Background: Microvascular invasion (MVI) is closely correlated with poor clinical outcomes in patients with hepatocellular carcinoma (HCC). A grading system of MVI is needed to assist in the management of HCC patient. Methods: Multicenter data of HCC patients who underwent liver resection with curative intent was analyzed. This grading system was established by detected number and distance from tumor boundary of MVI. Survival outcomes were compared among patients in each group. This system was verified by time-receiver operating characteristic curve, time-area under the curve, calibration curve, and decision curve analyses. Cox regression analysis was performed to study the associated factors of prognosis. Logistic analysis was used to study the predictive factors of MVI. Results: All patients were classified into 4 groups: M0: no MVI; M1: 1~5 proximal MVIs (≤1 cm from tumor boundary); M2a: >5 proximal MVIs (≤1 cm from tumor boundary); M2b: ≥1 distal MVIs (>1 cm from tumor boundary). The recurrence-free survival (RFS), overall survival (OS), and early RFS rates among all the individual groups were significantly different. Based on the number of proximal MVI (0~5 vs >5), patients in the M2b group were further divided into two subgroups which also showed different prognosis. Multiple methods showed this grading system to be significantly better than the MVI two-tiered system in prognostic evaluation. Four multivariate models for RFS, OS, early RFS, late RFS, and a predictive model of MVI were then established and were shown to satisfactorily evaluate prognosis and have a great discriminatory power, respectively. Conclusion: This MVI grading system could precisely evaluate prognosis of HCC patients after liver resection with curative intent and it could be employed in routine pathological reports. The severity of MVI from both adjacent and distant from tumor boundary should be stated. A hypothesis about two occurrence modes of distal MVI was proposed.
Background: To identify whether adjuvant transarterial chemoembolization (TACE) can improve prognosis in HCC patients with a low risk of recurrence (tumor size ≤ 5 cm, single nodule, no satellites, and no microvascular or macrovascular invasions) after hepatectomy. Methods: The data of 489 HCC patients with a low risk of recurrence after hepatectomy from Shanghai Cancer Center (SHCC) and Eastern Hepatobiliary Surgery Hospital (EHBH) were retrospectively reviewed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier curves and Cox proportional hazards regression models. The effects of selection bias and confounding factors were balanced using propensity score matching (PSM). Results: In the SHCC cohort, 40 patients (19.9%, 40/201) received adjuvant TACE, and in the EHBH cohort, 113 patients (46.2%, 133/288) received adjuvant TACE. Compared to the patients without adjuvant TACE after hepatectomy, patients receiving adjuvant TACE had significantly shorter RFS (P=0.022; P=0.014) in both cohorts before PSM. However, no significant difference existed in OS (P=0.568; P=0.082). Multivariate analysis revealed that serum alkaline phosphatase and adjuvant TACE were independent prognostic factors for recurrence in both cohorts. Furthermore, significant differences existed in tumor size between the adjuvant TACE and non-adjuvant TACE groups in the SHCC cohort. There were differences in transfusion, Barcelona Clinic Liver Cancer stage and tumor-node-metastasis stage in the EHBH cohort. These factors were balanced by PSM. After PSM, patients with adjuvant TACE after hepatectomy still had significantly shorter RFS than those without (P=0.035; P=0.035) in both cohorts, but there was no difference in OS (P=0.638; P=0.159). Adjuvant TACE was the only independent prognostic factor for recurrence in multivariate analysis, with hazard ratios of 1.95 and 1.57. Conclusions: Adjuvant TACE may not improve long-term survival and might promote postoperative recurrence in HCC patients with a low risk of recurrence after hepatectomy.
