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Han Wang,1,* Jun-Jie Chen,2,* Shu-Yi Yin,3,* Xia Sheng,4 Hong-Xia Wang,5 Wan Yee Lau,6 Hui Dong,1 Wen-Ming Cong1 1Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Radiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Pathology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 4Department of Pathology, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of Pathology, Jiading District Central Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, People’s Republic of China; 6Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China*These authors contributed equally to this workCorrespondence: Hui Dong; Wen-Ming Cong, Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, People’s Republic of China, Tel +86-021-81875191 ; +86-021-81875192, Email huidongwh@126.com; wmcong@smmu.edu.cnBackground: 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. Keywords: hepatocellular carcinoma, microvascular invasion, hepatectomy, hepatic resection, pathology

Wei Dong,1,2,* Hua Yu,1,2,* Yu-Yao Zhu,1,2,* Zhi-Hong Xian,1,2 Jia Chen,1,2 Hao Wang,3 Chun-Chao Shi,4 Guang-Zhi Jin,5 Hui Dong,1,2 Wen-Ming Cong1,2 1Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, People’s Republic of China; 2Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University, The Ministry of Education, Shanghai 200438, People’s Republic of China; 3Department of Hepatobiliary Diseases, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, People’s Republic of China; 4Second Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai 200438, People’s Republic of China; 5Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200050, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui DongDepartment of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People’s Republic of ChinaEmail 13917078308@126.comWen-Ming CongDepartment of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People’s Republic of ChinaEmail wmcong@smmu.edu.cnPurpose: 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.Keywords: cirrhosis, hepatocellular carcinoma, HCC, pathology, scoring system, nomogram

Background and Objective: Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC., Methods: We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023., Key Content and Findings: Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, Wnt/β-catenin , microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI., Conclusions: The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-527/coif). The authors have no conflicts of interest to declare., (2024 Hepatobiliary Surgery and Nutrition. All rights reserved.)

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 5 th edition of the World Health Organization Classification of Tumours of the Digestive System., Competing Interests: The authors have no conflict of interests related to this publication., (© 2023 Authors.)

Objective: To investigate the clinicopathological features, treatment, and prognosis of hepatic angiosarcoma. Methods: Clinicopathological data and prognostic conditions of 18 cases with hepatic angiosarcoma were collected retrospectively. The recurrence-free survival rate and overall survival rate were calculated by the Kaplan-Meier method. A Cox regression analysis was used to explore the survival-related risk factors. Results: There were 12 male and 6 female patients, with an average age of 57 (37 ~ 70) years. The tumor's average diameter was 8.40 (2.00 ~ 18.00) cm. Seven cases had multiple tumors, while two cases had large vessel tumor thrombuses. Microscopically, the tumor tissues were irregularly anastomosed, with vascular lacunar or solid bundle-like weaving, and the tissue morphology mimicked capillary hemangioma, cavernous hemangioma, or angioepithelioma, while tumor cells were spindle-shaped or epithelioid, lined with hobnails in the lumen, or formed papillary structures in the lumen. The proportion of highly, moderately, and poorly differentiated tumors was 4:8:6, with six cases having clear tumor boundaries, eight having microvascular tumor thrombi, and sixteen having blood lake formation. Different levels of expression of CD31, CD34, erythroblast transformation-specific related genes, and Fli-1 markers were demonstrated in all of the cases. Four cases had a P53 mutation, and six cases had Ki-67 > 10%. During the follow-up period of 0.23-114.20 months, the five-year recurrence-free survival rate and overall survival rate were 16.7% and 37.2%, respectively. Cox regression multivariate analysis showed that preoperative symptoms and multiple tumors were significant risk factors for recurrence-free survival, while preoperative symptoms and Ki-67 > 10% were significant risk factors for overall survival. Conclusion: Hepatic angiosarcoma is a rare hepatic mesenchymal tumor with high malignancy and a poor prognosis. Pathological morphology and immunohistochemical marker combinations are needed for a definite diagnosis. However, the complexity of angiosarcomas' histological and cytological conformations and the overlap of pathological features with benign vascular tumors, sarcomas, and carcinomas pose difficulties in the differential diagnosis. Thus, the only effective ways to prolong survival are early detection and radical surgical resection.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Feng, Zhu, Zhou, Wang, Xu, Zhang, Mao, Cong, Dong and Wang.)

