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PDF file - 122K, Clinical and pathological findings of HCC patients, and the expression level of YAP and AREG detected by western blot analysis in hepatocellular carcinoma patients.

Structural Variations across 71 WGS CCAs.

Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor that is methylated in many human cancers, including hepatocellular carcinoma (HCC). RASSF1A has been shown to suppress tumors via activation of the Hippo tumor suppressor pathway, including mammalian STE20-like kinase (MST). Amphiregulin (AREG), a target gene for Yes-associated protein (YAP), is a known oncogenic component of the Hippo pathway; however, the tumor-suppressive effect of RASSF1A on AREG in regard to regulation of the Hippo pathway remains unclear in HCC. Overexpression of RASSF1A in HCC cells, which lack functional RASSF1A, significantly inhibited cell proliferation and induced apoptosis by activating the Hippo pathway. Consequently, overexpression of RASSF1A inhibited the oncogenic functions of YAP, leading to a significant reduction in AREG secretion via regulation of the Hippo pathway. In human specimens, greater expression of RASSF1A was observed in chronic hepatitis/cirrhosis than in HCC, whereas expression of YAP and AREG was higher in 81% and 86% of HCC than in corresponding chronic hepatitis/cirrhosis, respectively. Furthermore, RASSF1A protein gradually decreased as multistep hepatocarcinogenesis progressed from chronic hepatitis/cirrhosis dysplastic nodules toward HCC, whereas the protein expression of YAP and AREG gradually increased. These findings provide mechanistic insight into the regulation of YAP and AREG by RASSF1A in human multistep hepatocarcinogenesis. Mol Cancer Res; 11(7); 748–58. ©2013 AACR.

Summary of CCA Alterations.

PDF file - 2527K, Relationship between RASSF1A, YAP, and AREG histoscores.

Further details of methods, in addition to the supplementary figure and table legends.

PDF file - 1379K, Immunohistochemical analysis of nuclear and cytoplasmic YAP protein localization in human multistep hepatocarcinogenesis.

Alterations in CCA Clusters.

Coverage Statistics and List of Genes for Targeted Sequencing.

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress–related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis.Significance:Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.

Purpose: Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment.Experimental Design: Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients.Results: We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort.Conclusions: The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy. Clin Cancer Res; 17(7); 1850–7. ©2011 AACR.

Supplementary Figures S1-S9 S1: The representative case showing CD90 expression. Morphology and character of hepatic stellate cell lines. S2: The expression change of KRT19 following S3I-201, TPA, U0126, and SCH772984. The transfection efficiency of HCC cell lines. S3: The HGF concentrations in conditioned media from hTERT-HSC, LX-2, and primary human hepatic stellate cells. Western blot analysis of hepatocellular carcinoma cell lines, showing expression of phospho-MET, MET, phsopho-ERK1/2, and KRT19. mRNA and protein expression of KRT19 in HepG2 and SNU475 cells, following transient expression of MET. S4: Morphologic changes in HepG2 and SNU423 induced by conditioned media (CM) from inducible HGF knockdown stable cell lines established from hTERT-HSC: shHGF-1 and shHGF-2. mRNA expression levels of KRT19 and morphologic changes in HepG2 and SNU423, following CM treatment combined with hepatocyte growth factor (HGF) neutralizing antibody. S5: The gene knock-down efficiencies of two pooled siRNAs targeting JUN, JUND, FOSL1, or FOSL2. The gene knock-down efficiencies of siRNAs targeting JUN or FOSL1. S6: Expression of HGF in hepatic stellate cell line of hTERT-HSC, and HCC cell lines of HepG2 and SNU423. Distribution of HGF and MET expression in HepG2 cells, at various time points after conditioned media (CM) treatment. S7: S7. Increased KRT19 expression and nuclear translocation of ERK1/2, phospho-ERK1/2, FOSL1, phospho-FOSL1 after the conditioned media treatment in HepG2. Rapid decline in phosphor-MET levels after removal of conditioned media. S8: Schematic representation of regulatory mechanism of KRT19 gene by cancer-associated fibroblast (CAF) derived HGF via MET-ERK1/2- AP1 and SP1 axis. S9: Conservation of AP1 and SP1 binding sites in KRT19 promoter.

Supplementary Table S1: Tissue specimens used for RNA-seq analysis. Supplementary Table S2: Tissues specimens used for immunohistochemical analysis. Supplementary Table S3: Gene signatures used in the study. Supplementary Table S4: Differentially methylated probes during hepatocarcinogenesis. Supplementary Table S5: Univariate and multivariate analysis for SPINK1 expression and HCC clinico-pathological features in TCGA-LIHC data.

Supplementary Figures S1-S6; Supplementary Tables S1-S2.

Supplementary Materials and Methods

Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC); however, regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that cross-talk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK–ERK1/2 pathway, which upregulated KRT19 expression in HCC cells. Furthermore, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n = 339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.Significance: These findings reveal KRT19 expression in hepatocellular carcinoma is regulated by cross-talk between cancer-associated fibroblasts and HCC cells, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(7); 1619–31. ©2018 AACR.

Supplementary materials and methods about the generation of conditioned media and ELISA, quantitative real time PCR, western blot analysis and phospho-receptor tyrosine kinase array, plasmids, siRNA, and transfection, dual luciferase assay, oligo pull-down and ChIP, immunofluorescence staining. Supplementary tables S1-S10. S1: Clinicopathologic characteristics of hepatocellular carcinoma cohort (n=339). S2: List of antibodies used for the immunohistochemistry. S3: Criteria for qualitative immunohistochemistry analysis. S4: Criteria for semiquantitative immunohistochemistry analysis. S5: Primer sequences for PCR reaction. S6: List of antibodies. S7: shRNA/siRNA target sequence for gene knockdown. S8: Clinicopathologic characteristics of hepatocellular carcinoma with HGF or MET expression. S9: Univariate and multivariate analyses of disease-specific survival. S10: Univariate and multivariate analyses of disease-free survival.

