Grade Of Hepatocellular Carcinoma Research Articles

Preoperative prediction of pathologic grade of HCC on gadobenate dimeglumine-enhanced dynamic MRI.

To evaluate the value of gadobenate dimeglumine-enhanced MRI in predicting the pathologic grade of hepatocellular carcinoma (HCC). Patients with pathologically proven HCC who underwent preoperative gadobenate dimeglumine-enhanced dynamic MRI were included. Two radiologists blinded to pathology results evaluated images in consensus. Lesions were evaluated quantitatively in terms of ratio of enhancement (RE), and qualitatively based on image features related to tumor aggressiveness. Logistic regression and ROC analyses were used to determine the value of these parameters to predict pathologic grade. In total, 221 patients (194 males, 27 females, aged 52.9 ± 11.7 years) with 49 poorly differentiated HCCs and 172 well/moderately differentiated HCCs were evaluated. Features significantly related to poorer pathologic grade at univariate analysis included lower RE in the early arterial phase (EAP) (p = 0.001), nonsmooth margins (p = 0.001), absence of capsule (p < 0.001), arterial peritumoral hyperenhancement (p < 0.001), higher AFP (p = 0.004), multiple tumors (p = 0.026), and larger tumor size (p = 0.028). At multivariate analysis, lower RE (EAP) (OR = 0.144, p = 0.002), absence of capsule (OR = 0.281, p = 0.004), and arterial peritumoral hyperenhancement (OR = 4.117, p < 0.001) were independent predictive factors for poorer pathologic grade. ROC analysis showed lower RE (EAP) was predictive of poorer pathologic grade (AUC = 0.667). AUC increased to 0.797 when combined with absence of capsule and presence of peritumoral hyperenhancement. Lower RE (EAP), absence of capsule, and arterial peritumoral hyperenhancement were predictive biomarkers for poorer pathologic grade of HCC on gadobenate dimeglumine-enhanced dynamic MRI. • Gadobenate dimeglumine-enhanced dynamic MRI was a useful quantitative biomarker for preoperative prediction of pathologic grade in patients with HCC. • Lower RE in the early arterial phase, absence of capsule, and arterial peritumoral hyperenhancement were potential imaging indicators for preoperative prediction of poorer pathologic grade of HCC on gadobenate dimeglumine-enhanced MRI. • A lower RE in the early arterial phase was effective at predicting poorer pathologic grade of HCCs but prediction is improved when combined with absence of capsule and presence of peritumoral hyperenhancement.

Clinical and Pathological Attributes of Hepatocellular Carcinoma Showing Lack of Restricted Diffusion on Magnetic Resonance Imaging

Objective: To correlate non-restricted diffusion magnetic resonance imaging (MRI) patterns of hepatocellular carcinoma (HCC), with histopathology and clinical outcome.Material and Methods: We retrospectively evaluated pre-treatment MRIs showing non-restricted diffusion HCC lesions (≥1-centimeter), excluding lesions with poor quality/non-available diffusion weighted imaging (DWI). Three radiologists evaluated 37 lesions in 27 patients, for: T1-weighted (T1W)/T2-weighted (T2W) characteristics, arterial enhancement, washout on portal venous/delayed phase, capsular enhancement, intralesional fat component and presence of cirrhosis. Histopathological reports were categorized as: well/moderate/poorly differentiated. Kaplan-Meier survival analysis was calculated for clinical outcome.Results: From a total of 37 lesions, 24 lesions had available pathological grading, which revealed well and moderately differentiated equally (12 lesions each). None of the non-restricted diffusion HCCs were poorly differentiated. Thirty-five of the 37 lesions (94.6%) showed arterial enhancement with washout; 34 lesions (91.9%) were T2W hypo-/isointense, 33 esions (89.2%) were T1W iso-/hyperintense, 19 lesions (51.4%) showed capsular enhancement and 8 lesions (21.6%) had intralesional fat. These findings in the well and moderately differentiated groups were not significantly different (p-value 0.178-1.000). Overall mean-survival was 6.972 years (95% confidence interval (CI); 5.3-8.6). The 1-year, overall survival rate was 83.6% and for 3-years was 67.9%. Mean survival of well and moderately differentiated groups were 6.88 and 7.23 years (95% CI 5.7-8.0 and 4.4-10.1), respectively (p-value=0.319).Conclusion: DWI may help to predict histological grading of HCC and clinical outcome. We found that non-restricted diffusion HCCs were histologically well or moderately differentiated, with no significant difference of imaging findings and survival rates between the two groups. No poorly differentiated lesions were seen in our non-restricted HCC cohort.