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., (© 2022. Society of Surgical Oncology.)

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., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

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., (© 2022. The Author(s).)

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., (Copyright © 2021. Published by Elsevier B.V.)

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.

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.

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.

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., (Copyright © 2020 Wang, Yu, Qian, Cao, Wu and Cong.)

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., Competing Interests: The authors declare there are no competing interests., (©2020 Yu et al.)

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., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

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., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

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.

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., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

The occurrence of hepatocellular carcinoma (HCC) is a multistep development process through precancerous lesions. A precancerous lesion of HCC is classified into hepatocyte dysplasia at the cytological level and dysplastic nodules at the histological level, and the corresponding lesion subtypes have different risks of canceration. Pathology is the "gold standard" for the diagnosis of early stage HCC and its precancerous lesions. However, it also faces many difficulties and challenges, such as the accumulation of experience in the pathological diagnosis, the understanding and grasp of key points of histopathological diagnosis and differential diagnosis, the combination application of immune and molecular diagnostic markers, and many others. This article briefly discusses the key points of pathological features and differential diagnosis of precancerous lesions of HCC.

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.

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 >10 3  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., (© 2018 The Japan Society of Hepatology.)

Background: The survival benefit of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) remained controversial. We aimed to investigate the prognosis effect of PA-TACE on the Barcelona Clinic Liver Cancer (BCLC) early stage multinodular hepatocellular carcinoma (MHCC) patients with/without microvascular invasion (MVI)., Methods: Two hundred and seventy-one patients from January 2010 to December 2014 undergoing curative hepatectomy were included in this study. Disease-free survival (DFS) rates and overall survival (OS) rates as well as prognostic factors were analyzed by the Kaplan-Meier method, the log-rank test and the Cox proportional hazard model., Results: Thirty-four point four percent (44/128) MVI positive and 55.2% (79/143) MVI negative patients underwent PA-TACE. Multivariate analysis revealed that HBV DNA load >10 3 copy/mL, >three tumors, MVI, and without PA-TACE were independent risk factors for poor DFS. Higher alkaline phosphatase (ALP), three tumors, MVI, and without PA-TACE were independent risk factors for poor OS. Both DFS and OS were significantly improved in patients with MVI who received PA-TACE as compared to those who underwent hepatic resection alone (5-year DFS, 26.3% vs. 20.7%, P=0.038; 5-year OS, 73.6% vs. 47.7%, P=0.005). No differences were noted in DFS and OS among MVI negative patients with or without PA-TACE (5-year DFS, 33.7% vs. 33.0%, P=0.471; 5-year OS, 84.1% vs. 80.3%, P=0.523). Early recurrence was more likely to occur in patients without PA-TACE (P=0.001)., Conclusions: PA-TACE was a safe intervention and could effectively prevent tumor recurrence and improve the survival of the BCLC early stage MHCC patients with MVI., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression., Competing Interests: The authors have declared that no competing interests exist.

The poor thermodynamic stability of gold nanoparticles (NPs) makes it very challenging to stabilize them in small sizes at elevated temperatures. Herein, we report the preparation of antisintering Au nanocatalyst by rationally selecting the sublattice matched MgGa 2 O 4 spinel as support based on theoretical predictions. Au/MgGa 2 O 4 retains Au NPs of 2-5 nm even after aging over the melting temperature of bulk gold (1064 °C)! By identifying the stable structure, the extraordinary stability is found to arise from the formation of a new phase structure, namely Au-MgGa 2 O 4 metal-oxide "hetero-bicrystal" that remains as crystallite without melting even at 1100 °C. More than 80% of the loaded Au can be efficiently stabilized so that the catalysts can exhibit excellent low-temperature activities for diesel exhaust (CO and C 3 H 6 ) oxidation after severely thermal and hydrothermal aging. These results may pave ways for constructing antisintering gold nanocatalysts for industrial applications.

