Imaging biomarkers for predicting poor prognosis of hepatocellular carcinoma: a review

Abstract

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high mortality rate. Heterogeneity is the main biological characteristic of HCC, which manifests through the different biological behaviors of each phenotype and ultimately, affects patient prognosis and treatment efficacy. Various aggressive biological behaviors are considered to be associated with the poor prognosis of HCC patients including poor differentiation, microvascular invasion, intracellular fat accumulation, invasive growth, bile duct invasion or tumor thrombosis, and tumor spread and metastasis, and have been reported as prognostic biomarkers. In addition, HCC results from multifactor synergistic damage, and various factors related to genetics, molecular pathology and immunohistochemistry such as β-catenin, Ki67, cytokeratin-19, and epithelial cell adhesion molecule have an impact on HCC differentiation and prognosis. This article is an overview of the biological behaviors that lead to poor prognosis of HCC, and the roles of morphological and quantitative noninvasive imaging biomarkers in the evaluation and prediction of these behaviors. Some common biomarkers related to genetics, molecular pathology and immunohistochemistry are also briefly summarized. It is hoped that this review will provide clinicians and radiologists with an update on the development of liver imaging, and provide directions for the combination of radiology, genetics, molecular pathology and histopathology to better predict the prognosis of HCC patients.

Keywords

Hepatocellular carcinoma / poor prognosis / biological behaviors / imaging biomarkers / genetics / molecular pathology / immunohistochemistry

References

[1] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries..Int J Cancer2018;68:394-424

[2] Selcuk H.Prognostic factors and staging systems in hepatocellular carcinoma..Exp Clin Transplant2017;15:45-9

[3] Farinati F,Spolverato G,Huo TL.Development and Validation of a new prognostic system for patients with hepatocellular carcinoma..PLoS Med2016;13:e1002006 PMCID:PMC4846017

[4] Rodríguez-Perálvarez M,Andreana L,Dhillon AP.A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability..Ann Surg Oncol2013;20:325-9

[5] Sohn JH,Zhao Y,Chapiro J.Validation of the Hong Kong liver cancer staging system in determining prognosis of the North American patients following intra-arterial therapy..Clin Gastroenterol Hepatol2017;15:746-55.e4 PMCID:PMC5823259

[6] Martins-Filho SN,Azevedo RS.Histological grading of hepatocellular carcinoma-a systematic review of literature..Front Med (Lausanne)2017;10:193 PMCID:PMC5701623

[7] Degasperi E.Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease..Lancet Gastroenterol Hepatol2016;1:156-64

[8] Coskun M.Hepatocellular carcinoma in the cirrhotic liver: evaluation using computed tomography and magnetic resonance imaging..Exp Clin Transplant2017;15:36-44

[9] Yoneda N,Kobayashi S,Kozaka K.Current status of imaging biomarkers predicting the biological nature of hepatocellular carcinoma..Jpn J Radiol2019;37:191-208

[10] Hu HT,Wang Z,Huang XW.Peritumoral tissue on preoperative imaging reveals microvascular invasion in hepatocellular carcinoma: a systematic review and meta-analysis..Abdom Radiol (NY)2018;43:3324-30

[11] Ayuso C,Vilana R,Darnell A.Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines..Eur J Radiol2018;101:72-81

[12] Schelhorn J,Dechêne A,Bertram S.Evaluation of combined Gd-EOB-DTPA and gadobutrol magnetic resonance imaging for the prediction of hepatocellular carcinoma grading..Acta Radiologica2016;57:932-8

[13] Navin PJ.Hepatocellular carcinoma: state of the art imaging and recent advances..J Clin Transl Hepatol2019;7:72-85 PMCID:PMC6441649

[14] Jiang T,Sahani DV.Established and novel imaging biomarkers for assessing response to therapy in hepatocellular carcinoma..J Hepatol2013;58:169-77