Overexpression of GINS4 Is Associated With Tumor Progression and Poor Survival in Hepatocellular Carcinoma.

PurposeOur research was aimed to identify the expression, clinical value and biological significance of GINS complex subunit 4 (GINS4) in hepatocellular carcinoma (HCC).Materials and MethodsGINS4 was initially screened through weighted gene co-expression network analysis (WGCNA). The TCGA, GEO, and TIMER databases were applied for analyzing the GINS4 mRNA expression in HCC. GINS4 protein levels were detected via immunohistochemistry (IHC). Receiver operating characteristic (ROC) curve was applied for estimating the diagnostic significance of GINS4 in HCC. Kaplan-Meier plots, Cox model, and nomogram were used to assess the prognostic performance of GINS4 in HCC. Nomogram validation was conducted through time-dependent ROC and decision curve analysis (DCA). The Wanderer, UALCAN, and DiseaseMeth databases were utilized to identify GINS4 methylation levels in HCC. Genes co-expressed with GINS4 in HCC were estimated through the TCGA, cBioPortal, and GEPIA. GO, KEGG, and GSEA unraveled the possible biological mechanisms of GINS4 in HCC.ResultsWGCNA confirmed that GINS4 was one of hub genes significantly associated with histological grade of HCC. Multiple databases confirmed the significant upregulation of GINS4 in HCC tissues compared with non-tumor controls. IHC analysis of 35 HCC patients demonstrated that overexpressed GINS4 positively correlated with advanced TNM stage and poor pathological differentiation. GINS4 could effectively differentiate HCC cases from healthy individuals, with an AUC of 0.865. Increased GINS4 expression predicted unsatisfactory prognosis in HCC patients, especially in age >60 years, histological grade 1, HBV infection-negative, and occurring relapse subgroup. Nomogram incorporating GINS4 level and TNM stage displayed satisfactory predictive accuracy and clinical utility in predicting HCC prognosis. Upregulated GINS4 exhibited hypomethylated levels in HCC. Functional analysis indicated that GINS4 potentially positively modulated cell cycle and PI3K/AKT/mTOR pathway.ConclusionGINS4 is overexpressed in HCC and is correlated with undesirable survival of HCC patients.

Convolutional neural network for classifying primary liver cancer based on triple-phase CT and tumor marker information: a pilot study.

To develop convolutional neural network (CNN) models for differentiating intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) and predicting histopathological grade of HCC. Preoperative computed tomography and tumor marker information of 617 primary liver cancer patients were retrospectively collected to develop CNN models categorizing tumors into three categories: moderately differentiated HCC (mHCC), poorly differentiated HCC (pHCC), and ICC, where the histopathological diagnoses were considered as ground truths. The models processed manually cropped tumor with and without tumor marker information (two-input and one-input models, respectively). Overall accuracy was assessed using a held-out dataset (10%). Area under the curve, sensitivity, and specificity for differentiating ICC from HCCs (mHCC + pHCC), and pHCC from mHCC were also evaluated. We assessed two radiologists' performance without tumor marker information as references (overall accuracy, sensitivity, and specificity). The two-input model was compared with the one-input model and radiologists using permutation tests. The overall accuracy was 0.61, 0.60, 0.55, 0.53 for the two-input model, one-input model, radiologist 1, and radiologist 2, respectively. For differentiating pHCC from mHCC, the two-input model showed significantly higher specificity than radiologist 1 (0.68 [95% confidence interval: 0.50-0.83] vs 0.45 [95% confidence interval: 0.27-0.63]; p = 0.04). Our CNN model with tumor marker information showed feasibility and potential for three-class classification within primary liver cancer.

The Relationship Between Plexin C1 Overexpression and Survival in Hepatocellular Carcinoma: a Turkish Oncology Group (TOG) Study