Supplementary Figure S1: Overall study design for multi-omic data analysis. Supplementary Figure S2: The distribution of beta-values in DNA methylation data. Supplementary Figure S3: The distribution of differentially methylated probes (DMPs). Supplementary Figure S4: Differentially methylated probes in the integrated data of GSE44970 and YSHCC. Supplementary Figure S5: Distribution of CNAs during stepwise hepatocarcinogenesis. Supplementary Figure S6: DNA methylation of oncogenes and TSGs during multi-step hepatocarcinogenesis. Supplementary Figure S7: Frequencies of nonsynonymous or missense mutations in each patient. Supplementary Figure S8: Functionally enriched expression in each step of hepatocarcinogenesis. Supplementary Figure S9: Validation of the three genes including SPINK1, CAP2, and RRAGD. Supplementary Figure S10: SPINK1 overexpression increases proliferation and invasion of Huh7 cells. Supplementary Figure S11: Correlation between methylation and expression. Supplementary Figure S12: Western blot of DNMT1 expression. Supplementary Figure S13: GRP78 expression under ER stress. Supplementary Figure S14: Effects of knockdown of p65 expression in the expression of GRP78 and SPINK1.

HER2 overexpression or amplification, which is present in 15% of all cases of biliary tract cancer, has been identified as a druggable molecular target by genomic profiling. In the phase 3 ABC-06 trial, the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen showed a survival benefit compared with active symptom control as second-line therapy for biliary tract cancer. We aimed to evaluate the clinical activity of FOLFOX plus anti-HER2 antibody trastuzumab as a second-line or third-line treatment for HER2-positive biliary tract cancer.This study was an investigator-initiated, open-label, non-randomised, single-arm, multi institutional, phase 2 trial in participants aged 19 years or older with HER2-positive (defined as immunohistochemistry 3+ or immunohistochemistry 2+ and in-situ hybridisation positive or ERBB2 gene copy number ≥6·0 by next-generation sequencing) biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) who progressed on chemotherapy containing gemcitabine and cisplatin (with one or two previous chemotherapy lines permitted). In cycle one, patients received intravenous trastuzumab-pkrb at 6 mg/kg on day 1, and FOLFOX (consisting of intravenous oxaliplatin [85 mg/m34 participants were enrolled between June 26, 2020, and Sept 1, 2021. At the time of data cutoff on May 1, 2022, median follow-up was 13·0 months (IQR 11·0-16·9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29·4% (95% CI 16·7-46·3) and the disease control rate was 79·4% (95% CI 62·9-89·9). Median progression-free survival was 5·1 months (95% CI 3·6-6·7); median overall survival was 10·7 (95%CI 7·9-not reached). The most common treatment-related grade 3 or 4 adverse events were neutropenia (ten [29%] participants with grade 3 and nine [26%] with grade 4), grade 3 anaemia (five [15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] participants). There were no treatment-related cardiac toxic effects or deaths. The overall health assessment (EuroQoL-VAS) score did not change significantly throughout the treatment. Sensory and motor neuropathy symptoms as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy twenty-item scale questionnaire did not change significantly over time.For HER2-positive biliary tract cancer, second-line or third-line trastuzumab biosimilar plus FOLFOX exhibited promising activity with acceptable toxicity, warranting further investigation.Boryung Pharmaceutical, Celltrion, National Research Foundation of Korea, National RD Program for Cancer Control through the National Cancer Center, Yonsei University College of Medicine.

BACKGROUND AND AIMS Biliary tract cancer (BTC) exhibits diverse molecular characteristics. However, reliable biomarkers that predict therapeutic responses are yet to be discovered. We aimed to identify the molecular features of treatment responses to chemotherapy and immunotherapy in BTCs. APPROACH AND RESULTS We enrolled 121 advanced BTC patients (68 cholangiocarcinomas [33 intrahepatic, 35 extrahepatic], 41 gallbladder cancers, and 12 Ampulla of Vater cancers) whose specimens were analyzed by clinical sequencing platforms. All patients received first-line palliative chemotherapy; 48 patients underwent programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy after failed chemotherapy. Molecular and histopathological characterization was performed using targeted sequencing and immunohistochemical staining to investigate treatment response-associated biomarkers. Genomic analysis revealed a broad spectrum of mutational profiles according to anatomical location. Favorable responses to chemotherapy were observed in the small-duct type compared with the large-duct type intrahepatic cholangiocarcinoma, with frequent mutations in BRCA1-associated protein-1/isocitrate dehydrogenase 1/2 and KRAS proto-oncogene, GTPase/SMAD family member 4 genes, respectively. The molecular features were further analyzed in BTCs, and transforming growth factor beta and DNA damage response pathway-altered tumors exhibited poor and favorable chemotherapy responses, respectively. In PD-1/PD-L1 blockade-treated patients, KRAS alteration and chromosomal instability tumors were associated with resistance to immunotherapy. The majority of patients (95.0%) with these resistance factors show no clinical benefit to PD-1/PD-L1 blockade and low tumor mutational burdens. Low tumor-infiltrating lymphocyte (TIL) density in tumors with these resistance factors indicated immune-suppressive tumor microenvironments, whereas high intratumoral TIL density was associated with a favorable immunotherapy response. CONCLUSIONS This study proposes predictive molecular features of chemotherapy and immunotherapy responses in advanced BTCs using clinical sequencing platforms. Our result provides an intuitive framework to guide the treatment of advanced BTCs benefiting from therapeutic agents based on the tumors' molecular features.