Background: Hepatocellular carcinoma (HCC) (about 85-90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people., Summary: This guideline presents official recommendations of the National Health and Family Planning Commission of the People's Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations., Key Messages: The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.

Copy number aberrations (CNAs) in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma (HCC). This study was to identify correlation of CNAs in 8q with clinical outcomes of HCC patients, and further screen for differentially expressed genes in outcome-related CNAs. Array comparative genomic hybridization and expression arrays were performed to detect CNAs and expression levels, respectively. The correlations between CNAs in 8q and outcomes were analyzed in 66 patients, with a median follow-up time of 45.0 months (range, 2.6-108.6 months). One hundred and nine cases were further evaluated to identify differentially expressed genes in the potential outcome-related CNAs. Copy number gain in 8q was observed in 22 (33.3%) of the 66 HCC cases. The most recurrent gains (with frequencies >20%) were 8q13.3-21.3,8q21.3-23.3,8q23.3-24.13,8q24.13-24.3, and 8q24.3. Survival analysis showed that 8q24.13-24.3 gain was significantly associated with reduced overall survival (jP=0.010). Multivariate Cox analysis identified 8q24.13-24.3 gain as an independent prognostic factor for poor overall survival (HR=2.47; 95% CI=1.16-5.26; Р=0.019). Apanel of 17 genes within the 8q24.13-24.3 region, including ATAD2,SQLE,PVT1,ASAP1, and NDRG1 were significantly upregulated in HCCs with 8q24.13-24.3 gain compared to those without. These results suggest that copy number gain at 8q24.13-24.3 is an unfavorable prognostic marker for HCC patients, and the potential oncogenes ATAD2,SQLE, PVT1, ASAP1,and NDRG1 within the regional gain, may contribute coordinately to the 8q24.13-24.3 gain-related poor prognosis.

Background: Chronic HBV plays an important role in hepatocellular carcinoma pathogenesis. Previously, most studies have been focusing on HBV DNA levels before the primary curative hepatectomy. However, the association of virus level before repeat hepatectomy with the degrees of inflammation and fibrosis on histopathology and prognosis has not been surveyed., Methods: From January 2002 to December 2009, all patients who were seropositive for hepatitis B surface antigen (HBsAg) were enrolled and assigned into four groups based on their HBV DNA levels before the primary and repeat hepatectomies. The cancer prognoses of these four groups of patients after the first and second operations were assessed and compared. The disease-free survival and overall survival were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify risk factors for the primary and repeat hepatectomies., Results: For the 385 patients in this study, a low level of serum HBV DNA before repeat hepatectomy, but not primary hepatectomy, was significantly associated with improvement in prognosis, in terms of tumor recurrence, liver fibrosis, and liver-related mortality., Conclusion: The levels of HBV DNA before hepatectomies were crucial prognostic risk factors of HBV-related hepatocellular carcinoma patients. Surveillance of serum HBV DNA levels at multiple time points, rather than at a single time point, and antiviral therapy to suppress the virus to a low level had beneficial effects for these patients.