Plexin C1 is a transmembrane receptor and plexin C1 overexpression might have role in carcinogenesis. Hepatocellular carcinoma (HCC) has poor prognosis because of its aggressive behavior and limited treatment options, especially in advanced stage. We recently documented that Plexin C1 was overexpressed in HCC. We aimed to evaluate the prognostic significance of Plexin C1 overexpression in HCC in the present study. Plexin C1 overexpression was evaluated immunohistochemically on paraffin-embedded blocks of the HCC patients. Plexin C1 immunohistochemical staining was scored. Plexin C1 overexpression staining intensity and prevalence were used for plexin scale staining evaluation and plexin scores were estimated according this staining scale. Plexin C1 score and its association with survival and clinicopathological features was assessed. Sixty-seven HCC patients with adequate tissue for pathological evaluation were included. Median age was 63 years with male predominance (male to female ratio was 4.75 (n 57/12). Well-differentiated HCC (53.7%) patients had higher plexin C1 overexpression (p < 0.05). Median OS was 22.1 months. Patients with lower plexin C1 score (< 12) had shorter OS (17.5 vs 30.1 months, p = 0.036). Neutrophil count, GGT, and PNR (platelet/neutrophil ratio) had prognostic significance (p = 0.047, p = 0.018, and p = 0.045). Plexin C1 overexpression is inversely correlated with grade in HCC. The patients with lower rate of Plexin C1 overexpression have worse survival outcome. It might be a prognostic factor in HCC.

Endothelial Cells of a Normal Liver and with Hepatocellular Carcinoma

The article presents a systematic review of the literature data on the role of endothelial cells and features of vascularization in the development of hepatocellular carcinoma. The capillaries of the normal liver are represented by sinusoids, which are characterized by the presence of specific fenestrations in endothelial cells and the absence of a basal membrane under the endothelium. The article shows that, as a rule, the development of hepatocellular carcinoma occurs upon chronic liver lesions, and it is a multistage process of the progression of tissue and cellular atypism, as well as changes in the vascularization of tumor tissue. The vascular network that forms in the tumor tissue is characterized by structural and functional atypism. The development and progression of liver carcinoma is accompanied by changes in the structure and metabolism of endothelial cells in the tumor node, as well as chromosomal aberrations with impaired gene expression and growth factors. The processes of angiogenesis and vascularization are based on the morphological determination of microvessel density on immunohistochemical specimens. The clinical diagnosis of hepatocellular carcinoma is based on the detection of radiation characteristics of the tumor, including those due to changes in vascularization of the tumor tissue. An increase in the malignancy grade of hepatocellular carcinoma is accompanied by a decrease in blood flow through the portal vein system and, accordingly, an increase in arterial blood flow. It is noted that knowledge of the processes of tumor angiogenesis is required to develop antitumor, targeted, antiangiogenic drugs.

Analysis and Validation of circRNA-miRNA Network in Regulating m6A RNA Methylation Modulators Reveals CircMAP2K4/miR-139-5p/YTHDF1 Axis Involving the Proliferation of Hepatocellular Carcinoma.

The m6A RNA methylation modulators play a crucial role in regulating hepatocellular carcinoma (HCC) progression. The circular RNA (circRNA) regulatory network in regulating m6A RNA methylation modulators in HCC remains largely unknown. In this study, 5 prognostic m6A RNA methylation modulators in HCC were identified from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects. The differentially expressed microRNAs (DEmiRNAs) and circRNAs (DEcircRNAs) between paired tumor and normal tissues were screened out from TCGA and or Gene Expression Omnibus (GEO) database to construct the circRNA-miRNA- m6A RNA methylation modulator regulatory network, which included three m6A RNA methylation modulators (HNRNPC, YTHDF1, and YTHDF2), 11 DEmiRNAs, and eight DEcircRNAs. Among the network, hsa-miR-139-5p expression was negatively correlated with YTHDF1. Hsa-miR-139-5p low or YTHDF1 high expression was correlated with high pathological grade, advanced stage and poor survival of HCC. Additionally, cell cycle, base excision repair, and homologous recombination were enriched in YTHDF1 high expression group by GSEA. A hub circRNA regulatory network was constructed based on hsa-miR-139-5p/YTHDF1 axis. Furthermore, hsa_circ_0007456(circMAP2K4) was validated to promote HCC cell proliferation by binding with hsa-miR-139-5p to promote YTHDF1 expression. Taken together, we identified certain circRNA regulatory network related to m6A RNA methylation modulators and provided clues for mechanism study and therapeutic targets for HCC.

Albumin-bilirubin index and platelet-albumin-bilirubin index contribute to identifying survival benefit candidates in patients with hepatocellular carcinoma and Child-Pugh grade A undergoing transcatheter arterial chemoembolization with sorafenib treatment.

