Diagnostic value of clusterin immunostaining in hepatocellular carcinoma

Abstract Background Histologic distinction between well differentiated hepatocellular carcinoma (HCC) and benign hepatocellular mass lesions is a known challenge. Existing biomarkers are of limited diagnostic value. Our previous studies observed an enhanced canalicular expression pattern of clusterin (CLU) in HCC, which was not observed in benign hepatocellular mass lesions such as hepatocellular adenoma. The aim of this study was to further investigate its diagnostic value for HCC by examining the expression pattern of CLU in a large number of non-hepatocellular tumors, and by comparing it with two other commonly used hepatocellular markers pCEA and CD10 that also show a canalicular staining pattern in HCC. Methods Enhanced canalicular staining patterns of CLU, pCEA and CD10 were analyzed on 54 surgically resected well to moderately differentiated HCCs on whole tissue sections, of which 37 had surrounding regenerative nodules while the remaining 17 had a non-cirrhotic background. CLU immunostaining was also performed on tissue microarray sections that contained 74 HCCs (40 of which were also stained for pCEA and CD10), 55 normal liver tissue samples, and 1305 non-hepatocellular tumors from multiple organs. Results Enhanced CLU canalicular staining was observed in 70% (89/128) HCCs but not in regenerative nodules, normal liver tissues or any non-hepatocellular tumors. The sensitivity and specificity for enhanced canalicular staining pattern of CLU in HCCs were 0.70 and 1.00. This enhanced canalicular pattern was observed in only 26 and 23% HCCs for CD10 and pCEA, respectively. These results further demonstrate that the distinctive enhanced canalicular pattern of CLU is unique to HCC. Conclusions CLU is superior to pCEA and CD10 as a diagnostic immunomarker in that it can help distinguish well to moderately differentiated HCC not only from non-HCC malignancies but also from benign hepatocellular mass lesions.

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Diagnostic Value of Clusterin Immunostaining in Hepatocellular Carcinoma

10.21203/rs.3.rs-27056/v3 ◽

2020 ◽

Author(s):

Yuan Li ◽

Fangfang Liu ◽

Wendi Zhou ◽

Sharon Zhang ◽

Peiguo Chu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Expression Pattern ◽

Staining Pattern ◽

Hepatocellular Adenoma ◽

Normal Liver ◽

Diagnostic Value ◽

Tissue Samples ◽

Multiple Organs ◽

Regenerative Nodules ◽

Mass Lesions

Abstract Background: Histologic distinction between well differentiated hepatocellular carcinoma (HCC) and benign hepatocellular mass lesions is a known challenging. Existing biomarkers are of limited diagnostic value. Our previous studies observed an enhanced canalicular expression pattern of clusterin (CLU) in HCC, which was not observed in benign hepatocellular mass lesions such as hepatocellular adenoma. The aim of this study was to further investigate its diagnostic value for HCC by examining the expression pattern of CLU in a large number of non-hepatocellular tumors, and by comparing it with two other commonly used hepatocellular markers pCEA and CD10 that also show a canalicular staining pattern in HCC. Methods: Enhanced canalicular staining patterns of CLU, pCEA and CD10 were analyzed on 54 surgically resected well to moderately differentiated HCCs on whole tissue sections, of which 37 had surrounding regenerative nodules while the remaining 17 had a non-cirrhotic background. CLU immunostaining was also performed on tissue microarray sections that contained 74 HCCs (40 of which were also stained for pCEA and CD10), 55 normal liver tissue samples, and 1305 non-hepatocellular tumors from multiple organs. Results: Enhanced CLU canalicular staining was observed in 70% (89/128) HCCs but not in regenerative nodules, normal liver tissues or any non-hepatocellular tumors. The sensitivity and specificity for enhanced canalicular staining pattern of CLU in HCCs were 0.70 and 1.00. This enhanced canalicular pattern was observed in only 26% and 23% HCCs for CD10 and pCEA, respectively. These results further demonstrate that the distinctive enhanced canalicular pattern of CLU is unique to HCC. Conclusions: CLU is superior to pCEA and CD10 as a diagnostic immunomarker in that it can help distinguish well to moderately differentiated HCC not only from non-HCC malignancies but also from benign hepatocellular mass lesions.