Alternative splicing of RNA transcripts plays an important role in cancer development and progression. Recent advances in RNA-seq technology have made it possible to identify alternately spliced events in various types of cancer; however, research on hepatocellular carcinoma (HCC) is still limited. Here, by performing RNA-seq profiling of HCC transcripts at isoform level, we identified tumor-specific and molecular subtype-dependent expression of the USO1 isoforms, which we designated as a normal form USO1-N (XM_001290049) and a tumor form USO1-T (NM_003715). The expression of USO1-T, but not USO1-N, was associated with worse prognostic outcomes of HCC patients. We confirmed that the expression of USO1-T promoted an aggressive phenotype of HCC, both in vitro and in vivo. In addition, structural modeling analyses revealed that USO1-T lacks an ARM10 loop encoded by exon 15, which may weaken the dimerization of USO1 and its tethering to GM130. We demonstrated that USO1-T ensured unstacking of the Golgi and accelerated the vesicles trafficking from endoplasmic reticulum (ER) to Golgi and plasma membrane in multiple liver cancer cells. ERK and GRASP65 were found to be involved in the USO1-T-mediated Golgi dysfunction. Conclusively, we provide new mechanophysical insights into the USO1 isoforms that differentially regulate the ER–Golgi network, promoting the heterogeneous HCC progression.

Purpose: To describe the imaging features of histologically defined early hepatocellular carcinoma (eHCC) on gadoxetate disodium-enhanced MRI (EOB-MRI) and diffusion-weighted imaging (DWI).Materials and Methods: We enrolled 173 surgically confirmed eHCCs in 119 patients examined by preoperative EOB-MRI and DWI between January 2006 and September 2017. The imaging features of preoperatively detected eHCCs were retrospectively analyzed by two radiologists. The clinical and imaging characteristics associated with false-negative detection were evaluated.Results: Of the 173 eHCCs, 118 (68%) in 78 patients were prospectively reported on preoperative EOB-MRI. After retrospective review, 17 eHCCs in 13 patients were additionally detected, with a per-lesion detection sensitivity of 78% (135/173). Thus, the imaging features of 135 eHCCs in 91 patients were analyzed. Most eHCCs exhibited hepatobiliary hypointensity (90%, 122/135). Arterial phase hyperenhancement, washout, and capsule appearance were seen in 68 (50%), 79 (59%), and 11 (8%) detected lesions, respectively. Diffusion restriction and fatty change were noted in 30 (22%) and 39 (29%) lesions, respectively; most eHCCs exhibited T1 and T2 isointensity (80 [59%] and 89 [66%], respectively). False-negative detection was associated with small lesion size (< 1 cm), history of HCC treatment (odds ratio, 0.34 [95% confidence interval, 0.13-0.92]), number of HCC lesions (≥ 2; odds ratio, 0.08 [0.01-0.66]), and poor functional liver imaging score (< 4; odds ratio, 0.13 [0.04-0.51]).Conclusions: Histologically defined eHCCs typically appear as hepatobiliary phase hypointensity. Detection sensitivity of eHCC may be affected by lesion size, history of HCC treatment, number of HCCs, and hepatobiliary enhancement.

The prevalence of non-alcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) has increased parallelly with that of metabolic syndrome. This study aimed to compare the clinical and survival outcomes of NAFLD-HCC and HBV-related HCC(HBV-HCC).The medical records of patients who underwent hepatectomy for HCC at Severance Hospital between 2005 and 2015 were retrospectively reviewed. Occult HBV infection was identified by nested PCR. Propensity score matching (PSM) was conducted to minimize lead-time bias caused by the lack of surveillance in NAFLD patients. Surgical and oncologic outcomes were compared between the two groups.There were 32 patients (7%) with NAFLD-HCC, 200 (46%) with HBV-HCC, and 194 (44%) with HBV/NAFLD-HCC (HBV and NAFLD). Before PSM, cirrhosis was more frequently detected in HBV-HCC patients (55% vs 15%, p 0.001) and the average tumor size was larger in the NAFLD-HCC group than in the HBV-HCC group (4.4 ± 3.3 cm vs 3.4 ± 1.8 cm, p = 0.014). After a median follow-up of 74 months (range 0-157 months), survival analyses before PSM showed better 5-year overall survival (OS) in HBV-HCC patients than in NAFLD-HCC patients (80% vs 63%, p = 0.041). After PSM, 5-year OS rates were similar (60% vs 63%, p = 0.978). There were no differences between the groups in recurrence-free or disease-specific survival before and after PSM.Patients with NAFLD-HCC were less likely to have underlying cirrhosis but more likely to have larger tumors at the time of diagnosis than patients with HBV-HCC. The OS of patients with NAFLD-HCC appeared to be worse than that of patients with HBV-HCC. Therefore, active HCC surveillance is recommended in patients with metabolic syndrome for the early detection of HCC.