BackgroundCombined therapy of transcatheter arterial chemoembolization (TACE) with sorafenib is used for a large number of patients with intermediate-stage or advanced-stage hepatocellular carcinoma (HCC), but its implementation is limited by the evaluation of pre-treatment liver function reserve. This study aimed to validate the performance of the albumin-bilirubin index (ALBI) and platelet-albumin-bilirubin index (PALBI) in predicting survival benefits in patients with HCC and Child-Pugh grade A receiving TACE combined with sorafenib treatment.MethodsFrom 2004 to 2018, 418 patients with intermediate/advanced-stage HCC and Child-Pugh grade A receiving TACE combined with sorafenib treatment were retrospectively enrolled. The predictive performance of ALBI and PALBI was explored by survival analysis and receiver operating characteristic curve (ROC) analysis.ResultsThe median overall survival (mOS) was 24 and 12 months in patients with ALBI grade 1 and grade 2, respectively. The mOS of patients with PALBI grade 1, grade 2, and grade 3 was 23, 16, and 7 months, respectively. The multivariate analysis showed that ALBI grade 2 [hazard ratio (HR) =1.39, 95% confidence interval (CI): 1.11–1.74] and PALBI grade 3 (HR =3.72, 95% CI: 2.26–6.06) were associated with unfavorable prognosis. The ROC analysis revealed that ALBI and PALBI scores had better prediction performance compared with the Child-Pugh score. Subgroup analysis confirmed that by using ALBI or PALBI, patients could be stratified into subgroups with different liver function reserves and distinctive prognosis, regardless of Barcelona Clinic Liver Cancer (BCLC) stage, combination modality, or α-fetoprotein (AFP) levels.ConclusionsBoth ALBI and PALBI could predict prognosis in patients with HCC and Child-Pugh grade A receiving TACE and sorafenib. Patients with ALBI or PALBI grade 1 harbored a more favorable survival outcome compared with those with ALBI or PALBI grade 2–3, and hence should be recommended as the best candidates for TACE combined with sorafenib treatment.

Pathological considerations of CEUS LI-RADS: correlation with fibrosis stage and tumour histological grade.

To evaluate the influence of pathological factors, such as fibrosis stage and histological grade, on the Liver Imaging Reporting and Data System (LI-RADS) v2017 category of contrast-enhanced ultrasonography (CEUS) in patients with high risk of hepatocellular carcinoma (HCC). Between June 2015 and December 2016, 441 consecutive patients at high risk of HCC with 460 pathologically proven HCCs were enrolled in this retrospective study. All patients underwent a CEUS examination. The major features (arterial phase hyperenhancement, late and mild washout) were assessed, and LI-RADS categories were assigned according to CEUS LI-RADS v2017. CEUS LI-RADS categories and major features were compared in different histological grades and fibrosis stages. The CEUS LR-5 category was more frequently assigned in the low-grade group (151/280) than in the high-grade group (66/159) (p = 0.013), whereas the LR-TIV category was more frequently assigned in the high-grade group (36/159) than in the low-grade group (40/280) (p= 0.035). CEUS LI-RADS category was not significantly different among different fibrosis stages (p ≥ 0.05). Arterial phase hyperenhancement (APHE) and the hepatic fibrosis stage showed a significant correlation in HCCs ≥ 2cm and the low-grade group (p= 0.027 and p= 0.003, respectively). No major features of CEUS LI-RADS showed statistically significant differences between the low- and high-grade groups (p≥ 0.05). Hepatic fibrosis stage can influence APHE but showed no impact on the CEUS LI-RADS classification, whereas the histological grade of HCC influenced the LR-5 and LR-TIV categories. • Histological grade influenced CEUS LR-5 and LR-TIV category (p = 0.013 and p = 0.035 respectively). Low-grade HCCs occurred more frequently in LR-5 category whereas high-grade HCCs occurred more frequently in LR-TIV category. • Fibrosis stage shows significant influence on APHE on HCCs of the size ≥ 2cm and low-grade group (p = 0.027 and p = 0.003, respectively). • Hepatic fibrosis stage and HCC histological grade exhibited limited impact on CEUS LI-RADS. CEUS LI-RADS may be feasible for diagnosing HCC in patients regardless of histological grade and fibrosis stage.