[15] Clark T,Meier J,Bhargava P.Hepatocellular carcinoma: review of epidemiology, screening, imaging diagnosis, response assessment, and treatment..Curr Prob Diagn Radiol2015;44:479-86

[16] Oishi K,Amano H,Ohdan H.Clinicopathologic features of poorly differentiated hepatocellular carcinoma..J Surg Oncol2007;95:311-6

[17] Himeno H,Saibara T,Yamamoto Y.Hitherto unrecognized arterioles within hepatocellular carcinoma..J Pathol1994;174:217-22

[18] Hayashi M,Ueda K,Gabata T.Progression to hypervascular hepatocellular carcinoma: correlation with intranodular blood supply evaluated with CT during intraarterial injection of contrast material..Radiology2002;225:143-9

[19] Ye XD,Zhang J.Radiological biomarkers for assessing response to locoregional therapies in hepatocellular carcinoma: From morphological to functional imaging (Review)..Oncol Rep2017;37:1337-46

[20] Feng Y,Luo Y,Zhou X.Efficacy of contrast-enhanced ultrasound washout rate in predicting hepatocellular carcinoma differentiation..Ultrasound Med Biol2015;41:1553-60

[21] Lassau N,Chami L,Benatsou B.Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at dynamic contrast-enhanced US with quantification--preliminary results..Radiology2011;258:291-300

[22] Mann CD,Garcea G,Dennison AR.Prognostic molecular markers in hepatocellular carcinoma: a systematic review..Eur J Cancer2007;43:979-92

[23] Chen J,Xia C,Zuo P.Quantitative free-breathing dynamic contrast-enhanced MRI in hepatocellular carcinoma using gadoxetic acid: correlations with Ki67 proliferation status, histological grades, and microvascular density..Abdom Radiol (NY)2018;43:1393-403

[24] Jiang K,Centeno BA.Primary liver cancers-part 1: histopathology, differential diagnoses, and risk stratification..Cancer Control2018;25:1073274817744625 PMCID:PMC5933592

[25] Park YN.Hepatocarcinogenesis: imaging-pathologic correlation..Abdom Imaging2011;36:232-43

[26] International Consensus Group for Hepatocellular NeoplasiaThe International Consensus Group for Hepatocellular NeoplasiaPathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia..Hepatology2009;49:658-64

[27] Calistri L,Matteuzzi B,Pradella S.Focal liver lesions classification and characterization: what value do DWI and ADC have?.J Comput Assist Tomogr2016;40:701-8

[28] Di Pietropaolo M,Federici GF,Begini P.Comparison of diffusion-weighted imaging and gadoxetic acid-enhanced MR images in the evaluation of hepatocellular carcinoma and hypovascular hepatocellular nodules..Clin Imaging2015;39:468-75

[29] Nasu K,Tsukamoto T,Mori K.Diffusion-weighted imaging of surgically resected hepatocellular carcinoma: imaging characteristics and relationship among signal intensity, apparent diffusion coefficient, and histopathologic grade..AJR Am J Roentgenol2009;193:438-44

[30] Heo SH,Shin SS,Lim HS.Apparent diffusion coefficient value of diffusion-weighted imaging for hepatocellular carcinoma: correlation with the histologic differentiation and the expression of vascular endothelial growth factor..Korean J Radiol2010;11:295-303 PMCID:PMC2864856

[31] Nakanishi M,Hige S,Yokoo H.Relationship between diffusion-weighted magnetic resonance imaging and histological tumor grading of hepatocellular carcinoma..Ann Surg Oncol2012;19:1302-9

[32] Li YT,Yuan J,Loffroy R.Liver intravoxel incoherent motion (IVIM) magnetic resonance imaging: a comprehensive review of published data on normal values and applications for fibrosis and tumor evaluation..Quant Imaging Med Surg2017;7:59-78 PMCID:PMC5337188