Hepatocellular adenoma (HCA) is a heterogeneous entity, from both the histomorphological and molecular aspects, and the resultant subclassification has brought a strong translational impact for both pathologists and clinicians. In this review, we provide an overview of the recent updates on HCA from the pathologists' perspective and discuss several practical issues and pitfalls that may be useful for diagnostic practice.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a malignant primary liver carcinoma characterized by the unequivocal presence of both hepatocytic and cholangiocytic differentiation within the same tumor. Recent research has highlighted that cHCC-CCAs are more heterogeneous than previously expected. In the updated consensus terminology and WHO 2019 classification, “classical type” and “subtypes with stem-cell features” of the WHO 2010 classification are no longer recommended. Instead, it is recommended that the presence and percentages of various histopathologic components and stem-cell features be mentioned in the pathologic report. The new terminology and classification enable the exchange of clearer and more objective information about cHCC-CCAs, facilitating multi-center and multinational research. However, there are limitations to the diagnosis of cHCC-CCA by imaging and biopsy. cHCC-CCAs showing typical imaging findings of HCC could be misdiagnosed as HCC and subjected to inappropriate treatment, if other clinical findings are not sufficiently considered. cHCC-CCAs showing at least one of the CCA-like imaging features or unusual clinical features should be subjected to biopsy. There may be a sampling error for the biopsy diagnosis of cHCC-CCA. An optimized diagnostic algorithm integrating clinical, radiological, and histopathologic information of biopsy is required to resolve these diagnostic pitfalls. (J Liver Cancer 2021;21:12-24)

Hepatocellular carcinoma (HCC) primarily originates in the liver with hepatic differentiation. However, HCCs are not homogenous, and approximately 35% of HCC cases are classified as histopathological variants that present distinct pathologic characteristics. In particular, the lymphocyte-rich variant is the rarest subtype accounting for less than 1% of HCCs, which is not well known to date about molecular features and pathophysiology. Herein, we present a case of a patient who was suspected of metastatic liver cancer and confirmed as lymphocyterich HCC pathologically. A 78-year-old woman who underwent a right hemicolectomy for colon cancer was referred to our hospital for a newly detected liver mass. We could not make a decision because of insufficient evidence for diagnosis from imaging studies. After resection, we found that it was a lymphocyte-rich HCC. The pathologic features and prognostic trends of this subtype are also discussed. (J Liver Cancer 2021;21:69-75)

To investigate the imaging findings of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) on CT and MRI, and examine their diagnostic performance and prognostic significance.We retrospectively enrolled 220 consecutive patients who underwent hepatic resection between June 2009 and December 2013 for single treatment-naïve HCC, who have preoperative CT and gadoxetic acid-enhanced MRI. Independent reviews of histopathology and imaging were performed by two reviewers. Previously reported imaging findings, LI-RADS category, and CT attenuation of MTM-HCC were investigated. The diagnostic performance of the MTM-HCC diagnostic criteria was compared across imaging modalities.MTM-HCC was associated with ≥ 50% arterial phase hypovascular component, intratumoral artery, arterial phase peritumoral enhancement, and non-smooth tumor margin on CT and MRI (p.05). Arterial phase hypovascular components were less commonly observed on MRI subtraction images than on CT or MRI, while non-rim arterial phase hyperenhancement and LR-5 were more commonly observed on MRI subtraction images than on MRI (p.05). MTM-HCC showed lower tumor attenuation in the CT arterial phase (p = .01). Rhee's criteria, defined as ≥ 50% hypovascular component and ≥ 2 ancillary findings (intratumoral artery, arterial phase peritumoral enhancement, and non-smooth tumor margin), showed similar diagnostic performance for MRI (sensitivity, 41%; specificity, 97%) and CT (sensitivity, 31%; specificity, 94%). Rhee's criteria on CT were independent prognostic factors for overall survival.The MRI diagnostic criteria for MTM-HCC are applicable on CT, showing similar diagnostic performance and prognostic significance. For MTM-HCC, arterial phase subtraction images can aid in the HCC diagnosis by depicting subtle arterial hypervascularity.• MTM-HCC on CT demonstrated previously described MRI findings, including arterial phase hypovascular component, intratumoral artery, arterial phase peritumoral enhancement, and necrosis. • The MRI diagnostic criteria for MTM-HCC were also applicable to CT, showing comparable diagnostic performance and prognostic significance. • On arterial phase subtraction imaging, MTM-HCC more frequently demonstrated non-rim enhancement and LR-5 and less frequently LR-M than MRI arterial phase, which may aid in the diagnosis of HCC.

Background: The differential diagnosis of intrahepatic cholangiocarcinomas (iCCAs) from metastatic adenocarcinomas from organs adjacent to the liver is difficult due to histopathological similarity and a lack of specific markers. This study evaluates the performance of albumin mRNA in situ hybridization (ISH) and immunohistochemistry (IHC) of filamin-A and cytokeratin 19 (CK19) for differential diagnosis.Methods: A total of 181 iCCAs and 116 adenocarcinomas from extrahepatic organs (30 gallbladder, 28 pancreas, and 58 stomach) were collected, and albumin ISH and IHC for filamin-A and CK19 were performed. The sensitivity, specificity, and the area under the curve (AUC) on the receiver operating characteristic (ROC) curve analysis of each marker were evaluated for the diagnosis of iCCA over extrahepatic adenocarcinoma.Results: Albumin ISH showed 23.2% sensitivity and 100% specificity for iCCAs, including both the small-duct and large-duct types. The expression of filamin-A and CK19 in albumin ISH-negative iCCAs was compared with that in extrahepatic adenocarcinomas. Filamin-A showed 71.1% sensitivity, 87.5% specificity, and 0.79 AUC on the ROC in small-duct-type iCCAs, whereas it had 27.5% sensitivity, 87.5% specificity, and 0.58 AUC on the ROC in large-duct-type iCCAs. CK19 showed 87.9% sensitivity, 59.4% specificity, and 0.74 AUC on the ROC in large-duct-type iCCAs, whereas it had 44.7% sensitivity, 59.4% specificity, and 0.52 AUC on the ROC in small-duct-type iCCAs.Conclusion: Albumin ISH and IHC for filamin-A and CK19 showed distinct expression patterns according to iCCA type. Albumin ISH positivity supports the possibility of iCCA, and filamin-A IHC is helpful for differentiating small-duct-type iCCA from extrahepatic adenocarcinomas.