Clinicocytological Analysis of Hepatic Neoplastic Lesions

Background: The liver is the site of numerous neoplastic and non-neoplastic lesions, with neoplastic lesions accounting for a prominent cause of morbidity and mortality. Being a common site for metastatic tumors, it becomes imperative to differentiate the same from hepatocellular carcinoma, owing to varied management modalities involved. Diagnosis by fine needle aspiration cytology (FNAC),is considered a prominent investigative procedure in this regard. However, it is not without its limitations and disadvantages. Aim and Objectives: This retrospective research analyzes the cytological features of hepatic masses, with particular reference to pattern assessment, cellular and nuclear details along with background characteristics of note which could define differentiating characteristics of hepatocellular carcinoma from metastatic malignancy. Accompanying clinico-radiological and biochemical parameters that could be helpful in this regard were also studied. An attempt was also made to distinguish the features characteristic to different grades of hepatocellular carcinoma (HCC). Method: FNAC of 114 hepatic neoplastic lesions received during a two years period in the pathology department of a tertiary care hospital were retrospectively analyzed. Clinico-radiological and biochemical parameters were correlated, and data thus retrieved was analyzed statistically for relevance. Results: Males were predominantly affected both by primary and metastatic malignancy with primary over 60 years of age. Jaundice, history of prior alcohol consumption, pre-existing liver disease, elevated LFT along with AFP levels >400 ng/ml was seen in significant cases of hepatocellular carcinoma. Radiologically, metastasis showed multiple lesions with most cases less than 5cms in diameter with invasion of adjacent structures. Analysis of three characteristic cytological features including presence of cytoplasmic bile, intranuclear inclusions and traversing blood vessel was carried out and it was observed that the highest chance of tumor being HCC was when all three were seen. After analyzing features to differentiate between the different grades of HCC it was observed that as the grades progressed the cells became undifferentiated and similarities increased. Cytohistological correlation was seen in 91.3% of cases of primary and 86.9% of metastatic malignancies. Conclusion: Close attention to cytological features like cell clusters, intranuclear inclusions, endothelial rimming in conjunction with radiological images and biochemical markers provide valuable pointers in distinguishing between primary HCC and hepatic metastatic carcinomas thus obviating the need of invasive procedures.

Clinicocytological Analysis of Hepatic Neoplastic Lesion's with Particular Reference to Morphological Pattern Assessment

Background: The liver is the site of numerous neoplastic and non-neoplastic lesions, with neoplastic lesions accounting for a prominent cause of morbidity and mortality. Being a common site for metastatic tumors, it becomes imperative to differentiate the same from hepatocellular carcinoma, owing to varied management modalities involved. Diagnosis by fine needle aspiration cytology (FNAC), is considered a prominent investigative procedure in this regard. However, it is not without its limitations and disadvantages. Aim and Objectives: This retrospective research analyzes the cytological features of hepatic masses, with particular reference to pattern assessment, cellular and nuclear details along with background characteristics of note which could define differentiating characteristics of hepatocellular carcinoma from metastatic malignancy. Accompanying clinico-radiological and biochemical parameters that could be helpful in this regard were also studied. An attempt was also made to distinguish the features characteristic to different grades of hepatocellular carcinoma (HCC). Method: FNAC of 114 hepatic neoplastic lesions received during a two years period in the pathology department of a tertiary care hospital were retrospectively analyzed. Clinico-radiological and biochemical parameters were correlated, and data thus retrieved was analyzed statistically for relevance. Results: Males were predominantly affected both by primary and metastatic malignancy with primary over 60 years of age. Jaundice, history of prior alcohol consumption, pre-existing liver disease, elevated LFT along with AFP levels >400 ng/ml was seen in significant cases of hepatocellular carcinoma. Radiologically, metastasis showed multiple lesions with most cases less than 5cms in diameter with invasion of adjacent structures. Analysis of three characteristic cytological features including presence of cytoplasmic bile, intranuclear inclusions and traversing blood vessel was carried out and it was observed that the highest chance of tumor being HCC was when all three were seen. After analyzing features to differentiate between the different grades of HCC it was observed that as the grades progressed the cells became undifferentiated and similarities increased. Cytohistological correlation was seen in 91.3% of cases of primary and 86.9% of metastatic malignancies. Conclusion: Close attention to cytological features like cell clusters, intranuclear inclusions, endothelial rimming in conjunction with radiological images and biochemical markers provide valuable pointers in distinguishing between primary HCC and hepatic metastatic carcinomas thus obviating the need of invasive procedures.

Identification of a Liver Progenitor Cell-Related Genes Signature Predicting Overall Survival for Hepatocellular Carcinoma.

