 level > 40 U/mL were prognostic factors among the preoperatively obtained clinical findings (hazard ratios (HRs) of all three factors for disease-specific survival (DSS) and disease-free survival (DFS: 2.4–3.3 and 1.7–2.9; all p < 0.05). The PRE-Stage was developed using these three prognostic factors, and it was able to significantly predict DSS and DFS when the patients were stratified into four stages (p < 0.05). In addition, the PRE-Stage resulted in similar HRs as those of the Liver Cancer Study Group of Japan (LCSGJ) stage (HRs for DSS: PRE-Stage, 1.985; LCSGJ stage, 1.923; HRs for DFS: LCSGJ stage, 1.909, and PRE-Stage, 1.623, all p < 0.05). Conclusion: The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the LCSGJ stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making.

Preoperative risk grade predicts the long-term prognosis of intrahepatic cholangiocarcinoma: a retrospective cohort analysis

BackgroundCumulating evidence indicates that the systemic inflammatory response (SIR) plays a crucial role in the prognosis of various cancers. We aimed to generate a preoperative risk grade (PRG) by integrating SIR markers to preoperatively predict the long-term prognosis of intrahepatic cholangiocarcinoma (ICC).Methods468 consecutive ICC patients who underwent hepatectomy between 2010 and 2017 were enrolled. The PRG and a nomogram were generated and their predictive accuracy was evaluated.ResultsThe PRG consisted of two non-tumor-specific SIR markers platelet-to-lymphocyte ratio (PLR) and albumin (ALB), which were both the independent predictors of overall survival (OS). Multivariate analysis showed that the PRG was significantly associated with OS (PRG = 1: hazard ratio (HR) = 3.800, p < 0.001; PRG = 2: HR = 7.585, p < 0.001). The C-index of the PRG for predicting survival was 0.685 (95% CI 0.655 to 0.716), which was statistically higher than that of the following systems: American Joint Committee on Cancer (AJCC) 8th edition (C-index 0.645), Liver Cancer Study Group of Japan (LCSGJ) (C-index 0.644) and Okabayashi (C-index 0.633) (p < 0.05). Besides, the C-index of the nomogram only consisting of the tumor-specific factors (serum carcinoembryonic antigen, carbohydrate antigen 19-9, tumor number) could be improved to 0.737 (95% CI 0.062–0.768) from 0.625 (95% CI 0.585–0.665) when the PRG was incorporated (p < 0.001).ConclusionsThe PRG integrating two non-tumor-specific SIR markers PLR and ALB was a novel method to preoperative predicting the prognosis of ICC.

A Novel Prognostic Scoring System of Intrahepatic Cholangiocarcinoma With Machine Learning Basing on Real-World Data.

Background and ObjectivesCurrently, the prognostic performance of the staging systems proposed by the 8th edition of the American Joint Committee on Cancer (AJCC 8th) and the Liver Cancer Study Group of Japan (LCSGJ) in resectable intrahepatic cholangiocarcinoma (ICC) remains controversial. The aim of this study was to use machine learning techniques to modify existing ICC staging strategies based on clinical data and to demonstrate the accuracy and discrimination capacity in prognostic prediction.Patients and MethodsThis is a retrospective study based on 1,390 patients who underwent surgical resection for ICC at Eastern Hepatobiliary Surgery Hospital from 2007 to 2015. External validation was performed for patients from 2015 to 2017. The ensemble of three machine learning algorithms was used to select the most important prognostic factors and stepwise Cox regression was employed to derive a modified scoring system. The discriminative ability and predictive accuracy were assessed using the Concordance Index (C-index) and Brier Score (BS). The results were externally validated through a cohort of 42 patients operated on from the same institution.ResultsSix independent prognosis factors were selected and incorporated in the modified scoring system, including carcinoembryonic antigen, carbohydrate antigen 19-9, alpha-fetoprotein, prealbumin, T and N of ICC staging category in 8th edition of AJCC. The proposed scoring system showed a more favorable discriminatory ability and model performance than the AJCC 8th and LCSGJ staging systems, with a higher C-index of 0.693 (95% CI, 0.663–0.723) in the internal validation cohort and 0.671 (95% CI, 0.602–0.740) in the external validation cohort, which was then confirmed with lower BS (0.103 in internal validation cohort and 0.169 in external validation cohort). Meanwhile, machine learning techniques for variable selection together with stepwise Cox regression for survival analysis shows a better prognostic accuracy than using stepwise Cox regression method only.ConclusionsThis study put forward a modified ICC scoring system based on prognosis factors selection incorporated with machine learning, for individualized prognosis evaluation in patients with ICC.