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Diagnostic Value of Clusterin Immunostaining in Hepatocellular Carcinoma

10.21203/rs.3.rs-27056/v2 ◽

2020 ◽

Author(s):

Yuan Li ◽

Fangfang Liu ◽

Wendi Zhou ◽

Sharon Zhang ◽

Peiguo Chu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Expression Pattern ◽

Staining Pattern ◽

Hepatocellular Adenoma ◽

Normal Liver ◽

Diagnostic Value ◽

Tissue Samples ◽

Multiple Organs ◽

Regenerative Nodules ◽

Mass Lesions

Abstract Background Histologic distinction between well differentiated hepatocellular carcinoma (HCC) and benign hepatocellular mass lesions is a known challenging. Existing biomarkers are of limited diagnostic value. Our previous studies observed an enhanced canalicular expression pattern of clusterin (CLU) in HCC, which was not observed in benign hepatocellular mass lesions such as hepatocellular adenoma. The aim of this study was to further investigate its diagnostic value for HCC by examining the expression pattern of CLU in a large number of non-hepatocellular tumors, and by comparing it with two other commonly used hepatocellular markers pCEA and CD10 that also show a canalicular staining pattern in HCC. Methods Enhanced canalicular staining patterns of CLU, pCEA and CD10 were analyzed on 54 surgically resected well to moderately differentiated HCCs on whole tissue sections, of which 37 had surrounding regenerative nodules while the remaining 17 had a non-cirrhotic background. CLU immunostaining was also performed on tissue microarray sections that contained 74 HCCs (40 of which were also stained for pCEA and CD10), 55 normal liver tissue samples, and 1305 non-hepatocellular tumors from multiple organs. Results Enhanced CLU canalicular staining was observed in 70% (89/128) HCCs but not in regenerative nodules, normal liver tissues or any non-hepatocellular tumors. The sensitivity and specificity for enhanced canalicular staining pattern of CLU in HCCs were 0.70 and 1.00. This enhanced canalicular pattern was observed in only 26% and 23% HCCs for CD10 and pCEA, respectively. These results further demonstrate that the distinctive enhanced canalicular pattern of CLU is unique to HCC. Conclusions CLU is superior to pCEA and CD10 as a diagnostic immunomarker in that it can help distinguish well to moderately differentiated HCC not only from non-HCC malignancies but also from benign hepatocellular mass lesions.

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Diagnostic Value of Clusterin Immunostaining in Hepatocellular Carcinoma

10.21203/rs.3.rs-27056/v1 ◽

2020 ◽

Author(s):

Yuan Li ◽

Fangfang Liu ◽

Wendi Zhou ◽

Sharon Zhang ◽

Peiguo Chu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Expression Pattern ◽