PURPOSE: This study was designed to establish risk classifications for early recurrence in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) after hepatectomy. METHODS: The data of 563 HCC patients with MVI after hepatectomy from two hospitals were retrospectively reviewed. Kaplan-Meier curves and Cox proportional hazards regression models were used to analyse early recurrence. The risk classification for early recurrence was established by using classification and regression tree (CART) analysis and validated by using two independent validation cohorts from two hospitals. RESULTS: Multivariate analysis revealed that four indices, namely, infection of chronic viral hepatitis, MVI classification, tumour size, and serum alpha-fetoprotein (AFP), were independent prognostic factors for early recurrence in HCC patients with MVI. By CART analysis, MVI classification and serum AFP became the nodes of a decision tree and 3-stratification classifications that satisfactorily determined the risk of early recurrence were established. The area under the time-dependent receiver operating characteristic curve (AUC) values of the classification for early recurrence at 0.5, 1.0, and 2.0 years were 0.75, 0.73, and 0.71, respectively, which were all significantly higher than three common classic HCC stages (BCLC stage, Chinese stage, and TNM stage). The calibration curves showed good agreement between predictions by classification for early recurrence and actual survival outcomes. These prediction results also were confirmed in the independent internal and external validation cohorts. CONCLUSIONS: The 3 stratification classifications enabled satisfactory risk evaluation of early recurrence in HCC patients with MVI after hepatectomy.
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/surgery , Retrospective Studies , Liver Neoplasms/surgery , Decision Trees
Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.
BACKGROUND: Microvascular invasion (MVI) is a prominent risk factor of postoperative recurrence for hepatocellular carcinoma (HCC). The MVI detection rate of conventional pathological examination approaches is relatively low and unsatisfactory. METHODS: By integrating pathological macro-slide with whole-mount slide imaging, we first created a novel pathological examination method called image-matching digital macro-slide (IDS). Surgical samples from eligible patients were collected to make IDS. The MVI detection rates, tumor recurrence rates and recurrence-free survival were compared among conventional 3-Point and 7-Point baseline sampling protocols and IDS. Additionally, biomarkers to recognize MVI false negative patients were probed via combining conventional pathological sampling protocols and IDS. Receiver operating characteristic curve (ROC) analysis was used to obtain the optimal cutoff of biomarkers to distinguish MVI false negative patients. RESULTS: The MVI detection rates were 21.98%, 32.97% and 63.74%, respectively, in 3-Point, 7-Point baseline sampling protocols and IDS (p < 0.001). Tumor recurrence rate of patients with MVI negative status in IDS (6.06%) was relatively lower than that of patients with MVI negative status in 3-Point (16.90%) and 7-Point (16.39%) sampling protocols. Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were selected as potential biomarkers to distinguish MVI false negative patients. CONCLUSIONS: Our study demonstrated that IDS can help enhance the detection rate of MVI in HCC and refine the prediction of HCC prognosis. Alpha-fetoprotein is identified as a suitable and robust biomarker to recognize MVI false-negative patients in conventional pathological protocols.
Carcinoma, Hepatocellular , Liver Neoplasms , Biomarkers , Carcinoma, Hepatocellular/pathology , Humans , Liver Neoplasms/pathology , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Retrospective Studies , alpha-Fetoproteins/analysis
BACKGROUND: Microvascular invasion (MVI) is a significant risk factor affecting survival outcomes of patients after R0 liver resection (LR) for hepatocellular carcinoma (HCC). The current classification of MVI is not refined enough to prognosticate long-term survival of these patients, and a new MVI classification is needed. METHODS: Patients with HCC who underwent R0 LR at the Eastern Hepatobiliary Surgery Hospital from January 2013 to December 2013 and with resected specimens showing MVI were included in this study with an aim to establish a novel MVI classification. The classification which was developed using multivariate cox regression analysis was externally validated. RESULTS: There were 180 patients in the derivation cohort and 131 patients in the external validation cohort. The following factors were used for scoring: α-fetoprotein level (AFP), liver cirrhosis, tumor number, tumor diameter, MVI number, and distance between MVI and HCC. Three classes of patients could be distinguished by using the total score: class A, ≤3 points; class B, 3.5-5 points and class C, >5 points with distinct long-term survival outcomes (median recurrence free survival (mRFS), 22.6, 10.2, and 1.9 months, P < 0.001). The predictive accuracy of this classification was more accurate than the other commonly used classifications for HCC patients with MVI. In addition, the mRFS of class C patients was significantly prolonged (1.9 months vs. 6.2 months, P < 0.001) after adjuvant transcatheter arterial chemoembolization (TACE). CONCLUSIONS: A novel MVI classification was established in predicting prognosis of HCC patients with MVI after R0 LR. Adjuvant TACE was useful for class C patients.