Background: Liver progenitor cells (LPCs) play significant roles in the development and progression of hepatocellular carcinoma (HCC). However, no studies on the value of LPC-related genes for evaluating HCC prognosis exist. We developed a gene signature of LPC-related genes for prognostication in HCC. Methods: To identify LPC-related genes, we analyzed mRNA expression arrays from a dataset (GSE57812 & GSE 37071) containing LPCs, mature hepatocytes, and embryonic stem cell samples. HCC RNA-Seq data from The Cancer Genome Atlas (TCGA) were used to explore the differentially expressed genes (DEGs) related to prognosis through DEG analysis and univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed to construct the LPC-related gene prognostic model in the TCGA training dataset. This model was validated in the TCGA testing set and an external dataset (International Cancer Genome Consortium [ICGC] dataset). Finally, we investigated the relationship between this prognostic model with tumor-node-metastasis stage, tumor grade, and vascular invasion of HCC. Results: Overall, 1770 genes were identified as LPC-related genes, of which 92 genes were identified as DEGs in HCC tissues compared with normal tissues. Furthermore, we randomly assigned patients from the TCGA dataset to the training and testing cohorts. Twenty-six DEGs correlated with overall survival (OS) in the univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed in the TCGA training set, and a 3-gene signature was constructed to stratify patients into 2 risk groups: high-risk and low-risk. Patients in the high-risk group had significantly lower OS than those in the low-risk group. Receiver operating characteristic curve analysis confirmed the signature's predictive capacity. Moreover, the risk score was confirmed to be an independent predictor for patients with HCC. Conclusion: We demonstrated that the LPC-related gene signature can be used for prognostication in HCC. Thus, targeting LPCs may serve as a therapeutic alternative for HCC.

EIF5A expression and its role as a potential diagnostic biomarker in hepatocellular carcinoma.

Introduction and objectives: Eukaryotic translation initiation factor 5A (EIF5A) is a member of the identified eIF family and played an important role in cell proliferation. There are few studies about the correlation between EIF5A and hepatocellular carcinoma (HCC).Materials and methods: We evaluated the expression of the EIF5A in human HCC cell lines and tissues by western blot analysis. Immunohistochemistry analysis of EIF5A was performed on a tissue microarray including 10 normal liver samples and 90 pathological section of HCC. Receiver operating characteristic (ROC) was introduced to obtain an optimal cut-off score for EIF5A positive expression.Results: Western blot results showed that EIF5A was highly expressed in HCC cell lines and tissues. Based on ROC curve analysis, 1/10 (10.0%) of normal hepatic tissues and 67/90 (74.4%) of HCC tissues were tested positive for EIF5A expression, which indicated that EIF5A were significantly up-regulated in HCC tissues compared with normal liver tissues (χ2=17.177, P<0.001). Furthermore, expression of EIF5A was significantly correlated with histological grade (P=0.048), clinical stage (P=0.003) and pT stage (P=0.003) but not correlated with sex (P=0.617) and age (P=0.831).Conclusions: In our study, we demonstrated the expression of EIF5A is closely correlated with HCC. In consideration of its relationship with clinicopathological parameters including histological grade, clinical stage and pT stage of HCC, EIF5A could be a potential biomarker.

Identifying 13 Hub Genes Associated with Progression and Prognosis of Hepatocellular Carcinoma with Weighted Gene Co-Expression Network Analysis

Hepatocellular carcinoma (HCC) is a type of common cancer, often accompanied by tumor recurrence and metastasis after surgery with poor prognosis. Therefore, searching into potential biomarkers that can effectively predict the prognosis and progression of HCC is crucial. In this study, we identified 1,981 differentially expressed genes (DEGs) using mRNA expression profiles from the TCGA-LIHC dataset. Subsequently, weighted gene co-expression network analysis found that the turquoise module closely associated with the pathological grade and clinical stage of HCC was identified. Then, from the key genes in the turquoise module and protein-protein interaction network analysis, 13 hub genes significantly related to the prognosis of HCC were screened. Through co-expression and functional enrichment analyses, these 13 hub genes were found to play an important role in mitosis. Finally, we evaluated the relationship between these hub genes and overall survival and disease-free survival through survival analysis. The result indicated that HCC patients with high hub gene expression had a poorer prognosis than HCC patients with low expression. Receiver operating characteristic curves showed that each hub gene could predict the prognosis of HCC patients. In summary, a total of 13 hub genes were identified that play an important role in the progression of HCC, which can be used as potential biomarkers for HCC patients.

Immunohistochemical Expression of Surviving in Viral Hepatitis and Hepatocellular Carcinoma, a Comparative Study