The long-term survival rate of hepatocellular carcinoma (HCC) is poor. One of the reasons for the poor rate of survival is the high rate of recurrence caused by intrahepatic metastas is that adversely affects long-term outcome. Many studies have indicated that microRNAs play an important role in HCC, but there has been no research of clonal origins on recurrent HCC (RHCC) by analzing microRNAs. In the present study, we found that miR-483-5p was significantly upregulated in RHCC tissues of short-term recurrence (≤ 2 years) by miRNA microarray screening, and can significantly promote migration and invasion of HCC cells in vitro and increase intrahepatic metastasis in nude mice in vivo . Furthermore, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM), which significantly suppressed migration and invasion of HCC cells, was a direct target of miR-483-5p, and the re-introduction of ALCAM expression could antagonize the promoting effects of miR-483-5p on the capacity of HCC cells for migration and invasion. In addition, expression level of ALCAM was negatively correlated with microvascular invasion and tumor size recognized as prognostic factors. The cases which were negative for ALCAM expression had shorter time to recurrence than positive cases, and univariate and multivariate survival analyses showed that ALCAM was an independent risk factor of HCC recurrence. qRT-PCR and Western blotting showed that the expression of EMT related genes (MMP-2, MMP-9, E-caherin and vimentin) significantly changed as a result of interfering or overexpression of ALCAM, and ALCAM was significantly associated with EMT in HCC. These results suggest that the miR-483-5p/ALCAM axis is an important regulator in invasion and metastasis and biomarker for recurrence risk assessment of HCC.

Intraductal papillary neoplasm of bile duct (IPNB) is characterized by a spectrum of diseases ranging from low-grade intraepithelial neoplasia to invasive carcinoma. In the present study, we aimed to investigate immunophenotypic features and KRAS mutations in relation to pathological subtypes and grades in Chinese patients with IPNBs. A total of 46 patients with IPNBs and 11 invasive adenocarcinomas arising in IPNBs (invasive IPNBs) were enrolled and clinicopathological data were analyzed. It was found that CK7 was expressed in 42 of the 46 neoplastic lesions. HepPar1 was expressed in 11 of the 46 noninvasive IPNBs, but not in invasive IPNBs. Additionally, CK19 was frequently expressed in both noninvasive IPNBs and invasive IPNBs. The intestinal-type IPNBs had a significantly higher percentage of MUC2 expression relative to the pancreaticobiliary (P=0.015) and gastric-type IPNBs (P<0.001). High-grade IPNBs and invasive IPNBs showed increased expression of cyclin D1, Ki-67, p53, mCEA, and CA19-9. The rate of KRAS mutation was significantly higher in high-grade IPNBs (P=0.001) and invasive IPNBs (P=0.006) than that in low- to intermediate-grade IPNBs. Additionally, KRAS mutation was significantly associated with tumor size, and Ki-67 expression. In conclusion, the expression of cyclin D, Ki-67, p53, mCEA and CA19-9 and KRAS mutation status are significantly correlated with histological grades of IPNBs., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6-positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6-positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment., Conclusion: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934-1951)., (© 2017 by the American Association for the Study of Liver Diseases.)

Aim: The stromal invasion has been regarded as the most valuable clue to distinguish high-grade dysplastic nodules (HGDNs) and well-differentiated small hepatocellular carcinomas (WD-SHCCs). The purposes of this study are to explore the stromal morphological changes for the differential diagnosis of these two equivocal lesions., Results: Based on the systemic studies of histological characteristics of HGDNs and WD-SHCCs, the stromal morphological changes, including sinusoid capillarization, ductular reaction and solitary artery, were performed to make a differential diagnosis between them. Separately, the solitary artery had the best sensitivity (93.75%) and accuracy (88.89%), and the sinusoid capillarization had the best specificity of 90.32%. On the whole, when at least 2 stromal morphological changes were abnormal, no matter what combination, the diagnostic performance was favorable and optimal with the highest accuracy of 92.06%, balancing the sensitivity (93.75%) and specificity (90.32%). The diagnostic performances were prior to the classical immunohistochemical panel comprising heat shock protein 70, glypican 3 and glutamine synthetase with the best sensitivity, specificity and accuracy of 62.50%, 80.65% and 71.43%, respectively., Materials and Methods: A retrospective case-control study was conducted on 63 patients who underwent partial hepatectomy for uninodular HGDNs or WD-SHCCs at the Eastern Hepatobiliary Surgery Hospital from 2005 to 2015., Conclusions: The stromal morphological changes, containing sinusoid capillarization, ductular reaction and solitary artery could provide a more considerable diagnostic and differential diagnostic performance between HGDNs and WD-SHCCs. And they should be the key points during the histopathological diagnosis., Competing Interests: CONFLICTS OF INTEREST No conflicts of interest.