Background and aims Intraductal papillary neoplasms of bile duct (IPNBs) remain a challenging entity to manage. Methods The pathologic spectrum of 34 gastric subtype of IPNB (gIPNB) cases was examined in consideration of the type 1 and 2 subclassification proposed by Japan-Korea consensus and compared with gastric subtype of pancreatic intraductal papillary mucinous neoplasm (gIPMN) (44 cases). Results Type 1 gIPNBs (17 cases) showed regular papillary foveola with variable tubular pyloric glands. Eight of the type 1 gIPNBs showed low-grade dysplasia. Type 2 cases (n = 17) showed complicated papillary and tubular structures and high-grade dysplastic foveola and pyloric glands. Foveolas were predominant in 15 cases, while pyloric glands were predominant in 10 cases, and considerable areas of foveolas and pyloric glands in the remaining: these three were found similarly in type 1 and 2 gIPNB. gIPMNs showed central foveola with a peripheral pyloric gland. Such a pattern was recognizable in type 1 but vague in type 2. Type 1 was frequently found in the intrahepatic bile ducts and showed abundant mucin, as in gIPMNs, while type 2 also occurred in the extrahepatic bile ducts and were pathologically more malignant. Conclusion Type 1 lesions shared features of gIPMN, while type 2 lesions differed from gIPMN and were more pathologically malignant.

Intrahepatic cholangiocarcinoma (iCCA) is subclassified into mass-forming (MF), periductal-infiltrative (PI), and mixed types grossly; however, their clinicopathological significance remains controversial.Clinicopathological characteristics of iCCA gross types were analysed according to histopathological type (small-duct, large-duct, indeterminate) or cholangiolocellular differentiation trait (CDT) in 108 iCCAs. The expression levels of inflammation-marker (CRP, FGB) and proliferation-marker (phospho-ERK1/2, Ki-67) were evaluated by immunohistochemistry.There were 87 MF, 8 PI, and 13 mixed-gross type. Small-duct-type (39, 44.8%) and CDT (19, 21.8%) were found only in MF-gross type. The inflammation-marker expression was higher in MF-type than in PI- and mixed-gross types (P = 0.023). It was high in small-duct-type, middle in indeterminate-type, and low in large-duct-type (P = 0.015), and iCCAs with CDT showed higher inflammation-marker expression compared to those without (P 0.001). Proliferation-marker expression did not differ according to gross type; however it was lower in iCCA with CDT compared to those without (P = 0.004). Subgrouping of the gross type according to histopathological type or CDT revealed that MF-type with small-duct-type or CDT had better overall survival compared to the others (P 0.05).MF-type iCCA is more heterogeneous than other gross types. High inflammation-marker/low proliferation-marker expression in MF-type with CDT or small-duct-type may be related to a good outcome.

Hepatocellular carcinoma (HCC) is heterogeneous in pathogenesis, phenotype and biological behavior. Various histopathological features of HCC had been sporadically described, and with the identification of common molecular alterations of HCC and its genomic landscape over the last decade, morpho-molecular correlation of HCC has become possible. As a result, up to 35% of HCCs can now be classified into histopathological variants, many of which have unique molecular characteristics. This review will provide an introduction to the variously described histopathological variants of HCC in the updated WHO Classification of Digestive System Tumors. (J Liver Cancer 2020;20:17-24)

Primary liver cancers (LCs), including HCC and intrahepatic cholangiocarcinoma (iCCA), are derived from a common developmental lineage, conferring a molecular spectrum between them. To elucidate the molecular spectrum, we performed an integrative analysis of transcriptome profiles associated with patients' radiopathologic features.We identified four LC subtypes (LC1-LC4) from RNA-sequencing profiles, revealing intermediate subtypes between HCC and iCCA. LC1 is a typical HCC characterized by active bile acid metabolism, telomerase reverse transcriptase promoter mutations, and high uptake of gadoxetic acid in MRI. LC2 is an iCCA-like HCC characterized by expression of the progenitor cell-like trait, tumor protein p53 mutations, and rim arterial-phase hyperenhancement in MRI. LC3 is an HCC-like iCCA, mainly small duct (SD) type, associated with HCC-related etiologic factors. LC4 is further subclassified into LC4-SD and LC4-large duct iCCAs according to the pathological features, which exhibited distinct genetic variations (e.g., KRAS, isocitrate dehydrogenase 1/2 mutation, and FGF receptor 2 fusion), stromal type, and prognostic outcomes.Our integrated view of the molecular spectrum of LCs can identify subtypes associated with transcriptomic, genomic, and radiopathologic features, providing mechanistic insights into heterogeneous LC progression.