Laparoscopic liver resection for intrahepatic cholangiocarcinoma

Background: Cholangiocarcinoma is the most common biliary tract malignancy, and the second most common type of primary liver cancer. It is more common in Asia but its incidence in North America is increasing. CCA can be categorized as intrahepatic (iCCA) or extrahepatic (perihilar – pCCA/distal – dCCA). There are three main staging systems: American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC); Liver Cancer Study Group of Japan (LCSGJ); and National Cancer Center of Japan (NCCN). Its clinical presentation is unspecific, and it varies depending on tumor location and stage disease. Combined interpretation with different diagnostic modalities is necessary. Methods: A 73-year-old female presented with mild abdominal discomfort and back pain to her primary care physician. Laboratorial exams were requested, and elevated liver enzymes were noted. Abdominal ultrasound was performed that showed left-sided bile duct dilation. Patient underwent an abdominal MRI that identified tortuous and markedly dilated left intrahepatic bile ducts with lobular enhancing intraductal mass with restricted diffusion in the left main hepatic duct measuring approximately 2.3 x 0.9 x 0.8 cm. ERCP with biopsy was made, and a polypoid lesion in the left bile duct was seen. The papillary epithelium was consistent with high-grade dysplasia with possible intraductal papillary neoplasm or cholangiocarcinoma. Laparoscopic surgery was indicated. Patient underwent a cholecystectomy, hepatoduodenal lymphadenectomy, left hepatectomy, and en bloc caudate resection. Results: The Patient was in supine position. General anesthesia was induced. A supraumbilical incision was made. The abdomen was entered without difficulty. Hasson trocar was placed, pneumoperitoneum established. The laparoscope was induced, and the abdomen was explored. The patient had no signs of metastatic or peritoneal disease. The left lobe appeared atrophied, and the right lobe appeared quite hypertrophied. No signs of underlying liver disease. Therefore, 2 additional right-sided 12-mm trocars, an epigastric 5 and a left side 5 trocars were placed. An enlarged hepatic artery lymph node was identified, resected and sent for frozen, it was negative for neoplasia. Cholecystectomy and hepatoduodenal lymphadenectomy were performed. The intrahepatic lesion was resectable, and the caudate lobe appeared potentially involved. It was decided to perform a left hepatectomy with en bloc caudate lobe resection. Specimen was analyzed by Pathology, that confirmed grossly and microscopically widely negative margins. The surface of the liver was cut, and packed with gauze and Surgicel. This was completely dry. There was adequate arterial and portal inflow with biliary drainage to the right lobe of the liver, and no sign of bile leak. Surgicel SNoW and Surgicel gauze were placed against the cut surface of the liver, and closed the specimen extraction site with multiple figure-of-eight 0 Vicryl sutures, and desufflated the abdomen through the trocars, removed the trocars, and closed the 12-mm trocar with a single interrupted 0 Vicryl, and closed the skin with running 4-0 subcuticular stitch and covered with Dermabond. Counts were reported as correct. No complications. No drains. Estimated blood loss was 300 mL. Patient tolerated the surgery well, and was discharged on postoperative day 3. Conclusion: Surgery is the only potentially curative therapeutic option for Cholangiocarcinoma. Minimally invasive approach is challenging, and not widely performed by surgeons. It requires expertise in liver and laparoscopic technique. Despite this, it is feasible, and safe for intrahepatic Cholangiocarcinoma. There are no differences in oncologic outcomes. Blood loss seems to be higher when open surgery is performed, and lymphadenectomy higher in minimally invasive approaches. There are no significant differences between length of hospital stay and complication rates. Laparoscopic liver resection is a treatment modality that should be considered for selected patients with intrahepatic cholangiocarcinoma.