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, the major cause of death in patients with cirrhosis, and the third most common cause of cancer-related death in the world. In Egypt, hepatocellular carcinoma (HCC) is the second most common cancer in men and the 6th most common cancers in women. Egypt has the highest prevalence of HCV in the world and the prevalence of HCC is increasing in the last years. Nowadays, HCV infection and its complications are among the leading public health challenges in Egypt with 13.8% of population infected and, in these patients, the risk of HCC is increased 17-fold. Glypican-3 (GPC3) is a member of heparin sulfate proteoglycan family which is linked to cell surface. It plays an important role in regulation of cell growth, differentiation, and migration. It is normally expressed in fetal liver and placenta but not in normal adult liver tissue. 8-Hydroxydeoxyguanosine (8-OHdG) is an oxidatively modified promutagenic DNA that is produced by oxygen radicals and is recognized as a useful marker in estimating DNA damage induced by oxidative stress. The present work is a retrospective, cross-sectional, study performed on 150 liver paraffin blocks that included 100 cases of chronic hepatitis C and 50 cases of hepatocellular carcinoma. These cases were collected from the Pathology Department. The 100 cases of chronic hepatitis C were graded into low grade chronic hepatitis (58) cases and high-grade chronic hepatitis (42) cases, 30 patients had cirrhosis, all in the high-grade group. The 50 cases of hepatocellular carcinoma (HCC) included 18 cases of well-differentiated HCC (grade I), 22 cases of moderately differentiated HCC (grade II) and 10 cases of poorly differentiated HCC (grade III). Among 50 cases of HCC, 44 cases showed cirrhosis in the non-neoplastic liver tissue. There was a statistically significant difference in 8-OHdG index between chronic hepatitis and hepatocellular carcinoma (P = 0.006).

Preoperative Prediction of Pathological Grading of Hepatocellular Carcinoma Using Machine Learning-Based Ultrasomics: A Multicenter Study

Background: The present study investigated the value of ultrasomics signatures in the preoperative prediction of the pathological grading of hepatocellular carcinoma (HCC) via machine learning. Methods: A total of 193 patients were collected from three hospitals. The patients from two hospitals (n=160) were randomly divided into training set (n=128) and test set (n=32) at a 8:2 ratio. The patients from a third hospital were used as an independent validation set (n=33). The ultrasomics features were extracted from the tumor lesions on the ultrasound images. Support vector machine method was used to construct three preoperative pathological grading models for HCC on each dataset. The performance of the three models was evaluated by area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy. Findings: The ultrasomics signatures extracted from the grayscale ultrasound images could successfully differentiate between high- and low-grade HCC lesions on the training set, test set, and the independent validation set (p<0.05). On the test set and the validation set, the combined model's performance was the highest, followed by the ultrasomics model and the clinical model successively (p<0.05). Their AUC (along with 95%CI) of these models was 0.874(0.709-0.964), 0.789(0.608-0.912), 0.720(0.534-0.863) and 0.849(0.682-0.949), 0.825(0.654-0.935), 0.770(0.591-0.898), respectively. Interpretation: Machine learning-based ultrasomics signatures could be used for noninvasive preoperative prediction of pathological grading of HCC. The combined model displayed a better predictive performance for pathological grading of HCC and had a stronger generalization ability. Funding: The study was funded by the National Key Research and Development Program of China (Grant No. 2018YFC0114606). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: The present study was approved by the ethics committee, and informed consent was waived.

Identification of Biomarkers Based on Bioinformatics Analysis: The Expression of Ubiquitin-Conjugating Enzyme E2T (UBE2T) in the Carcinogenesis and Progression of Hepatocellular Carcinoma.

BackgroundThe purpose of this study was to screen and identify key genes in the occurrence and development of hepatocellular carcinoma (HCC) based on bioinformatics analysis.Material/MethodsThree Gene Expression Omnibus (GEO) series (GSE) – GSE121248, GSE87630, and GSE84598 – were downloaded from the GEO database. GEO2R was used to screen different genes and a Venn diagram was drawn to screen coexpressed differentially expressed genes (DEGs). Coexpressed DEGs were obtained by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, a protein-protein interaction network diagram was produced by Cytoscape, and module genes were calculated by the Molecular Complex Detection Cytoscape plug-in. Finally, overall survival, progression-free survival, and relapse-free survival analysis of the key genes selected were performed using the online Kaplan-Meier plotter. For the target genes, the online network UCSC Cancer Genome Browser was used to analyze the gene expression profiles of the grade and vascular invasion of HCC.ResultsA total of 296 coexpressed DEGs were obtained from the 3 GSEs and 12 key genes were obtained from the modular analysis. Survival analysis showed that the upregulated genes UBE2T and FBLN5 were involved in the poor prognosis of HCC. Furthermore, the expression of UBE2T was significantly related to the grade and vascular invasion of HCC.ConclusionsThe expression of the UBE2T gene was significantly upregulated in HCC tissue compared to in normal liver tissue. UBE2T may be a new marker for the diagnosis and subsequent therapy of HCC.

Prostate-specific membrane antigen expression in hepatocellular carcinoma, cholangiocarcinoma, and liver cirrhosis.