OBJECTIVE To investigate whether subclassification of microscopic vascular invasion (MiVI) affects the long-term outcome after curative surgical resection or liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). SUMMARY OF BACKGROUND DATA The most important factor for TNM staging in HCC is MiVI, which includes all vascular invasions detected on microscopic examination. However, there is a broad spectrum of current definitions for MiVI. METHODS In total, 412 consecutive patients with HCC who underwent curative surgical resection without any preoperative treatment or gross vascular invasion were histologically evaluated for MiVI. Patients with MiVI were subclassified into 2 groups: microvessel invasion (MI; n = 164) only and microscopic portal vein invasion (MPVI; n = 36). Clinicopathologic features were compared between 2 groups (MI vs MPVI), whereas disease-free survival (DFS) and overall survival (OS) after resection were analyzed among 3 groups (no vascular invasion [NVI] vs MI vs MPVI). These subclassifications were validated in a cohort of 197 patients with HCC who underwent LT. RESULTS The MPVI group showed more aggressive tumor characteristics, such as higher tumor marker levels (alpha-fetoprotein, P = 0.006; protein induced by vitamin K absence-II, P = 0.001) and poorer differentiation (P = 0.011), than the MI group. In multivariate analysis, both MI and MPVI were independent prognostic factors for DFS (P = 0.001 and

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress–related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. Significance: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.

Background Gallbladder cancer (GBC) is a rare neoplasia of the biliary tract with high mortality rates and poor prognosis. Signs and symptoms of GBC are not specific and often arise at late stage of disease. For this reason, diagnosis is typically made when the cancer is already in advanced stages, and prognosis for survival is less than 5 years in 90% of cases. Biomarkers to monitor disease progression and novel therapeutic alternative targets for these tumors are strongly required. Commonly, dysregulated protein synthesis contributes to carcinogenesis and cancer progression. In this case, protein synthesis directs translation of specific mRNAs, and, in turn, promotes cell survival, invasion, angiogenesis, and metastasis of tumors. In eukaryotes, protein synthesis is regulated at its initiation, which is a rate-limiting step involving eukaryotic translation initiation factors (eIFs). We hypothesize that eIFs represent crossroads in the development of GBC, and might serve as potential biomarkers. The study focus was the role of eIF6 (an anti-association factor for the ribosomal subunits) in GBC. Methods In human GBC samples, the expression of eIF6 was analyzed biochemically at the protein (immunohistochemistry, immunoblot analyses) and mRNA levels (qRT-PCR). Results High levels of eIF6 correlated with shorter overall survival in biliary tract cancer (BTC) patients (n = 28). Immunohistochemical data from tissue microarrays (n = 114) demonstrated significantly higher expression levels of eIF6 in GBC compared to non-neoplastic tissue. Higher eIF6 expression on protein (immunoblot) and mRNA (qRT-PCR) level was confirmed by analyzing fresh frozen GBC patient samples (n = 14). Depletion of eIF6 (using specific siRNA-mediated knockdown) in Mz-ChA-2 and TFK-1 cell lines inhibited cell proliferation and induced apoptosis. Conclusion Our data indicates that eIF6 overexpression plays a major role in the translational control of GBC, and indicates its potential as a new biomarker and therapeutic target in GBC.

The fibrosis in chronic hepatitis shows dynamic changes during antiviral therapy (AVT). We investigated whether P-I-R (progressive vs. indeterminate vs. regressive) staging is predictive of hepatocellular carcinoma (HCC) recurrence in patients with chronic hepatitis B (CHB) taking AVT who underwent resection. Patients with CHB-related HCC who underwent curative resection between 2004 and 2017 and had received ≥2 years AVT at the time of resection were eligible. Two pathologists performed P-I-R staging. In total, 104 patients with CHB-related HCC were enrolled. The mean age of the study population was 56.3 years. The mean duration of AVT at the time of resection was 62.6 months. During the follow-up period (mean, 45.5 months), 20 (19.2%) and 14 (13.5%) patients developed early and late recurrence of HCC, respectively. The cumulative incidence of late recurrence was significantly lower in patients with regressive patterns than in those with indeterminate and progressive patterns according to P-I-R staging (P = 0.015, log-rank test), although the cumulative incidence of overall recurrence according to P-I-R staging was similar. Hepatitis B virus DNA levels (hazard ratio [HR] = 3.200, P = 0.020) and the regressive P-I-R staging pattern (HR = 0.127, P = 0.047) independently predicted the risk of late recurrence. One-time assessment of the P-I-R staging at the time of curative resection in patients with CHB-related HCC receiving AVT independently predicted late HCC recurrence. Therefore, qualitative fibrosis assessment by P-I-R staging might be useful in predicting the outcomes of patients with CHB undergoing AVT.

We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. VETC was assessed in a large multi-institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small-sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa-fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio [HR]: 1.52 [1.06-2.19], P = 0.023), disease-free survival (HR: 1.66 [1.21-2.27], P = 0.002), and overall survival (HR: 2.26 [1.37-3.72], P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (β-catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.

Biliary tract cancer (BTC) represents a malignant tumor of the biliary tract including cholangiocarcinoma (CCA) and the carcinoma of the gallbladder (GBC) with a 5-year survival rate between 5 and 18% due to late diagnosis and rapid disease progression. Chronic inflammation is one of the main risk factors for CCA and GBC in particular. IL-6, as a mediator of inflammation, can act through a membrane-bound receptor alpha-chain (mIL-6R, "IL-6 classic signaling") or via soluble forms (sIL-6R, "IL-6 trans-signaling"). However, little is known about the impact on cellular responses of IL-6 trans-signaling on BTC. We analyzed primary tumors as whole sections and as tissue microarrays, and also searched The Cancer Genome Atlas database. Compared to non-neoplastic, non-inflamed gallbladder tissue, IL-6Rα was downregulated in GBC, and this correlated with the patients' overall survival. Furthermore, different CCA cell lines and compounds for activation (IL-6 and Hyper-IL-6) or inhibition (Tocilizumab and sgp130Fc) of IL-6 classic signaling and trans-signaling were used to determine their effects on cellular processes between the two modes of IL-6 signaling. Inhibition of IL-6 trans-signaling by sgp130Fc reduced CCA cell line viability and apoptosis, whereas migration and proliferation were increased. We conclude that IL-6Rα expression is a good prognostic marker for GBC, and that the blocking of IL-6 trans-signaling and activation of IL-6 classic signaling have tumor promoting activity. These findings warrant the exclusion of patients with GBC or other malignancies associated with bile metabolism from IL-6R inhibitor therapy.