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Humans , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Microvessels/pathology , Neoplasm Invasiveness/pathology , Prognosis , Retrospective Studies
BACKGROUND: Surgical resection of huge hepatocellular carcinoma (HCC, ≥ 10 cm) is potentially curative. More adjuvant treatments are needed to reduce relapses in these patients. We evaluated the influence of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) on the prognosis of huge HCC. METHODS: Data from consecutive patients who underwent curative resection for huge HCC in our center were retrospectively collected. Recurrence-free survival (RFS) and overall survival (OS) were compared between patients who did and did not undergo PA-TACE. Propensity score matching (PSM) was used. RESULTS: Among the 255 enrolled patients, 93 underwent PA-TACE. The clinical outcomes were significantly better in the PA-TACE group than those in the non PA-TACE group (5-year RFS rate: 33.5% vs. 18.0%; 5-year OS rate: 47.0% vs. 28.0%, all P < 0.001). After PSM, similar results were obtained (5-year RFS rate: 28.8% vs. 17.6%, P < 0.001; 5-year OS rate: 42.5% vs. 25.0%, P = 0.004). PA-TACE decreased the possibility of early recurrence (< 2 years, crude cohort: P < 0.001, PSM cohort: P < 0.001) but not late recurrence (≥ 2 years, crude cohort: P = 0.692, PSM cohort: P = 0.325). Multivariable Cox regression analysis suggested that PA-TACE was an independent protective factor prolonging early RFS, RFS and OS. CONCLUSIONS: PA-TACE is a safe intervention for huge HCC patients after liver resection and improves outcomes.
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic/adverse effects , Humans , Liver Neoplasms/therapy , Neoplasm Recurrence, Local/therapy , Prognosis , Retrospective Studies
BACKGROUND AND AIMS: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. METHODS: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. RESULTS: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS. CONCLUSIONS: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/surgery , Humans , Microvessels , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Retrospective Studies
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common tumor in primary liver cancer, but the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. This study aimed to develop a novel prognostic classifier for patients with ICC after surgery. METHODS: Using a proteomics approach, we screened tumor markers that up-regulated in ICC tissues, and narrowed down by bioinformatics analysis, western blot and immunohistochemistry. Prognostic markers were identified using Cox regression analyses in primary training cohort and the predictive models for time to recurrence (TTR) were established. The predictive accuracy of predictive model was validated in external validation cohort and prospective validation cohort. MTT assay, clonal formation assay and trans-well assays were used to verify the effect on the proliferation and migration in ICC cell line. RESULTS: Triosephosphate isomerise (TPI1) was significantly up-regulated in ICC tissues and Kaplan-Meier analysis reveals that higher TPI1 expression was strongly correlated with higher recurrence rate of ICC patients. In the primary training cohort, mean TTR was significantly longer (p < 0.0001) than in the low-risk group (26.9 months for TTR, 95% CI 22.4-31.5) than in the high-risk group (14.5 months for TTR, 95% CI 10.6-18.4). Similar results were observed in two validation cohorts. In addition, a nomogram to predict recurrence was developed. Moreover, Knockdown of TPI1 by shRNA inhibited ICC cell growth, colony information, migration, invasion in vitro. CONCLUSIONS: Current prognostic models were accurate in predicting recurrence for ICC patients after surgical resection.
Bile Duct Neoplasms/pathology , Cholangiocarcinoma/pathology , Proteomics/methods , Triose-Phosphate Isomerase/genetics , Bile Duct Neoplasms/genetics , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Cholangiocarcinoma/genetics , Cohort Studies , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Nomograms , Prognosis , Prospective Studies , Time Factors , Up-Regulation
PURPOSE: This study aimed to propose an effective quantitative pathological scoring system and to establish nomogram to assess the stage of cirrhosis and predict postoperative survival of hepatocellular carcinoma (HCC) with cirrhosis patients after hepatectomy. METHODS: The scoring system was based on a retrospective study on 163 patients who underwent partial hepatectomy for HCC with cirrhosis. The clinicopathological and follow-up data of 163 HCC with cirrhosis patients who underwent hepatectomy in our hospital from 2010 to 2014 were retrospectively reviewed. A scoring system was established based on the total value of independent predictive factors of cirrhosis. The results were validated using 97 patients operated on from 2011 to 2015 at the same institution. Nomogram was then formulated using a multivariate Cox proportional hazards model to analyze. RESULTS: The scoring system was ultimately composed of 4 independent predictive factors and was divided into 3 levels. The new cirrhosis system score strongly correlated with Child-Pugh score (r=0.8058, P<0.0001) 3 months after surgery; higher cirrhosis system scores predicted poorer liver function and stronger liver damage 3 months after surgery. Then, a four-factor nomogram for survival prediction was established. The concordance indices were 0.79 for the survival-prediction nomogram. The calibration curves showed good agreement between predictions by the nomogram and actual survival outcomes. CONCLUSION: This new scoring system of cirrhosis can help us predict the liver function and liver injury 3 months after surgery, and the nomogram enabled accurate predictions of risk of overall survival in patients of HCC with cirrhosis after hepatectomy.