Serum tumor markers enhance the predictive power of the AJCC and LCSGJ staging systems in resectable intrahepatic cholangiocarcinoma

BackgroundWhile several prognostic models have been developed to predict long-term outcomes in resectable intrahepatic cholangiocarcinoma (ICC), their prognostic discrimination remains limited. The addition of tumor markers might improve the prognostic power of the classification schemas proposed by the AJCC 8th edition and the Liver Cancer Study Group of Japan (LCSGJ). MethodsThe prognostic discrimination of the AJCC and the LCSGJ were compared before and after the addition of CA 19-9 and CEA, using Harrell's C-index, net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) in an international, multi-institutional cohort. ResultsEight hundred and five surgically treated patients with ICC that met the inclusion criteria were identified. On multivariable analysis, CEA5 ng/mL, 100IU/mL CA 19-9< 500IU/mL and CA 19-9500 IU/mL were associated with worse overall survival. The C-index of the AJCC and the LCSGJ improved from 0.540 to 0.626 and 0.553 to 0.626, respectively following incorporation of CA 19-9 and CEA. The NRI and IDI metrics confirmed the superiority of the modified AJCC and LCSGJ, compared to the original versions. ConclusionThe inclusion of preoperative CA 19-9 and CEA in the AJCC and LCSGJ staging schemas may improve prognostic discrimination among surgically treated patients with ICC.

Survival Analysis over 28 Years of 173,378 Patients with Hepatocellular Carcinoma in Japan

Background: Beginning in 1967, the Liver Cancer Study Group of Japan (LCSGJ) started a nationwide prospective registry of all patients with hepatocellular carcinoma (HCC) diagnosed at more than 700 institutions. To determine the effectiveness of surveillance and treatment methods longitudinally, we analyzed improvements over time in overall survival (OS) of 173,378 patients with HCC prospectively entered into the LCSGJ registry between 1978 and 2005. Methods: All patients from more than 700 institutions throughout Japan with HCC were entered into the LCSGJ registry. Patients were grouped by years of diagnosis, with OS and 5-year OS rates being calculated. We also assessed OS and 5-year OS rates in patients who underwent resection, local ablation, transarterial chemoembolization (TACE), and hepatic arterial infusion chemotherapy (HAIC) and in those with baseline serum alpha-fetoprotein (AFP) levels ≥400 ng/ml. Results: The 5- and 10-year OS rates in the cohort of 173,378 patients were 37.9% and 16.5%, respectively. However, over time, the mean maximum tumor size decreased significantly, whereas 5-year OS rates and median survival time increased significantly. Similar findings were observed separately in patients who underwent resection, local ablation, TACE, and HAIC, as well as in patients with AFP levels ≥400 ng/ml. Conclusion: The establishment of a nationwide HCC surveillance program in Japan has contributed to longer median OS and increased OS rates in patients diagnosed with this disease. These findings suggest that the establishment of a surveillance program in other countries with patients at risk for HCC may provide significant survival benefits.