Patients with Fontan circulation exhibit a high incidence of liver fibrosis and cirrhosis. Transient elastography (TE) and the enhanced liver fibrosis (ELF) test have proven useful as noninvasive surrogate markers of liver fibrosis for other chronic liver diseases. We evaluated whether TE and the ELF score can predict the degree of liver fibrosis in patients with Fontan circulation.We retrospectively reviewed the medical records of 45 adult patients with at least 10 years of Fontan duration who had undergone liver biopsy and investigated the relation between the fibrosis stage and TE and the ELF test results. Additionally, the association of these variables and other biochemical and hemodynamic parameters was assessed.The mean age was 25.9 years and the mean Fontan duration was 20.8 years. Advanced liver fibrosis was present in 36 (80.0%) patients. TE or ELF score are comparable for patients with and without advanced liver fibrosis (mean 23.3 vs 24.8 kPa [P = .85] for TE; mean 8.94 vs 9.25 [P = .44] for the ELF score). However, N-terminal pro-brain natriuretic peptide level and ventricular end-diastolic pressure were higher in patients with advanced liver fibrosis (mean 224 vs 80 pg/mL [P .01]; and mean 12 vs 9 mm Hg [P = .04], respectively). No independent predictor of advanced liver fibrosis was found in multivariate analysis.TE and the ELF score were unable to predict the degree of liver fibrosis in Fontan patients. Liver biopsy remains as the only valid method to assess fibrotic burden in this population.

BACKGROUND & AIMS Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ-specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs. METHODS We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast-associated protein (FAP), CAIX, VEGF, PD-L1, CD3, CD8, Foxp3, CD163 and epithelial-mesenchymal transition (EMT)-related markers were performed. RESULTS Independent factors for extrahepatic metastasis included BCLC stage B-C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)-HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P

Background & aims Non-coding RNAs (ncRNAs) play critical roles in hepatocellular carcinoma (HCC) progression. Here, by performing RNA-sequencing (RNA-Seq) profiling, we sought to identify novel ncRNAs that potentially drive the heterogeneous progression of liver cancers. Methods RNA-Seq profiles were obtained from 68 HCC specimens and ten samples of adjacent non-tumor liver tissues. The functional significance of the potential driver ncRNAs was evaluated by cell experiments. Results TPRG1-AS1 was identified as a potential driver noncoding RNA that promotes heterogeneous liver cancer progression. TPRG1-AS1 induced tumor suppressor RNA-binding motif protein 24 (RBM24), suppressing tumor growth by activating apoptotic tumor cell death. In addition, we report that TPRG1-AS1 acts as a competing endogenous RNA (ceRNA) for RBM24, sponging miR-4691-5p and miR-3659 to interfere with their binding to RBM24. Conclusions We suggest that TPRG1-AS1 is a novel ceRNA sponging miR-4691-5p and miR-3659, resulting in RBM24 expression and suppression of liver cancer growth. Our results provide new insights into the functions of ncRNAs in heterogeneous HCC progression.

BACKGROUND Development of a pragmatic pathologic classifier of pancreatic ductal adenocarcinoma (PDAC) that reflects biological behavior is needed. METHODS The tumor epithelial and stromal features of PDAC and molecular subtype-related markers were evaluated in three independent cohorts. RESULTS In the non-neoadjuvant therapy cohort (n = 108), regarding tumor-epithelial feature, non-gland-forming type showed worse prognosis compared to gland-forming type (P

HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression. Advancements in imaging techniques have allowed imaging diagnosis to become a critical part of managing HCC in the clinical setting, even without pathologic diagnosis. With the identification of many HCC subtypes, there is increasing correlative evidence between imaging phenotypes and histologic, molecular, and genetic characteristics of various HCC subtypes. In this review, current knowledge of histologic heterogeneity of HCC correlated to features on gadolinium-enhanced dynamic liver MRI will be discussed. In addition, HCC subtype classification according to transcriptomic profiles will be outlined with descriptions of histologic, genetic, and molecular characteristics of some relatively well-established morphologic subtypes, namely the low proliferation class (steatohepatitic HCC and CTNNB1-mutated HCC) and the high proliferation class (macrotrabecular-massive HCC (MTM-HCC), scirrhous HCC, and CK19-positive HCC). Characteristics of sarcomatoid HCC and fibrolamellar HCC will also be discussed. Further research on radiological characteristics of HCC subtypes may ultimately enable non-invasive diagnosis and serve as a biomarker in predicting prognosis, molecular characteristics, and therapeutic response. In the era of precision medicine, a multidisciplinary effort to develop an integrated radiologic and clinical diagnostic system of various HCC subtypes is necessary. KEY POINTS: • HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression, which can be divided into many subtypes according to transcriptome profiles. • There is increasing evidence of a correlation between imaging phenotypes and histologic, genetic, and molecular biologic characteristics of various HCC subtypes. • Imaging characteristics may ultimately enable non-invasive diagnosis and subtype characterization, serving as a biomarker for predicting prognosis, molecular characteristics, and therapeutic response.