Aim: The influence of surgical margin on the prognosis of patients with early solitary hepatocellular carcinoma (HCC) (≤5 cm) is undetermined. Methods: The data of 904 patients with early solitary HCC who underwent liver resection were collected for recurrence-free survival (RFS) and overall survival (OS). Propensity score matching (PSM) was performed to balance the potential bias. Results: Log-rank tests showed that 2 mm was the best cutoff value to discriminate the prognosis of early HCC. Liver resection with a >2 mm surgical margin distance (wide-margin group) led to better 5-year RFS and OS rate compared with liver resection with a ≤2 mm surgical margin distance (narrow-margin group) among patients both before (RFS: 59.1% vs. 39.6%, P < 0.001; OS: 85.3% vs. 73.7%, P < 0.001) and after PSM (RFS: 56.3% vs. 41.0%, P < 0.001; OS: 83.0% vs. 75.0%, P = 0.010). Subgroup analysis showed that a wide-margin resection significantly improved the prognosis of patients with microvascular invasion (RFS: P < 0.001; OS: P = 0.001) and patients without liver cirrhosis (RFS: P < 0.001; OS: P = 0.001) after PSM. Multivariable Cox regression analysis revealed that narrow-margin resection is associated with poorer RFS [hazard ratio (HR) = 1.781, P < 0.001), OS (HR = 1.935, P < 0.001], and early recurrence (HR = 1.925, P < 0.001). Conclusions: A wide-margin resection resulted in better clinical outcomes than a narrow-margin resection among patients with early solitary HCC, especially for those with microvascular invasion and without cirrhosis. An individual strategy of surgical margin should be formulated preoperation according to both tumor factors and background liver factors.
BACKGROUND: Ubiquitin-conjugating enzyme E2T (UBE2T) is overexpressed in several types of malignancies. However, little is known about its diagnostic significance in intrahepatic cholangiocarcinoma (ICC) and other bile duct diseases or its prognostic value in ICC. METHODS: The expression levels of UBE2T in the intrahepatic bile duct (IHBD, N = 13), biliary intraepithelial neoplasia (BilIN; BilIN-1/2, N = 23; BilIN-3, N = 11), and ICC (N = 401) were examined by immunohistochemistry. The differential diagnostic and prognostic values were also assessed. RESULTS: The number of UBE2T-positive cells was significantly higher in ICC tissues than in nonmalignant tissues, including the IHBD, BilIN-1/2, and BilIN-3 tissues. Kaplan-Meier analysis showed that overexpression of UBE2T was correlated with a shorter time to recurrence (TTR) and overall survival (OS). The 5-year TTR rates in the high UBE2T and low UBE2T groups were 100% and 86.2%, respectively. The corresponding OS rates were 1.9% and 22.2%, respectively. High expression of UBE2T was an independent risk factor for both TTR (hazard ratio: 1.345; 95% confidence interval: 1.047,1.728) and OS (hazard ratio: 1.420; 95% confidence interval: 1.098,1.837). CONCLUSIONS: UBE2T can assist in differentiating benign bile duct diseases from ICC, and high expression of UBE2T suggests a poor prognosis for ICC.