Validation of the Criteria of Transcatheter Arterial Chemoembolization Failure or Refractoriness in Patients with Advanced Hepatocellular Carcinoma Proposed by the LCSGJ

Background: Transcatheter arterial chemoembolization (TACE) failure or refractoriness is an indication for sorafenib therapy in patients with advanced hepatocellular carcinoma. The study evaluated the validity of the definition of TACE failure or refractoriness as proposed by the Liver Cancer Study Group of Japan (LCSGJ) through a retrospective analysis of sorafenib treatment. Methods: Out of 265 patients with advanced hepatocellular carcinoma who were treated with sorafenib at our hospital, 45 experienced TACE failure or refractoriness and were included in this study and retrospectively analyzed. Results: Multivariate analysis only identified the number of ineffective TACE procedures performed before starting sorafenib treatment as significant factors. Overall survival (OS) after starting sorafenib was statistically longer in patients treated with ≤2 consecutive ineffective TACE procedures before sorafenib administration than in patients treated with ≥3 consecutive ineffective TACE procedures (p < 0.005). This result matched the LCSGJ criteria. Conclusion: In patients treated with sorafenib, OS was extended with ≤2 consecutive ineffective TACE procedures compared to that with ≥3 consecutive ineffective TACE procedures. Thus, if tumors are uncontrolled, TACE should not be repeated. The result of this study supports the definition of TACE failure or refractoriness proposed by the LCSGJ.

Proposal of a new staging system for mass-forming intrahepatic cholangiocarcinoma: a multicenter analysis by the Study Group for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery

Recently, the Liver Cancer Study Group of Japan (LCSGJ) staging system for intrahepatic cholangiocarcinoma (ICC) was followed by a proposal of the American Committee on Cancer (AJCC)/International Union Against Cancer (UICC) system. The present study aimed to assess the accuracy of both systems to predict survival after curative resection for mass-forming ICC and to establish a new staging system based on survival analysis results. The present study was conducted as a project study of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Clinical data from 233 patients who underwent curative resection for mass-forming ICC were retrospectively reviewed. Survival analysis was performed to identify predictors of postoperative outcomes, and a new staging system was established. The survival stratification of our proposed system was compared with two previous staging systems. A N0M0 cohort analysis demonstrated that tumor size, tumor number, and vascular invasion were independently associated with survival after curative resection for mass-forming ICC, whereas serosal and periductal invasion were not. Of patients with nodal metastases, patients with T4 tumor had significantly lower overall survival rate than patients with T1, T2, or T3 tumor. Thus, we proposed a new staging system as follows: serosal invasion was excluded from the LCSGJ T categories, and patients with nodal metastases were divided into stage IVA or IVB according to T classification. The new system better stratified survival after curative resection for mass-forming ICC than the two previous systems. The AJCC/UICC staging system failed to stratify the Japanese patients with mass-forming ICC. The new staging system provided better survival prediction in the patients who underwent curative resection for mass-forming ICC, although further studies are necessary to evaluate the impact of tumor size on survival.

Chemoembolization for Unresectable Hepatocellular Carcinoma in Japan

Of 15,681 patients with hepatocellular carcinoma (HCC), 30% underwent transcatheter arterial chemoembolization with lipiodol (Lip-TACE) including infusion chemotherapy with lipiodol (Lip-TAI) for the initial treatment, and 58% underwent it for recurrent HCC according to the latest biannual report of the Liver Cancer Study Group of Japan (LCSGJ). Superselective Lip-TACE is considered to be indispensable to maximize the therapeutic effect (TE) and to minimize injury to the non-cancerous liver. The local recurrence rate of a single session Lip-TACE for HCC ≤5 cm in diameter ranged from 33 to 38% at 3 years. A pathologic study using resected specimens of 26 HCCs treated by Lip-TACE showed that the mean necrosis rates and frequency of complete necrosis in three groups, small (≤3 cm, n = 6 HCCs), medium (3.1–5 cm, n = 10), and large size (≧5.1 cm, n = 10) were 95, 87.1%; 68.4, 66.7%; 30, 0%, respectively. Namely, the smaller the tumor size, the higher the TE. However, Lip-TAI showed no correlation between TEs and tumor size. A comparative study between the pathologically proven necrosis rate on the maximum cut surface of the lesion and radiologic necrosis estimated by CT showed a significantly good correlation when the lipiodol-retained area was presumed necrotic, but a poor correlation when it was presumed a viable one. No correlation was seen between the pathologic necrosis rate and the decreased rate of the lesion treated by Lip-TACE assessed by WHO criteria. The modified version of the assessment criteria of the TE of treatment for liver cancer was proposed by the LCSGJ in 2009, using a 4-grade treatment effect with two factors of tumor necrosis and tumor regression.