BACKGROUNDPrimary liver cancer includes three subtypes: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and combined hepatocellular carcinoma. Patients with primary liver cancer experienced poor prognosis and high mortality, so early detection of liver cancer and improved management of metastases are both key strategies to reduce the death toll from liver cancer. Prostate-specific membrane antigen (PSMA) expression in the tumor-associated neovasculature of nonprostate malignancies including liver cancer has been reported recently, but conclusive evidence of PSMA expression based on the pathological type of liver cancer remains limited.AIMTo study the expression of PSMA in HCC, CCA, and liver cirrhosis.METHODSA total of 446 formalin-fixed paraffin-embedded (FFPE) liver tumor and liver cirrhosis tissue samples were obtained retrospectively from the Pathology Department of Tongji Hospital. Immunohistochemistry was used to detect PSMA expression in these 446 FFPE liver biopsy specimens (213 HCC, 203 CCA, and 30 liver cirrhosis). The tumor compartment and the associated neovascular endothelium were separately analyzed. PSMA expression was examined by two certified pathologists, and the final results were presented in a 4-point scoring system (0-3 points). Correlation between PSMA expression and clinicopathological information was also assessed.RESULTSPSMA was expressed primarily in the neovascular endothelium associated with tumors. The positive rate of PSMA staining in HCC was significantly higher than that in CCA (86.8% vs 79.3%; P = 0.001) but was only 6.6% in liver cirrhosis (P = 0.000). HCC cases had more 3-score PSMA staining than CCA had (89/213, 41.8% vs 35/203, 17.2%; P = 0.001). PSMA expression correlated positively with the stage and grade of HCC and CCA. In both liver cancer subtypes, there were more PSMA+ cases in stages III–V diseases than in stages I and II. High staining intensity of PSMA was more frequently observed in liver cancers at high grade and advanced stage. There was no significant association of PSMA expression with sex, age, region, α-fetoprotein, hepatitis B surface antigen, or tumor size in both tumor subtypes.CONCLUSIONNeovascular PSMA may be a promising marker to differentiate HCC from liver cirrhosis and a prognostic marker for anti-tumor angiogenesis therapy for HCC.

Integrative analysis reveals novel driver genes and molecular subclasses of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a heterogeneous disease with various genetic and epigenetic abnormalities. Previous studies of HCC driver genes were primarily based on frequency of mutations and copy number alterations. Here, we performed an integrative analysis of genomic and epigenomic data from 377 HCC patients to identify driver genes that regulate gene expression in HCC. This integrative approach has significant advantages over single-platform analyses for identifying cancer drivers. Using this approach, HCC tissues were divided into four subgroups, based on expression of the transcription factor E2F and the mutation status of TP53. HCC tissues with E2F overexpression and TP53 mutation had the highest cell cycle activity, indicating a synergistic effect of E2F and TP53. We found that overexpression of the identified driver genes, stratifin (SFN) and SPP1, correlates with tumor grade and poor survival in HCC and promotes HCC cell proliferation. These findings indicate SFN and SPP1 function as oncogenes in HCC and highlight the important role of enhancers in the regulation of gene expression in HCC.

DYNLL1 is hypomethylated and upregulated in a tumor stage- and grade-dependent manner and associated with increased mortality in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and cellular mechanisms regulating HCC pathogenesis and progression are not completely understood. DYNLL1 is essential for the development and expansion of MYC-driven B cell lymphoma, and also regulates genomic stability and responses to DNA-damaging chemotherapy in BRCA1-deficient tumors. However, the role and regulation of DYNLL1 has not been previously studied in the context of HCC. Here we report that DYNLL1 gene is hypomethylated and its expression is upregulated in HCC patients compared to healthy controls. The expression of DYNLL1 changes in a tumor grade- and stage-dependent manner in HCC. In this study, we further show that high DYNLL1 expression results in shorter overall and progression-free survival in hepatocellular carcinoma patients. Similar to DYNLL1, one of its protein interactors, RACK1, also shows decreased CpG-aggregated methylation and increased expression in HCC. RACK1 expression increases from early to late stage and from low to high grade in HCC. We found that high RACK1 expression is significantly associated with increased mortality of HCC patients. The present study shows that the epigenetic regulation of DYNLL1 and its consequent upregulation might be contributing to cancer development and progression in HCC. Its higher expression in late stage or high grade HCC may favor more aggressive disease as pointed by the increased mortality in high expression cohort. A better mechanistic understanding of the role of DYNLL1 in HCC will be needed to develop targeted treatment strategies in the future.