[33] Granata V,Catalano O,Granata F.Intravoxel incoherent motion (IVIM) in diffusion-weighted imaging (DWI) for Hepatocellular carcinoma: correlation with histologic grade..Oncotarget2016;7:79357-64 PMCID:PMC5346719

[34] Woo S,Yoon JH,Han JK.Intravoxel incoherent motion diffusion-weighted MR imaging of hepatocellular carcinoma: correlation with enhancement degree and histologic grade..Radiology2014;270:758-67

[35] Sokmen BK,Oz A,Namal E.Value of intravoxel incoherent motion for hepatocellular carcinoma grading..Transplant Proc2019;51:1861-6

[36] Wu EX.MR diffusion kurtosis imaging for neural tissue characterization..NMR Biomed2010;23:836-48

[37] Cao L,Duan T,Jiang H.Diffusion kurtosis imaging (DKI) of hepatocellular carcinoma: correlation with microvascular invasion and histologic grade..Quant Imaging Med Surg2019;9:590-602 PMCID:PMC6511714

[38] Jensen JH.MRI quantification of non-Gaussian water diffusion by kurtosis analysis..NMR Biomed2010;23:698-710 PMCID:PMC2997680

[39] Hennedige TP,Leung FP,Iyer S.Comparison of magnetic resonance elastography and diffusion-weighted imaging for differentiating benign and malignant liver lesions..Eur Radiol2016;26:398-406

[40] Thompson SM,Chandan VS,Roberts LR.MR elastography of hepatocellular carcinoma: correlation of tumor stiffness with histopathology features-Preliminary findings..Magn Reson Imaging2017;37:41-5 PMCID:PMC5587120

[41] Toth CA.Liver endocytosis and Kupffer cells..Hepatology1992;16:255-66

[42] Choi BI,Han MC.Small hepatocellular carcinomas and associated nodular lesions of the liver: pathology, pathogenesis, and imaging findings..AJR Am J Roentgenol1993;160:1177-87

[43] Nassif A,Keiser M,Modess C.Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging..Radiology2012;264:741-50

[44] Fukuda K,Hasegawa N,Ishige K.Safety margin of radiofrequency ablation for hepatocellular carcinoma: a prospective study using magnetic resonance imaging with superparamagnetic iron oxide..Jpn J Radiol2019;37:555-63

[45] Kitao A,Yoneda N,Shinmura R.The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging..Eur Radiol2011;21:2056-66

[46] Kogita S,Okada M,Onishi H.Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow..Eur Radiol2010;20:2405-13

[47] Zech CJ,Berg T,Chau GY.Consensus report from the 8th International Forum for Liver Magnetic Resonance Imaging..Eur Radiol2020;30:370-82 PMCID:PMC6890618

[48] Huang K,Cai H,Peng Z.Imaging biomarkers for well and moderate hepatocellular carcinoma: preoperative magnetic resonance image and histopathological correlation..BMC Cancer2019;19:364 PMCID:PMC6472074

[49] Zois CE.Glycogen metabolism has a key role in the cancer microenvironment and provides new targets for cancer therapy..J Mol Med (Berl)2016;94:137-54 PMCID:PMC4762924

[50] Cervello M,Cusimano A,Balasus D.Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma..Adv Biol Regul2017;65:59-76

[51] Chen R,Zhou X,Huang G.Fructose-1,6-bisphosphatase 1 reduces (18)F FDG uptake in hepatocellular carcinoma..Radiology2017;284:844-53

[52] Seo S,Higashi T,Tada M.Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma..Clin Cancer Res2007;13:427-33

[53] Castilla-Lievre MA,Gervais P,Agostini H.Diagnostic value of combining ¹¹C-choline and ¹⁸F-FDG PET/CT in hepatocellular carcinoma..Eur J Nucl Med Mol Imaging2016;43:852-9

[54] Kong E,Cho IH.Quantitative assessment of simultaneous F-18 FDG PET/MRI in patients with various types of hepatic tumors: correlation between glucose metabolism and apparent diffusion coefficient..PLoS One2017;12:e0180184 PMCID:PMC5495334