Single HCC smaller than 2 cm: surgery or ablation?

For hepatocellular carcinoma (HCC), surgical resection and radiofrequency ablation (RFA) are accepted as effective treatments. To clarify the long-term outcome in patients with small HCC, we analyzed data from a nationwide survey of Japan. Between 2000 and 2003, a total of 2,550 patients who had undergone resection (n = 1,235) or RFA (n = 1,315) for single small HCC (<or=2 cm) were registered to the database of the Liver Cancer Study Group of Japan (LCSGJ). After a median follow-up period of 37 months, disease-free survival after resection was significantly better than after RFA (1-year, 91 vs. 87%; 2-year, 46 vs. 25%; P = 0.001), but overall survival after resection and RFA were similar (98 vs. 99%; 94 vs. 95%, P = 0.28). In the patients of Child-Pugh class A, disease-free survival was significantly better after resection (n = 1,056) than after RFA (n = 965) (P = 0.001), while overall survival was not significantly different (P = 0.16). In the patients of Child-Pugh class B, both disease-free and overall survival were almost similar (P = 0.63 and P = 0.66) after resection (n = 136) and RFA (n = 303). For single small HCC (<or=2 cm), surgical resection provides better disease-free survival than does RFA. Longer follow-up is needed to regard this indication as conclusive.

Interventional oncology: new options for interstitial treatments and intravascular approaches

Superselective TACE is defined as TACE from the distal portion of the feeding subsegmental hepatic artery to evoke strong ischemic effects on a small area of the liver, thus avoiding damage to liver function. Lipiodol (iodized oil) is semi-fluid, and it can flow into the surrounding portal venules and hepatic sinusoids through peribiliary plexus (PBP) and the drainage route from the hypervascular HCC. Therefore, the reversed flow from the hepatic sinusoids and portal venules to the peripheral portion of the tumor and daughter nodules can be blocked by Lipiodol injected before a particulate embolus (such as gelatin sponge particles). Common complications of superselective TACE are mild local pain and fever and temporary minimal changes of liver function. Reported CR ratio of definitely hypervascular HCC are around 30-60% by superselective TACE with Lipiodol for hypervascular HCC less than 5 cm. According to a nationwide survey by the Liver Cancer Study Group of Japan (LCSGJ), overall 5-year survival rate was 26% in patients with HCCs not indicated for surgery or RFA (PEI), mainly treated by segmental or subsegmental TACE using Lipiodol. Therefore, this TACE technique should be widely introduced as the first line technique for TACE therapy of HCC.

A comparative study of pathological staging systems in predicting recurrent hepatocellular carcinoma after liver transplantation

The applicability of the staging systems of hepatocellular carcinoma (HCC) to liver transplantation (LT) has not been fully evaluated. Therefore, we compared the HCC recurrence after LT as predicted by various staging systems, including the American Joint Committee on Cancer (AJCC) system 5th edition, the AJCC system 6th edition, the American Liver Tumor Study Group (ALTSG) system, and the Liver Cancer Study Group of Japan (LCSGJ) system. A total of 108 patients who had HCC were classified according to these systems. We compared cumulative recurrence curves, recurrence-free survival curves, and overall survival curves of the systems estimated by Kaplan-Meier method. We compared cumulative event rates among different stages with the log-rank test for each staging system. The log-rank test showed that the cumulative recurrence rates were different among different stages with a statistical significance for the staging systems except for the AJCC 5th edition system. Cumulative recurrence curves by the AJCC 6th edition system and the LCSGJ system showed better visual separation than the other two systems. With respect to recurrence-free survival and overall survival, no staging systems showed significant discriminative power. The current AJCC tumor-node-metastasis staging and the LCSGJ system are superior in predicting HCC recurrence after LT.