Staining Pattern ◽

Hepatocellular Adenoma ◽

Normal Liver ◽

Diagnostic Value ◽

Tissue Samples ◽

Regenerative Nodules ◽

Well Differentiated ◽

Mass Lesions

Abstract Background Histologic distinction between well differentiated hepatocellular carcinoma (HCC) and benign hepatocellular mass lesions is a known challenging. Existing biomarkers are of limited diagnostic value. Our previous studies observed an enhanced canalicular expression pattern of clusterin (CLU) in HCC, which was not observed in benign hepatocellular mass lesions such as hepatocellular adenoma. The aim of this study was to further investigate its diagnostic value for HCC by examining the expression pattern of CLU in a large number of non-hepatocellular tumors, and by comparing it with two other commonly used hepatocellular markers pCEA and CD10 that also show a canalicular staining pattern in HCC.Methods Enhanced canalicular staining patterns of CLU, pCEA and CD10 were analyzed on 54 surgically resected well to moderately differentiated HCCs on whole tissue sections, of which 37 had surrounding regenerative nodules while the remaining 17 had a non-cirrhotic background. CLU immunostaining was also performed on tissue microarray sections that contained 74 HCCs (40 of which were also stained for pCEA and CD10), 55 normal liver tissue samples, and 1305 non-hepatocellular tumors from multiple organs.Results Enhanced CLU canalicular staining was observed in 70% (89/128) HCCs but not in regenerative nodules, normal liver tissues or any non-hepatocellular tumors. The sensitivity and specificity for enhanced canalicular staining pattern of CLU in HCCs were 0.70 and 1.00. This enhanced canalicular pattern was observed in only 26% and 23% HCCs for CD10 and pCEA, respectively. These results further demonstrate that the distinctive enhanced canalicular pattern of CLU is unique to HCC.Conclusions CLU is superior to pCEA and CD10 as a diagnostic immunomarker in that it can help distinguish HCC not only from non-HCC malignancies but also from benign hepatocellular mass lesions.

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Glypican-3 as a Useful Diagnostic Marker That Distinguishes Hepatocellular Carcinoma From Benign Hepatocellular Mass Lesions

Archives of Pathology & Laboratory Medicine ◽

10.5858/132.11.1723 ◽

2008 ◽

Vol 132 (11) ◽

pp. 1723-1728 ◽

Cited By ~ 3

Author(s):

Hanlin L. Wang ◽

Florencia Anatelli ◽

Qihui“Jim” Zhai ◽

Brian Adley ◽

Shang-Tian Chuang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatocellular Adenoma ◽

Diagnostic Value ◽

Small Subset ◽

Resected Liver ◽

Background Staining ◽

Gpc3 Expression ◽

Regenerative Nodules ◽

A Cell ◽

Mass Lesions

Abstract Context.—Histopathologic distinction between hepatocellular carcinoma (HCC) and benign hepatocellular mass lesions, particularly hepatocellular adenoma, can sometimes be challenging. The currently available ancillary tools are suboptimal in terms of sensitivity and specificity. Objective.—To further characterize the diagnostic value of glypican-3 (GPC3), a cell surface proteoglycan that has recently been shown to be overexpressed in HCC, in the distinction between HCC and benign hepatocellular mass lesions. Design.—A total of 221 surgically resected liver specimens were subjected to immunohistochemical staining using a monoclonal antibody specific for GPC3. These included 111 HCCs, 48 hepatocellular adenomas, 30 focal nodular hyperplasias, and 32 large regenerative nodules in the background of cirrhosis. Results.—Cytoplasmic, membranous, and canalicular staining for GPC3 was detected in 84 (75.7%) of the 111 HCCs, among which, 61 (72.6%) of the 84 cases exhibited diffuse immunoreactivity. In contrast, none of the 110 cases of hepatocellular adenoma, focal nodular hyperplasia, and large regenerative nodule showed detectable GPC3 staining. Focal GPC3 immunoreactivity was detected in cirrhotic nodules in 11 (16.4%) of 67 HCC cases with a cirrhotic background, but no background staining was observed in the remaining 44 HCCs without cirrhosis. GPC3 expression in HCCs did not correlate with the size, differentiation, or stage of the tumors; the presence or absence of cirrhotic background; or the underlying etiologies. Conclusions.—GPC3 is a specific immunomarker for HCC that can be used to distinguish HCC from benign hepatocellular mass lesions, particularly hepatocellular adenoma. However, the diagnosis of HCC should not rely entirely on positive GPC3 immunostaining because focal immunoreactivity can be detected in a small subset of cirrhotic nodules. In addition, GPC3 expression in HCC can also be focal, and thus, the lack of GPC3 staining does not exclude the diagnosis of HCC.