Objective: To investigate the molecular markers of copy number aberrations (CNAs) of genes related to extrohepatic metastasis-free survival after the operation for hepatocellular carcinoma (HCC). Methods: The CNA status of 20 candidate genes in 66 HCC samples was detected by microarray comparative genomic hybridization. The associations between gene CNAs and extrohepatic metastasis-free survival were evaluated using the Cox regression model, Log-rank test, and Kaplan-Meier survival analysis. Results: Multivariate Cox analysis revealed that the independent risk factors for metastasis-free survival were MDM4 gain (hazard ratio [ HR ] = 2.74, 95% confidence interval [ CI ] = 1.18-6.37, P < 0.05), APC loss ( HR = 8.43, 95% CI = 2.48-28.66, P < 0.01), and BCL2L1 gain ( HR = 3.45, 95% CI = 1.13-10.52, P < 0.05) and the independent protective factor was FBXW7 loss ( HR = 0.32, 95% CI = 0.12-0.89, P < 0.05). By stepwise Cox regression analysis, three CNAs related to metastasis-free survival were screened out: MDM4 gain ( HR = 2.71, 95% CI = 1.11-6.64, P < 0.05), APC loss ( HR = 7.19, 95% CI = 1.88-27.60, P < 0.005), and FBXW7 loss ( HR = 0.16, 95% CI = 0.05-0.46, P < 0.01). There were significant differences in metastasis-free survival rate between the HCC patients with FBXW7 loss and without MDM4 gain or APC loss, those with MDM4 gain and/or APC loss and without FBXW7 loss, and those with other CNA combinations (log-rank test, P < 0.01). Conclusion: MDM4 gain, APC loss, and FBXW7 loss are the independent prognostic factors for extrohepatic metastasis-free survival after the operation for HCC and can be used to predict the risk of extrohepatic metastasis after the operation for HCC.

Purpose: To propose a novel histopathological classification system for microvascular invasion (MVI) and to establish nomograms to predict postoperative survival and early tumor recurrence in patients with hepatocellular carcinoma (HCC) after R0 liver resection., Methods: The clinicopathological and follow-up data of 686 consecutive patients with HCC who underwent R0 liver resection in our hospital between December 2009 and April 2010 were retrospectively reviewed. A classification system was established based on histological characteristics of MVI. Nomograms were then formulated using a multivariate Cox proportional hazards model to analyze. The results were validated using bootstrap resampling and a new 225-patient validation cohort operated in May and June 2010 at the same institution., Results: A 4-stratification classification system of MVI was established, which satisfactorily determined the risk of survival and early tumor recurrence. Then, an eight-factor nomogram for survival prediction and a seven-factor nomogram for prediction of early tumor recurrence were established. The concordance indices were 0.78 for the survival-prediction nomogram and 0.72 for the recurrence-prediction nomogram. These indices were both significantly higher than the following three commonly used staging systems: tumor-node-metastasis staging system (seventh edition, 0.67/0.65), Japan Integrated Staging System (0.58/0.58) and Chinese University Prognostic Index (0.52/0.51). The calibration curves showed good agreement between predictions by the nomograms and actual survival outcomes. These results were confirmed in the validation cohort., Conclusions: The novel classification system of MVI and the nomograms enabled more accurate predictions of risk of tumor recurrence and overall survival in patients with HCC after R0 liver resection.