BACKGROUND: Large, multinodular (> 3 nodules and/or > 3 cm) hepatocellular carcinoma (HCC) is not an indication for liver resection based on the Barcelona Clinic Liver Cancer (BCLC) staging classification. We hypothesize that microvascular invasion (MVI) is a strong indication for surgery in these patients. METHODS: Between December 2009 and December 2010, a retrospective cohort of the patients with BCLC intermediate stage HCC undergoing surgical resection at Eastern Hepatobiliary Surgery Hospital was analyzed. Propensity score matching (PSM) was conducted to balance the patients with regard to their baseline characteristics. Survival analysis was performed according to the Kaplan-Meier method. Logistic regression was conducted to identify the predictors of MVI. Risk factors were evaluated using the Cox proportional hazards model. RESULTS: Among 323 patients, the MVI-negative group (26.0%) had a more favorable prognosis than did the MVI-positive group (5-year recurrence-free survival: 25.2% vs. 7.8%; 5-year overall survival: 49.5% vs. 24.0%). Similar results were identified after PSM. Compared with MVI-negative patients, MVI-positive patients experienced more early recurrence (< 2 years, P = 0.006), multinodular recurrence (P = 0.004), and extrahepatic recurrence (P = 0.026). Total bilirubin levels > 17.1 µmol/L, alpha fetal protein levels > 400 ng/mL, the presence of > 2 nodules, and the lack of a capsule were independent predictors of MVI. CONCLUSIONS: In BCLC intermediate stage HCC, MVI predicted an adverse recurrence pattern and poor prognosis and has the potential to be used as a reference index when deciding whether to operate. Factors predictive of MVI could assist in choosing preoperative treatment and postoperative surveillance.
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/surgery , Hepatectomy , Humans , Liver Neoplasms/surgery , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Retrospective Studies
BACKGROUND: To identify the impact of tumor number on Barcelona Clinic Liver Cancer (BCLC) early-stage hepatocellular carcinoma (HCC) and the impact of microvascular invasion (MVI) on multinodular HCC (MHCC). METHODS: We retrospectively analyzed 1,548 patients who had early-stage HCC [solitary HCC (SHCC, n=1,481) and MHCC (n=67)], according to the BCLC classification, after curative resection. Recurrence-free survival (RFS) and overall survival (OS) were compared. Propensity score matching (PSM) was used to balance potential confounding factors. RESULTS: Both before and after PSM, significant differences were noted between the MHCC group and the SHCC group in RFS but not in OS. For the PSM cohort, the 5-year RFS rates were 7.5% and 41.2% for the MVI-positive MHCC group and the SHCC group, respectively (P<0.001). The 5-year OS rates were 48.9% and 75.2% for the MVI-positive MHCC group and the SHCC group, respectively (P=0.017). The RFS and OS were not significantly different between the MVI-negative MHCC group and the SHCC group. MVI (P=0.029) and multiple nodules (P=0.029) were associated with early recurrence. CONCLUSIONS: The presence of MVI in BCLC early-stage MHCC was highly suggestive of a poor prognosis and should not be classified as early-stage biological behavior.
Extrahepatic metastasis confers unfavorable patient prognosis in patients with hepatocellular carcinoma (HCC), however, reliable markers allowing prediction of extrahepatic metastasis at the time of initial diagnosis are still lacking. This study was to identify gene-level copy number aberrations (CNAs) related to extrahepatic metastasis-free survival of HCC patients, and further examine the associations between CNAs and gene expression. Array comparative genomic hybridization (aCGH) and expression array were used to analyze gene CNAs and expression levels, respectively. The associations between CNAs of a panel of 20 genes and extrahepatic metastasis-free survival were analyzed in 66 patients with follow-up period of 1.6-90.5 months. The gene expression levels between HCCs with and without gene CNA were compared in 109 patients with HCC. We observed that gains at MDM4 and BCL2L1, and losses at APC and FBXW7 were independent prognostic markers for extrahepatic metastasis-free survival of HCC patients. Integration analysis of aCGH and expression data showed that MDM4 and BCL2L1 were significantly upregulated in HCCs with gene gain, while APC and FBXW7 were significantly downregulated in HCCs with gene loss. We concluded that gene gains at MDM4 and BCL2L1, and losses at APC and FBXW7, with concordant expression changes, were associated with extrahepatic metastasis-free survival of HCC patients and have potential to act as novel prognostic markers.