[55] Zhang X,Shen F.Significance of presence of microvascular invasion in specimens obtained after surgical treatment of hepatocellular carcinoma..J Gastroenterol Hepatol2018;33:347-54

[56] Wu TH,Yamanaka K,Taura K.A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of hepatocellular carcinoma..Surg Today2016;46:1275-81

[57] Renzulli M,Conti F,Serio I.Imaging features of microvascular invasion in hepatocellular carcinoma developed after direct-acting antiviral therapy in HCV-related cirrhosis..Eur Radiol2018;28:506-13

[58] Ma XL,Wu J,Gao YY.Significance of PIVKA-II levels for predicting microvascular invasion and tumor cell proliferation in Chinese patients with hepatitis B virus-associated hepatocellular carcinoma..Oncol Lett2018;15:8396-404 PMCID:PMC5950517

[59] Zheng J,Gonen M,Kingham TP.Utility of serum inflammatory markers for predicting microvascular invasion and survival for patients with hepatocellular carcinoma..Ann Surg Oncol2017;24:3706-14

[60] Long J,Cui S,Liu X.IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression..Oncotarget2016;7:45678-86 PMCID:PMC5216752

[61] Fransvea E,Antonaci S.Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma..Hepatology2009;49:839-50

[62] Chou CT,Lin WC,Chen CB.Prediction of microvascular invasion of hepatocellular carcinoma: preoperative CT and histopathologic correlation..AJR Am J Roentgenol2014;203:W253-9

[63] Rhee H,Kim HY,Park YN.Hepatocellular carcinoma with irregular rim-like arterial phase hyperenhancement: more aggressive pathologic features..Liver Cancer2019;8:24-40 PMCID:PMC6388566

[64] Chernyak V,Kamaya A,Elsayes KM.Liver imaging reporting and data system (LI-RADS) Version 2018: imaging of hepatocellular carcinoma in at-risk patients..Radiology2018;289:816-30 PMCID:PMC6677371

[65] Zhao J,Zhang K,Meng X.Prediction of microvascular invasion of hepatocellular carcinoma with preoperative diffusion-weighted imaging: A comparison of mean and minimum apparent diffusion coefficient values..Medicine2017;96:e7754 PMCID:PMC5571689

[66] Wang WT,Yang ZX,Ding Y.Assessment of microvascular invasion of hepatocellular carcinoma with diffusion kurtosis imaging..Radiology2018;286:571-80

[67] Jensen JH,Ramani A,Kaczynski K.Diffusional kurtosis imaging: the quantification of non-gaussian water diffusion by means of magnetic resonance imaging..Magn Reson Med2005;53:1432-40

[68] Ahn SJ,Park SJ,Han JK.Hepatocellular carcinoma: preoperative gadoxetic acid-enhanced MR imaging can predict early recurrence after curative resection using image features and texture analysis..Abdom Radiol (NY)2019;44:539-48

[69] Lee S,Lee JE,Park CK.Preoperative gadoxetic acid-enhanced MRI for predicting microvascular invasion in patients with single hepatocellular carcinoma..J Hepatol2017;67:526-34

[70] Ryu T,Wada Y,Hara T.A clinical scoring system for predicting microvascular invasion in patients with hepatocellular carcinoma within the milan criteria..J Gastrointest Surg2019;23:779-87

[71] Peng J,Zhang Q,Zhou J.A radiomics nomogram for preoperative prediction of microvascular invasion risk in hepatitis B virus-related hepatocellular carcinoma..Diagn Interv Radiol2018;24:121-7 PMCID:PMC5951199

[72] Xu X,Liu QP,Zhang J.Radiomic analysis of contrast-enhanced CT predicts microvascular invasion and outcome in hepatocellular carcinoma..J Hepatol2019;70:1133-44