Intrahepatic Cholangiocarcinoma: Prognostic Factors After Surgical Resection

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor. The resectability rate is low because at the time of diagnosis this disease is frequently beyond the limits of surgical therapy. Curative resection (R0) is the most effective treatment and the only therapy associated with prolonged disease-free survival. Based on the gross appearance of the tumor the Liver Cancer Study Group of Japan (LCSGJ) defined three types: mass-forming type (MF), periductal infiltrating type (PI), intraductal growth (IG) type. The prognostic significance of gross type has been demonstrated in Eastern countries, but this issue has not been clarified in Western countries. The aim of this study was to identify the prognostic factors for survival in a group of patients submitted to surgical resection for ICC. Between 1990 and 2007 a total of 81 consecutive patients with ICC were submitted to surgery. Patients with peritoneal carcinomatosis, extensive vascular involvement, or multiple intrahepatic metastases were excluded from surgical resection. Tumors were classified according to TMN stage (6th edition, 2002) and LCSGJ gross type classification. Tumor gross appearance on the cut surface was categorized into the following types according to the classification proposed by the Liver Cancer Study Group of Japan: MF, PI, or IG type. During the study period 52 patients were submitted to surgical resection with curative intent, whereas in 29 patients surgery was limited to explorative laparotomy. Curative resection (R0) was achieved in 43 patients (83%); and a major hepatic resection was performed in 63% (33/52) of the patients. Extrahepatic bile duct resection was carried out in 36% (19/52) of cases. According to the LCSGJ classification, the MF type was present in 34 patients (65%), the MF + PI type in 13 (25%), the PI type in 3 (6%), and the IG type in 2 (4%). Overall median survival time was 40 months, with a 1-, 3-, and 5-year actuarial survival rates of 83%, 50%, 20%, respectively. Survival was significantly related to the macroscopic gross type, with a median survival of 50 months for patients with the MF type, 19 months for the MF + PI type, 15 months for the PI type, and 17 months for the IG type. At univariate analysis, the macroscopic gross appearance of the tumor, the presence of lymph node metastasis, involvement of extrahepatic bile ducts, the presence of macroscopic vascular invasion, and positive resection margins were significant related to survival. At multivariate analysis, macroscopic vascular invasion and lymph nodes metastases were significant related to survival with hazard ratios of 4.11 and 2.79, respectively. Further statistical analyses were carried out to identify the relation between macroscopic gross type and prognosis. We identified that the MF + PI type tumors were significantly associated with negative prognostic factors, such as the involvement of extrahepatic bile ducts, the presence of lymph nodes metastases, the presence of macroscopic vascular invasion, the presence of perineural invasion, and higher T stage. Curative resection of ICC is the only therapy that can achieve long-term survival. The best results were observed in patients who underwent R0 resection for MF tumors without lymph node metastases or vascular invasion. Important predictive factors related to poor survival are MF + PI macroscopic tumor type, lymph node metastases, and vascular invasion. In these patients, other therapeutic approaches (i.e., adjuvant or neoadjuvant therapy) should be evaluated to improve results.

LCSGJ-T Classification, 6th or 5th Edition TNM Staging Did Not Independently Predict the Long-Term Prognosis of HBV-Related Hepatocellular Carcinoma After Radical Hepatectomy