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SUMO-Activating Enzyme Subunit 1 (SAE1) Is a Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma

Cells ◽

10.3390/cells10010178 ◽

2021 ◽

Vol 10 (1) ◽

pp. 178

Author(s):

Jiann Ruey Ong ◽

Oluwaseun Adebayo Bamodu ◽

Nguyen Viet Khang ◽

Yen-Kuang Lin ◽

Chi-Tai Yeh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Metabolism ◽

Interaction Analysis ◽

Normal Liver ◽

Diagnostic Value ◽

Vital Role ◽

Regulation Of Transcription ◽

Dependent Manner ◽

Post Translational Modification ◽

Characteristic Analysis

Hepatocellular carcinoma (HCC) is one of the most diagnosed malignancies and a leading cause of cancer-related mortality globally. This is exacerbated by its highly aggressive phenotype, and limitation in early diagnosis and effective therapies. The SUMO-activating enzyme subunit 1 (SAE1) is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. Reported overexpression of SAE1 in glioma in a stage-dependent manner suggests it has a probable role in cancer initiation and progression. In this study, hypothesizing that SAE1 is implicated in HCC metastatic phenotype and poor prognosis, we analyzed the expression of SAE1 in several cancer databases and to unravel the underlying molecular mechanism of SAE1-associated hepatocarcinogenesis. Here, we demonstrated that SAE1 is over-expressed in HCC samples compared to normal liver tissue, and this observed SAE1 overexpression is stage and grade-dependent and associated with poor survival. The receiver operating characteristic analysis of SAE1 in TCGA−LIHC patients (n = 421) showed an AUC of 0.925, indicating an excellent diagnostic value of SAE1 in HCC. Our protein-protein interaction analysis for SAE1 showed that SAE1 interacted with and activated oncogenes such as PLK1, CCNB1, CDK4 and CDK1, while simultaneously inhibiting tumor suppressors including PDK4, KLF9, FOXO1 and ALDH2. Immunohistochemical staining and clinicopathological correlate analysis of SAE1 in our TMU-SHH HCC cohort (n = 54) further validated the overexpression of SAE1 in cancerous liver tissues compared with ‘normal’ paracancerous tissue, and high SAE1 expression was strongly correlated with metastasis and disease progression. The oncogenic effect of upregulated SAE1 is associated with dysregulated cancer metabolic signaling. In conclusion, the present study demonstrates that SAE1 is a targetable cancer metabolic biomarker with high potential diagnostic and prognostic implications for patients with HCC.

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The diagnostic and prognostic value of H2AFY in hepatocellular carcinoma

10.21203/rs.3.rs-17889/v2 ◽

2020 ◽

Author(s):

xuyang ma ◽

Ying Ding ◽

Li Zeng

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Prognostic Value ◽

Clinical Characteristics ◽

Cox Regression ◽

Normal Liver ◽

Diagnostic Value ◽

The Relationship ◽

Diagnostic And Prognostic Value

Abstract Background: The potential correlation between H2AFY (also known as MacroH2A1) and the clinical characteristics of hepatocellular carcinoma (HCC) patients was analysed through gene expression profiles and clinical data in The Cancer Genome Atlas (TCGA) database, and the diagnostic and prognostic value of H2AFY in HCC was discussed. Methods: The gene expression data of HCC and the corresponding clinical characteristics of HCC patients were downloaded from the TCGA database. The differences in H2AFY in normal liver tissues and HCC were analysed. The relationship between H2AFY and clinical characteristics was analysed by Wilcoxon signed-rank test, logistic regression and Kruskal-Wallis test. The Kaplan-Meier method and the Cox regression method were used to analyse the relationship between overall survival and clinical characteristics of the patients. An ROC curve was used to predict the diagnostic value of H2AFY in HCC. Gene set enrichment analysis (GSEA) was used to analyse the pathway enrichment of H2AFY. Result: Compared with normal liver tissues, H2AFY was significantly highly expressed in HCC. H2AFY was positively correlated with the age, clinical stage, G stage (grade) and T stage (tumor stage) of liver cancer patients. Higher H2AFY expression predicted a poor prognosis in HCC patients. Cox regression analysis suggested that H2AFY was an independent risk factor for the prognosis of HCC patients. The ROC curve suggested that H2AFY had certain diagnostic value in HCC. GSEA suggested that H2AFY was correlated with lipid metabolism and a variety of tumour pathways. Conclusion: Our study showed that H2AFY was significantly overexpressed in HCC. H2AFY may be a potential diagnostic and prognostic marker for HCC, and high expression of H2AFY predicts a poor prognosis in patients with HCC.