[73] Ji GW.Radiomic features at contrast-enhanced CT predict recurrence in early stage hepatocellular carcinoma: a multi-institutional study..Radiology2020;294:568-79

[74] Zhu YJ,Wang S,Wu JF.Model-based three-dimensional texture analysis of contrast-enhanced magnetic resonance imaging as a potential tool for preoperative prediction of microvascular invasion in hepatocellular carcinoma..Oncol Lett2019;18:720-32 PMCID:PMC6546996

[75] Kutami R,Nakashima O,Kojiro M.Pathomorphologic study on the mechanism of fatty change in small hepatocellular carcinoma of humans..J Hepatol2000;33:282-9

[76] Takayama T,Hirohashi S,Okazaki N.Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma..Lancet1990;336:1150-3

[77] Villanueva A,Chiang DY,Llovet JM.Genomics and signaling pathways in hepatocellular carcinoma..Semin Liver Dis2007;27:55-76

[78] Asayama Y,Ishigami K,Takayama Y.Fatty change in moderately and poorly differentiated hepatocellular carcinoma on MRI: a possible mechanism related to decreased arterial flow..Clin Radiol2016;71:1277-83

[79] Min JH,Lim S,Choi D.Prediction of microvascular invasion of hepatocellular carcinomas with gadoxetic acid-enhanced MR imaging: Impact of intra-tumoral fat detected on chemical-shift images..Eur J Radiol2015;84:1036-43

[80] Kubota N,Hatano M,Masugi Y.Clinicopathological features of hepatocellular carcinoma with fatty change: tumors with macrovesicular steatosis have better prognosis and aberrant expression patterns of perilipin and adipophilin..Pathol Int2020;70:199-209

[81] Yamaguchi H.Regulation of the actin cytoskeleton in cancer cell migration and invasion..Biochimica et biophysica acta2007;1773:642-652 PMCID:PMC4266238

[82] Kim YY,Sirlin CB,Kim MJ.Pitfalls and problems to be solved in the diagnostic CT/MRI Liver Imaging Reporting and Data System (LI-RADS)..Eur Radiol2019;29:1124-32

[83] Qin S.Guidelines on the diagnosis and treatment of primary liver cancer (2011 edition)..Chin Clin Oncol2012;1:10

[84] Hennedige T.Advances in computed tomography and magnetic resonance imaging of hepatocellular carcinoma..World J Gastroenterol2016;22:205-20 PMCID:PMC4698486

[85] Cheng S,Cai J.Chinese expert consensus on multidisciplinary diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus: 2016 edition..Oncotarget2017;8:8867-76 PMCID:PMC5352449

[86] Ponziani FR,Campanale C,Tortora A.Portal vein thrombosis: insight into physiopathology, diagnosis, and treatment..World J Gastroenterol2010;16:143-55 PMCID:PMC2806552

[87] Kanematsu M,Leonardou P,Lee JK.Hepatocellular carcinoma of diffuse type: MR imaging findings and clinical manifestations..J Magn Reson Imaging2003;18:189-95

[88] An J,Kim KM.Clinical features and outcomes of patients with hepatocellular carcinoma complicated with bile duct invasion..Clin Mol Hepatol2017;23:160-9 PMCID:PMC5497660

[89] Chotirosniramit A,Lapisatepun W,Sandhu T.A single institution report of 19 hepatocellular carcinoma patients with bile duct tumor thrombus..J Hepatocell Carcinoma2017;4:41-7 PMCID:PMC5349699

[90] Suh YG,Han KH.Effective biliary drainage and proper treatment improve outcomes of hepatocellular carcinoma with obstructive jaundice..Gut Liver2014;8:526-35 PMCID:PMC4164257

[91] Liu QY,Chen JY,Gao M.Small hepatocellular carcinoma with bile duct tumor thrombi: CT and MRI findings..Abdom Imaging2010;35:537-42