The 6th edition tumor-node-metastasis (TNM) staging (TNM-6) for hepatocellular carcinoma (HCC) was recommended. Besides, Liver Cancer Study Group of Japan (LCSGJ)-T classification has been recently proposed. However, these newly established staging systems should be further verified in different subgroups of HCC patients. The current study mainly aimed to validate the predictive power of these novel criteria in a cohort of patients with hepatitis B virus-related HCC after radical hepatectomy. As a control, the 5th edition TNM staging (TNM-5) was also evaluated. Clinicopathological and follow-up data of consecutive 142 patients with HBV-related HCC undergoing radical hepatectomy were reviewed. The impact of variables on prognosis was determined by uni- and multivariate analyses. By univariate analysis, LCSGJ-T classification, TNM-6, and TNM-5 were almost significantly prognostic, except for TNM-5 for disease-free survival. Meanwhile, tumor size>or=5 cm, alpha-fetoprotein>400 ng/mL, high Edmondson-Steiner grade, presence of microvascular invasion, portal vein tumor thrombosis, satellite nodule, and resection margin<or=1 cm were also associated with decreased overall or disease-free survival. Multivariate analysis, including aforementioned factors, suggested that Edmondson-Steiner grade was the sole independent prognosticator for both overall and disease-free survival, when LCSGJ-T classification, TNM-6, and TNM-5 were entered, respectively. However, all 3 staging systems lost their predictive potentials in multivariate analysis. LCSGJ-T classification, TNM-6, and TNM-5 were not revealed to be independently prognostic in patients with HBV-related HCC after radical hepatectomy. Therefore, these staging criteria, especially the newly developed ones, call for more support in many subsets of HCC patients.

Staging of Hepatocellular Carcinoma

The aims of this study were to present evidence to develop and validate the Japanese Tumor-Node-Metastasis (TNM) staging system for primary liver cancer and to compare its discriminatory ability and predictive power with those of Vauthey's simplified staging, which was adopted as the TNM staging system of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC). Among many staging systems for hepatocellular carcinoma, the Japanese TNM staging system and the AJCC/UICC staging system were developed based on a survival analysis of surgical patients. These 2 staging systems have not been compared in large series. The Liver Cancer Study Group of Japan (LCSGJ) prospectively collected clinicopathologic data of 63,736 patients with primary liver cancer from 1995 to 2001. Among them, 13,772 patients received curative hepatic resection. Based on univariate and multivariate survival analyses, the Japanese TNM staging system was developed. The accuracy of the Japanese TNM staging system for predicting patient survival was compared with that of the AJCC/UICC staging system using the cross-validation method. The independent prognostic factors (relative risk; 95% confidence interval) were vascular or bile duct invasion (1.36;1.29-1.43), liver cirrhosis (1.26;1.20-1.32), diameter (< or =2 cm or >2 cm) (1.21;1.14-1.28), alpha-fetoprotein (1.20;1.15-1.25), single/multiple (1.18;1.12-1.23), liver damage (1.15;1.10-1.20), hepatic involvement (1.14;1.09-1.19), histologic differentiation (1.14;1.08-1.20), gross classification (1.13;1.08-1.18), and esophageal varices (1.07;1.02-1.13). Based on these results, 3 criteria (vascular or bile duct invasion, diameter, and single/multiple) were selected. Patients with none of these 3 factors were considered T1, and those with 1, 2, and 3 factors were T2, T3, and T4, respectively. The number of patients and 5-year survival rates for T1, T2, T3, and T4 were 2078, 70%; 6853, 58%; 3021, 41%; and 582, 24% (P < 0.0001), respectively, while those for the AJCC-T were 8457, 61% in T1, 2888, 46% in T2, and 1189, 30% in T3 (P < 0.0001). While both the LCSGJ-T and the AJCC-T had good discriminating ability, the former was significantly superior (P = 0.0007). Our findings support the development of LCSG stage. While both staging systems allow for the clear stratification of patients into prognostic groups, the LCSGJ staging may be more appropriate for stratifying patients with early-stage HCC.

肝細胞癌のステージングシステム

In this article, the concept and clinical impact of the staging systems for hepatocellular carcinoma (HCC) were reviewed. Among the several scoring systems so far available, such as Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), and Japan Integrated Staging (JIS) systems, the JIS system is extremely efficient in the stratification ability of the HCC patients from the very early stage through highly advanced stage of HCC: particularly in the areas like Japan, where small HCC less than 2 cm in diameter can be diagnosed based on the screening program for early detection of HCC. This efficiency of the JIS system is due to an excellent tumor-node-metastasis (TNM) staging system developed by Liver Cancer Study Group of Japan (LCSGJ). JIS system is an integated staging system between child-Pugh stage and the TNM stage by LCSGJ. Therefore, the TNM stage by LCSGJ and the JIS score is expected to be used as a global standard staging system in the near future.

Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score).

A clinical staging system for cancer patients provides guidance for patient assessment and making therapeutic decisions. It is useful in deciding whether to treat a patient aggressively, and in avoiding the overtreatment of patients who would not tolerate the treatment or patients whose life expectancy rules out any chance of treatment. Clinical staging is also an essential tool for comparison between groups in therapeutic trials and for comparison between different studies. The current classifications most commonly used for hepatocellular carcinoma (HCC) are the Okuda stages, the Child-Pugh staging system, tumor node metastasis (TNM) staging, and the Cancer of the Liver Italian Program (CLIP) score. Among these, the CLIP score is currently the most commonly used integrated staging score, including both tumor stage and liver disease stage. Although the CLIP score has been well validated by many authors in terms of its prognostic value in HCC patients, this score has some problems and limitations when applied to currently diagnosed HCC patients, who are diagnosed in the early stage of disease. First, the CLIP score can discriminate score 0- to 3-patient populations, but it is not able to discriminate score 4- to 6-patient groups. Second, the definition of tumor morphology in the best prognostic group is too advanced, i.e., uninodular and a tumor extent of less than 50% of the liver. As a result, the prognosis of the CLIP system best prognostic group is not so good. In other words, this system cannot identify the best prognostic group who would benefit from curative and aggressive treatment. Third, nearly 80% of the patient population is classified as having a CLIP score of 0-2, as confirmed by many studies, which shows poor stratification ability. In contrast, a new staging system based on the Liver Cancer Study Group of Japan (LCSGJ), the Japan Integrated Staging (JIS) score is currently proposed in Japan. This staging system combines Child-Pugh grade (grade A, score 0; grade B, score 1; grade C, score 2) and TNM staging by the LCSGJ criteria (stage I, score 0; stage II, score 1; stage III, score 2; stage IV, score 3). The stratification ability of the JIS scoring system is much better than that of the CLIP scoring system. The JIS scoring system also performed better than the CLIP scoring system in selecting the best prognostic patient group. The cumulative 10-year survival rates of the best prognostic groups in the CLIP staging system (CLIP score 0) and JIS staging system (JIS score 0) were 23% and 65%, respectively (P < 0.01). All scoring systems arise as a compromise between simplicity and discriminatory ability. We confirmed that the JIS score increases predictive efficacy, while remaining simple compared with the CLIP score. Because the JIS score is quite easily obtained and is objective, we strongly propose it for widespread use as a prognostic staging system for HCC in clinical practice.

IHPBA concordant classification of primary liver cancer: working group report.

The working group of the International Scientific Committee of the International Hepato-Pancreato-Biliary Association(IHPBA) examined conventional staging systems and decided to establish a new staging system that depended on macroscopic findings after liver resection. The TNM/International Union Against Cancer (UICC) classification has been widely used but is too complicated. Vauthey and colleagues, and the Liver Cancer Study Group of Japan (LCSGJ) have proposed new simplified classifications. These are compared and discussed. The IHPBA working group proposed a new classification, as follows. T factor. 1. Solitary 2. No more than 2 cm 3. No vascular invasion to portal vein, hepatic vein, and bile duct T1 meets all of the above three requirements.T2 meets two of the three requirements.T3 meets one of the three requirements.T4 does not meet any requirements. Stage: I T1N0M0 II T2N0M0 III T3N0M0IV A T4N0M0 Any TN1M0 IV B Any T/N, M1 The survival curves of each stage were separated clearly (P < 0.0001). The staging system is easy to remember and easy to use. We hope this staging system will be generally used in future.