In 2010, a panel of Chinese pathologists reported the first expert consensus for the pathological diagnosis of primary liver cancers to address the many contradictions and inconsistencies in the pathological characteristics and diagnostic criteria for PLC. Since then considerable clinicopathological studies have been conducted globally, prompting us to update the practice guidelines for the pathological diagnosis of PLC. In April 18, 2014, a Guideline Committee consisting of 40 specialists from seven Chinese Societies (including Chinese Society of Liver Cancer, Chinese Anti-Cancer Association; Liver Cancer Study Group, Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Pathology, Chinese Anti-Cancer Association; Digestive Disease Group, Chinese Society of Pathology, Chinese Medical Association; Chinese Society of Surgery, Chinese Medical Association; Chinese Society of Clinical Oncology, Chinese Anti-Cancer Association; Pathological Group of Hepatobiliary Tumor and Liver Transplantation, Chinese Society of Pathology, Chinese Medical Association) was created for the formulation of the first guidelines for the standardization of the pathological diagnosis of PLC, mainly focusing on the following topics: gross specimen sampling, concepts and diagnostic criteria of small hepatocellular carcinoma (SHCC), microvascular invasion (MVI), satellite nodules, and immunohistochemical and molecular diagnosis. The present updated guidelines are reflective of current clinicopathological studies, and include a novel 7-point baseline sampling protocol, which stipulate that at least four tissue specimens should be sampled at the junction of the tumor and adjacent liver tissues in a 1:1 ratio at the 12, 3, 6 and 9 o'clock reference positions. For the purposes of molecular pathological examination, at least one specimen should be sampled at the intratumoral zone, but more specimens should be sampled for tumors harboring different textures or colors. Specimens should be sampled at both adjacent and distant peritumoral liver tissues or the tumor margin in order to observe MVI, satellite nodules and dysplastic foci/nodules distributed throughout the background liver tissues. Complete sampling of whole SHCC ≤ 3 cm should be performed to assess its biological behavior, and in clinical practice, therapeutic borders should be also preserved, even in SHCC. The diagnostic criteria of MVI and satellite nodules, immunohistochemical panels, as well as molecular diagnostic principles, such as clonal typing, for recurrent HCC and multinodule HCC were also proposed and recommended. The standardized process of pathological examination is aimed at ensuring the accuracy of pathological PLC diagnoses as well as providing a valuable frame of reference for the clinical assessment of tumor invasive potential, the risk of postoperative recurrence, long-term survival, and the development of individualized treatment regimens. The updated guidelines could ensure the accuracy of pathological diagnoses of PLC, and provide a valuable frame of reference for its clinical assessment., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this work.

Background: Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin remains unclear. The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC., Methods: The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC (SHC). Loss of heterozygosity (LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC. Expression of hepatocyte markers [hepatocyte paraffin 1 (Hep Par 1) and glypican 3 (GPC3)] and cholangiocyte markers [cytokeratin (CK)7 and 19] in tumor tissues was examined by immuno histochemical analysis., Results: In the 16 CHC specimens, the difference in LOH patterns between HCC and ICC was less than 30%, suggesting the same clonal origin of HCC and ICC. Consistent with this finding, immunohistochemical analysis revealed that hepatocyte markers (Hep Par 1 and GPC3) and cholangiocyte markers (CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9% of CHC specimens, suggesting that the two components shared a similar phenotype with hepatic progenitor cells (HPCs). On the contrary, in all 10 SHC cases, the difference in LOH patterns between the HCC and ICC components was greater than 30%, suggesting different clonal origins of HCC and ICC. Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC (P < 0.05)., Conclusions: Our results suggest that the HCC and ICC components of CHC may originate from the same clone, having the potential for dual-directional differentiation similar to HPCs. CHC tended to exhibit the biological behaviors of both HCC and ICC, which may enhance the infiltrative capacity of tumor cells, leading to poor clinical outcomes for patients with CHC.

The strong invasiveness and metastasis of hepatocellular carcinoma (HCC) are not only the important pathological mechanisms of high recurrence rate and poor long-term outcome, but also the important pathological basis for developing individualized regimens to control metastasis and recurrence in clinical practice. This article introduces the important molecular events in invasion-metastasis cascade discovered in recent years, including the formation mechanism of metastatic niches, methods for molecular pathological evaluation, and standardized pathological diagnosis.