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Diagnostic Test of PIVKA-II as A Tumor Marker for Hepatocellular Carcinoma (HCC)

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v26i2.1436 ◽

2020 ◽

Vol 26 (2) ◽

Author(s):

Dwi Priyadi Djatmiko ◽

I Putu Adi Santosa ◽

Elvin Richela Lawanto ◽

Bogi Pratomo ◽

Hani Susianti

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Marker ◽

Diagnostic Test ◽

Method Comparison ◽

Normal Liver ◽

Diagnostic Value ◽

Roc Curve Analysis ◽

Healthy Control ◽

Cirrhotic Patients ◽

Sensitivity Specificity

Introduction. Alpha-Fetoprotein (AFP) is a tumor marker that has been widely used for HCC, but there has been no increased AFP in 35-45% patients with HCC. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an abnormal prothrombin secreted in HCC and is expected can be used for HCC diagnostic marker. The objective of this study was to compare serum PIVKA-II levels in the patients with HCC, cirrhosis and healthy control and determine the diagnostic value of PIVKA-II for hepatocellular carcinoma. Methods. This was a cross-section analytic observational study to identify the diagnostic value of PIVKA-II for HCC diagnosis. The diagnosis of 20 cirrhotic patients and 15 patients with HCC was established by history taking, physical examination, and additional examination according to the diagnosis criteria. A group of 12 individuals with normal liver function were used as healthy control subjects. Serum PIVKA-II levels were analyzed with immunoassay method. Comparison study used the Independent-Samples Kruskal Wallis Test. ROC curve analysis and 2x2 contingency table was used to calculate sensitivity, specificity, positive and negative predictive value (PPV and NPV).Results. The serum PIVKA-II level in the patients with HCC was significantly higher than in cirrhotic (p = 0,000) and healthy control patients (p = 0,000). Sensitivity, specificity, PPV, and NPV of PIVKA-II for diagnosis of HCC in cirrhotic patients at a cut-off value of 140.85 mAU/mL were 93.33%, 75%, 73.68%, and 93.75%, respectively (AUC = 0.87).Conclusions and Suggestions. PIVKA-II has high diagnostic value for HCC diagnosis. Diagnostic test that compare serum PIVKA-II level in any size of HCC nodules may be needed in the future.

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Thymosin β 10 is overexpressed and associated with unfavorable prognosis in hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20182355 ◽

2019 ◽

Vol 39 (3) ◽

Cited By ~ 2

Author(s):

Chunrong Song ◽

Zhong Su ◽

Jing Guo

Keyword(s):

Hepatocellular Carcinoma ◽

Human Cancer ◽

Normal Liver ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Tumor Biomarker ◽

Advanced Tumor Stage ◽

Poor Overall Survival ◽

Tissue Samples ◽

Advanced Tumor

Abstract Thymosin β 10 (TMSB10) has been demonstrated to be overexpressed and function as an oncogene in most types of human cancer including hepatocellular carcinoma (HCC). In our study, we present more evidence about the clinical significance and biological function of TMSB10 in HCC. First, we observed levels of TMSB10 expression were obviously increased in HCC tissues compared with normal liver tissues at The Cancer Genome Atlas (TCGA) datasets. Furthermore, we confirmed that TMSB10 mRNA and protein levels were also increased in HCC tissue samples compared with normal adjacent normal liver tissue samples. In addition, we found high TMSB10 expression was remarkably associated with the advanced tumor stage, large tumor size, distant metastasis, and poor prognosis, and acted as an independent factor for predicting poor overall survival in HCC patients. Loss-of-function studies suggested silencing of TMSB10 expression dramatically reduced cell proliferation, migration, and invasion in HCC. In conclusion, TMSB10 may hold promise as a tumor biomarker for predicting prognosis and a potential target for developing a novel therapeutic strategy.