Adenomatous Polyposis Coli Protein/genetics , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Cell Cycle Proteins/genetics , F-Box-WD Repeat-Containing Protein 7/genetics , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , Proto-Oncogene Proteins/genetics , bcl-X Protein/genetics , Adenomatous Polyposis Coli Protein/metabolism , Adult , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/mortality , Cell Cycle Proteins/metabolism , Comparative Genomic Hybridization , F-Box-WD Repeat-Containing Protein 7/metabolism , Female , Follow-Up Studies , Gene Dosage , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/metabolism , Liver Neoplasms/mortality , Lymphatic Metastasis , Male , Middle Aged , Prognosis , Proto-Oncogene Proteins/metabolism , Retrospective Studies , Survival Analysis , bcl-X Protein/metabolism
BACKGROUND: Microvascular invasion (MVI) is a major determinant of survival outcome for hepatocellular carcinoma (HCC). This study aimed to investigate the efficacy of postoperative adjuvant Sorafenib (PA-Sorafenib) in HCC patients with MVI after R0 liver resection (LR). METHODS: The data of patients who underwent R0 LR for HCC with histologically confirmed MVI at the Eastern Hepatobiliary Surgery Hospital were retrospectively analyzed. The survival outcomes for patients who underwent PA-Sorafenib were compared with those who underwent R0 LR alone. Propensity score matching (PSM) analysis was performed. RESULTS: 728 HCC patients had MVI in the resected specimens after R0 resection, with 581 who underwent LR alone and 147 patients who received in additional adjuvant sorafenib. PSM matched 113 patients in each of these two groups. The overall survival (OS) and recurrence free survival (RFS) were significantly better for patients in the PA-sorafenib group (for OS: before PSM, P = 0.003; after PSM, P = 0.007), (for RFS: before PSM, P = 0.029; after PSM, P = 0.001), respectively. Similar results were obtained in patients with BCLC 0-A, BCLC B and Child-Pugh A stages of disease. CONCLUSIONS: PA-Sorafenib was associated with significantly better survival outcomes than LR alone for HCC patients with MVI.
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/mortality , Liver Neoplasms/therapy , Sorafenib/therapeutic use , Adult , Chemotherapy, Adjuvant , Female , Hepatectomy , Humans , Male , Matched-Pair Analysis , Middle Aged , Neoplasm Invasiveness , Propensity Score , Retrospective Studies
BACKGROUND: Microvascular invasion (MVI) is associated with poor postoperative survival outcomes in patients with hepatocellular carcinoma (HCC). An Eastern Hepatobiliary Surgery Hospital (EHBH) MVI scoring system was established to predict prognosis in patients with HCC with MVI after R0 liver resection (LR) and to supplement the most commonly used classification systems. MATERIALS AND METHODS: Patients with HCC with MVI who underwent R0 LR as an initial therapy were included. The EHBH-MVI score was developed from a retrospective cohort from 2003 to 2009 to form the training cohort. The variables associated with overall survival (OS) on univariate analysis were subsequently investigated using the log-rank test, and the EHBH-MVI score was developed using the Cox regression model. It was validated using an internal prospective cohort from 2011 to 2013 as well as three independent external validation cohorts. RESULTS: There were 1,033 patients in the training cohort; 322 patients in the prospective internal validation cohort; and 493, 282, and 149 patients in the three external validation cohorts, respectively. The score was developed using the following factors: α-fetoprotein level, tumor encapsulation, tumor diameter, hepatitis B e antigen positivity, hepatitis B virus DNA load, tumor number, and gastric fundal/esophageal varicosity. The score differentiated two groups of patients (≤4, >4 points) with distinct long-term prognoses outcomes (median OS, 55.8 vs. 19.6 months; p < .001). The predictive accuracy of the score was greater than the other four commonly used staging systems for HCC. CONCLUSION: The EHBH-MVI scoring system was more accurate in predicting prognosis in patients with HCC with MVI after R0 LR than the other four commonly used staging systems. The score can be used to supplement these systems. IMPLICATIONS FOR PRACTICE: Microvascular invasion (MVI) is a major determinant of survival outcomes after curative liver resection for patients with hepatocellular carcinoma (HCC). Currently, there is no scoring system aiming to predict prognosis of patients with HCC and MVI after R0 liver resection (LR). Most of the widely used staging systems for HCC do not use MVI as an independent risk factor, and they cannot be used to predict the prognosis of patients with HCC and MVI after surgery. In this study, a new Eastern Hepatobiliary Surgery Hospital (EHBH) MVI scoring system was established to predict prognosis of patients with HCC and MVI after R0 LR. Based on the results of this study, postoperative adjuvant therapy may be recommended for patients with HCC and MVI with an EHBH-MVI score >4. This score can be used to supplement the currently used HCC classifications to predict postoperative survival outcomes in patients with HCC and MVI.