Background/aims Circulating tumor cells (CTCs) with cancer stemness have been demonstrated to be a direct cause of tumor recurrence, and only few studies have reported the role of CTCs in liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods Epithelial cell adhesion molecule+ (EpCAM+), cluster of differentiation 90+ (CD90+) and EpCAM+/CD90+ CTCs were sorted via fluorescence-activated cell sorting, and transcripts level of EpCAM, K19 and CD90 in the peripheral blood were analyzed via real-time polymerase chain reaction preoperatively and on postoperative days 1 and 7 in 25 patients who underwent living donor liver transplantation (LDLT) for HCC. EpCAM protein was assessed in HCC tissue using immunohistochemical staining. The median follow-up duration was 40 months. Results HCC after LDLT recurred in four out of 25 patients. Detection of EpCAM+ or CD90+ CTCs correlated well with their messenger RNA levels (p 100 mAU/mL and postoperative day 1 EpCAM+/CD90+ CTCs were independent risk factors for HCC recurrence (hazard ratio, 14.64; 95% confidence interval, 1.08 to 198.20; p=0.043 and hazard ratio, 26.88; 95% confidence interval, 1.86 to 387.51; p=0.016, respectively). Conclusions EpCAM+/CD90+ CTCs can be used preoperatively and 1 day after LDLT as key biological markers in LT candidate selection and post-LDLT management.

BACKGROUND & AIMS: Late recurrence of hepatocellular carcinoma (HCC) is regarded as de novo HCC from chronic hepatitis. This study investigated clinicopathological and molecular factors to develop a nomogram for predicting late HCC recurrence (> 2 years after curative resection). METHODS: The training and validation cohorts included HCC patients with a major etiology of hepatitis B who underwent curative resection. Clinicopathological features including lobular and porto-periportal inflammatory activity, fibrosis, and liver cell change were evaluated. Proteins encoded by genes related to late recurrence were identified using a reverse phase protein array of 95 non-tumorous liver tissues. Immunoexpression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), plasminogen activator inhibitor-1, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), and spleen tyrosine kinase (SYK) was measured. RESULTS: Late recurrence occurred in 74/402 (18%) and 47/243 (19%) in the training and validation cohorts, respectively. Cirrhosis, moderate/severe lobular inflammatory activity, and expression of pSTAT3, pERK1/2, and SYK proteins correlated to the gene signature of hepatocyte injury and regeneration were independently associated with late recurrence, with odds ratios (95% confidence intervals) of 2.0 (1.2–3.3), 21.1 (4.3–102.7), and 6.0 (2.1–17.7), respectively (p < 0.05 for all). A nomogram based on these variables (histological parameters and immunohistochemical marker combinations) showed high reliability in both the training and validation cohorts (Harrell’s C index: 0.701 and 0.716; 95% confidence intervals: 0.64–0.76 and 0.64–0.79, respectively). CONCLUSIONS: The combination of pSTAT3, pERK1/2, and SYK immunoexpression with high lobular inflammatory activity and cirrhosis (fibrosis) predicts late HCC recurrence.

Differences in combined hepatocellular-cholangiocarcinomas (cHCC-CCAs) arising in high-risk patients with or without liver cirrhosis have not been elucidated. This study aimed to compare the clinicopathologic and imaging characteristics of cHCC-CCAs in patients with or without cirrhosis and to determine the prognostic factors for recurrence-free survival (RFS) after curative resections of single cHCC-CCAs.This retrospective study included 113 patients with surgically resected single cHCC-CCAs who underwent preoperative magnetic resonance imaging from January 2008 to December 2019 at two tertiary referral centres. Clinical, pathologic and imaging features of tumours were compared in high-risk patients with or without cirrhosis. Imaging features were assessed using the Liver Imaging Reporting and Data System (LI-RADS) version 2018. RFS and associated factors were evaluated using Cox proportional hazards regression analysis, Kaplan-Meier analysis and log-rank test.cHCC-CCAs arising from cirrhotic livers had a smaller mean tumour size (2.9 cm vs. 4.5 cm; P .001) and were more frequently categorized as LR-5 or 4 (41.2% vs. 20.0%; P = .024) than those arising from non-cirrhotic livers. In multivariable analysis, a tumour size of 3 cm (hazard ratio [HR], 2.081; 95% confidence interval [CI], 1.180-3.668; P = .011) and the LR-M category (HR, 2.302; 95% CI, 1.198-4.424; P = .012) were independent predictors associated with worse RFS.The tumour size and distribution of LI-RADS categories of cHCC-CCAs differed in high-risk patients with or without cirrhosis. And LR-M category was a worse prognosis predictor after curative resections than LR-5 or 4 category.

The expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016–0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18–0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p, Liver cancer: How estrogen receptors hinder tumor growth Estrogen receptor signaling can act as a brake preventing the progression of an often deadly form of liver cancer. Studies have shown that women are at a lower risk of developing and succumbing to hepatocellular carcinoma (HCC) than men, suggesting a potential role for sex hormones. Researchers in South Korea led by Hyun Goo Woo of the Ajou University School of Medicine, Suwon, and Young Nyun Park of Yonsei University College of Medicine, Seoul, have now shown that expression of the estrogen receptor α is a strong prognostic predictor for HCC. In a survey of patient tumor samples, they found that expression of this hormone receptor is associated with nearly a tenfold increased likelihood of survival. The researchers identified a mechanism by which estrogen receptor α signaling impedes cancerous growth, revealing potential new drug targets.