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Prognostic significance and oncogene function of cathepsin A in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-93998-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Huaxiang Wang ◽

Fengfeng Xu ◽

Fang Yang ◽

Lizhi Lv ◽

Yi Jiang

Keyword(s):

Hepatocellular Carcinoma ◽

Oxidative Phosphorylation ◽

Prognostic Significance ◽

Enrichment Analysis ◽

Normal Liver ◽

Diagnostic Value ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Clinical Value ◽

Lysosomal Protease

AbstractCathepsin A (CTSA) is a lysosomal protease that regulates galactoside metabolism. The previous study has shown CTSA is abnormally expressed in various types of cancer. However, rarely the previous study has addressed the role of CTSA in hepatocellular carcinoma (HCC) and its prognostic value. To study the clinical value and potential function of CTSA in HCC, datasets from the Cancer Genome Atlas (TCGA) database and a 136 HCC patient cohort were analyzed. CTSA expression was found to be significantly higher in HCC patients compared with normal liver tissues, which was supported by immunohistochemistry (IHC) validation. Both gene ontology (GO) and The Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that CTSA co-expressed genes were involved in ATP hydrolysis coupled proton transport, carbohydrate metabolic process, lysosome organization, oxidative phosphorylation, other glycan degradation, etc. Survival analysis showed a significant reduction both in overall survival (OS) and recurrence-free survival (RFS) of patients with high CTSA expression from both the TCGA HCC cohort and 136 patients with the HCC cohort. Furthermore, CTSA overexpression has diagnostic value in distinguishing between HCC and normal liver tissue [Area under curve (AUC) = 0.864]. Moreover, Gene set enrichment analysis (GSEA) showed that CTSA expression correlated with the oxidative phosphorylation, proteasome, and lysosome, etc. in HCC tissues. These findings demonstrate that CTSA may as a potential diagnostic and prognostic biomarker in HCC.

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The diagnostic and prognostic value of H2AFY in hepatocellular carcinoma

BMC Cancer ◽

10.1186/s12885-021-08161-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xuyang Ma ◽

Ying Ding ◽

Li Zeng

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Prognostic Value ◽

Clinical Characteristics ◽

Cox Regression ◽

Normal Liver ◽

Diagnostic Value ◽

The Relationship ◽

Diagnostic And Prognostic Value

Abstract Background The potential correlation between H2AFY (also known as MacroH2A1) and the clinical characteristics of hepatocellular carcinoma (HCC) patients was analysed through gene expression profiles and clinical data in The Cancer Genome Atlas (TCGA) database, and the diagnostic and prognostic value of H2AFY in HCC was discussed. Methods The gene expression data of HCC and the corresponding clinical characteristics of HCC patients were downloaded from the TCGA database. The differences in H2AFY in normal liver tissues and HCC were analysed. The relationship between H2AFY and clinical characteristics was analysed by Wilcoxon signed-rank test, logistic regression and Kruskal-Wallis test. The Kaplan-Meier method and the Cox regression method were used to analyse the relationship between overall survival and clinical characteristics of the patients. An ROC curve was used to predict the diagnostic value of H2AFY in HCC. Gene set enrichment analysis (GSEA) was used to analyse the pathway enrichment of H2AFY. Result Compared with normal liver tissues, H2AFY was significantly highly expressed in HCC. H2AFY was positively correlated with the age, clinical stage, G stage (grade) and T stage (tumor stage) of liver cancer patients. Higher H2AFY expression predicted a poor prognosis in HCC patients. Cox regression analysis suggested that H2AFY was an independent risk factor for the prognosis of HCC patients. The ROC curve suggested that H2AFY had certain diagnostic value in HCC. GSEA suggested that H2AFY was correlated with lipid metabolism and a variety of tumour pathways. Conclusion Our study showed that H2AFY was significantly overexpressed in HCC. H2AFY may be a potential diagnostic and prognostic marker for HCC, and high expression of H2AFY predicts a poor prognosis in patients with HCC.

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