Carcinoma, Hepatocellular/surgery , Liver Neoplasms/surgery , Carcinoma, Hepatocellular/pathology , Cohort Studies , Female , Hospitals , Humans , Liver Neoplasms/pathology , Male , Neoplasm Invasiveness , Prognosis , Retrospective Studies
Aim: MTHFD1 was the enzyme providing one-carbon derivatives of tetrahydrofolate. We sought to investigate the impact of MTHFD1 on hepatocellular carcinoma (HCC). Methods: Bioinformatic analysis, western blot and immunohistochemistry were conducted to detect MTHFD1 expression in HCC. The relationships between MTHFD1 and prognosis of 172 HCCs were analyzed by Kaplan-Meier method and Cox proportional hazards model. Results: High MTHFD1 expression in HCC represented poor prognosis (overall survival p = 0.025; time to recurrence p = 0.044). Combining MTHFD1 with serum AFP, survival analysis demonstrated the prognosis of the MTHFD1 low expression and AFP ≤20 ng/ml group was better than that of the MTHFD1 high expression or AFP >20 ng/ml group and the MTHFD1 high expression and AFP >20 ng/ml group (overall survival p < 0.0001; time to recurrence p < 0.0001). Conclusion: High MTHFD1 expression in HCC indicated poorer prognosis. Combining MTHFD1 with serum AFP improved the accuracy of prognostic prediction.
Biomarkers, Tumor , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/mortality , Gene Expression , Liver Neoplasms/genetics , Liver Neoplasms/mortality , Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics , Minor Histocompatibility Antigens/genetics , Adult , Aged , Carcinoma, Hepatocellular/pathology , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Liver Neoplasms/pathology , Male , Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism , Middle Aged , Minor Histocompatibility Antigens/metabolism , Neoplasm Recurrence, Local , Neoplasm Staging , Prognosis , ROC Curve , Reproducibility of Results , Risk Factors , Tumor Burden , alpha-Fetoproteins/metabolism
AIM: Microvascular invasion (MVI) is not discussed for solitary hepatocellular carcinoma (HCC) up to 2 cm in the 8th Edition of the American Joint Committee on Cancer Staging Manual. The present study aimed to reappraise the influence of MVI on solitary HCC up to 2 cm in diameter. METHODS: Between January 2010 and December 2012, a retrospective cohort of 496 HCC patients from the Eastern Hepatobiliary Surgery Hospital was analyzed. Propensity score matching was carried out to balance the baseline characteristics. Survival analysis was carried out using the Kaplan-Meier method. Risk factors were evaluated using the Cox proportional hazards model. Multivariate logistic regression was used to identify the risk factors associated with MVI. RESULTS: All patients were classified into either an MVI-negative group (n = 332) or an MVI-positive group (n = 164). The MVI-positive group had poorer recurrence-free survival and overall survival before and after propensity score matching. The multivariate analysis showed that MVI; being male; increased total bilirubin levels, alanine transaminase levels and γ-glutamyl transpeptidase levels; decreased albumin levels; and HBV DNA load >103 IU/mL were risk factors for recurrence-free survival. MVI, older age, lower albumin levels, and cirrhosis were risk factors for overall survival. Age <50 years, alpha-fetoprotein >20 ng/mL, and lack of or an incomplete capsule were significantly independent predictors for MVI. CONCLUSIONS: MVI had a negative impact on the prognosis of solitary HCC up to 2 cm after curative hepatectomy. The 8th edition of the American Joint Committee on Cancer staging system could be improved by subdividing solitary HCC up to 2 cm according to MVI.