[92] Lu CH,Cheng YF,Tsang LL.Correlation between imaging and pathologic findings in explanted livers of hepatocellular carcinoma cases..Transplant Proc2010;42:830-3

[93] Liu Q,Li H,Zhang L.Hepatocellular carcinoma with bile duct tumor thrombi: correlation of magnetic resonance imaging features to histopathologic manifestations..Eur J Radiol2010;76:103-9

[94] Giannelli G,Dituri F,Palasciano G.Moving towards personalised therapy in patients with hepatocellular carcinoma: the role of the microenvironment..Gut2014;63:1668-76

[95] Ariizumi S,Kotera Y,Katagiri S.A non-smooth tumor margin in the hepatobiliary phase of gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging predicts microscopic portal vein invasion, intrahepatic metastasis, and early recurrence after hepatectomy in patients with hepatocellular carcinoma..J Hepatobiliary Pancreat Sci2011;18:575-85

[96] Seo HJ,Kim JH,Choi HJ.¹⁸F-FDG PET/CT in hepatocellular carcinoma: detection of bone metastasis and prediction of prognosis..Nucl Med Commun2015;36:226-33

[97] Hwang SH,Cho HJ,Choi GH.Prognostic value of metabolic tumor volume and total lesion glycolysis on preoperative ¹⁸F-FDG PET/CT in patients with very early and early hepatocellular carcinoma..Clin Nucl Med2017;42:34-9

[98] Ho CL,Yeung DW.Dual-tracer PET/CT imaging in evaluation of metastatic hepatocellular carcinoma..J Nucl Med2007;48:902-9

[99] Kitao A,Yoneda N,Kobayashi S.Hepatocellular carcinoma with β-catenin mutation: Imaging and pathologic characteristics..Radiology2015;275:708-17

[100] Zucman-Rossi J,Nhieu JT,Guettier C.Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC..Hepatology2006;43:515-24

[101] Kitao A,Yoneda N,Kobayashi S.Gadoxetic acid-enhanced MR imaging for hepatocellular carcinoma: molecular and genetic background..Eur Radiol2020;Epub ahead of print. doi: 10.1007/s00330-020-06687-y

[102] Guzman G,Layden-Almer JE,Testa G.p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients..Mod Pathol2005;18:1498-503

[103] Chen J,Xia C,Zuo P.Quantitative free-breathing dynamic contrast-enhanced MRI in hepatocellular carcinoma using gadoxetic acid: correlations with Ki67 proliferation status, histological grades, and microvascular density..Abdom Radiol (NY)2018;43:1393-403

[104] Chen Y,Long L,Huang Z.Diagnostic value of Gd-EOB-DTPA-enhanced MRI for the expression of Ki67 and microvascular density in hepatocellular carcinoma..J Magn Reson Imaging2019;Epub ahead of print. doi: 10.1002/jmri.26974

[105] Li Y,Weng S,Yan C.Small hepatocellular carcinoma: using MRI to predict histological grade and Ki-67 expression..Clin Radiol2019;74:653.e1-653.e9

[106] Surov A,Wienke A.Associations between apparent diffusion coefficient (ADC) and KI 67 in different tumors: a meta-analysis. Part 1: ADCmean..Oncotarget2017;8:75434-44 PMCID:PMC5650434

[107] Ye Z,Chen J,Wei Y.Texture analysis on gadoxetic acid enhanced-MRI for predicting Ki-67 status in hepatocellular carcinoma: a prospective study..Chin J Cancer Res2019;31:806-17 PMCID:PMC6856708

[108] Tsuchiya K,Yasui Y,Hosokawa T.Expression of keratin 19 is related to high recurrence of hepatocellular carcinoma after radiofrequency ablation..Oncology2011;80:278-88

[109] Wang W,Wei J,Yang L.A radiomics-based biomarker for cytokeratin 19 status of hepatocellular carcinoma with gadoxetic acid-enhanced MRI.2020;30:3004-14

[110] Chen J,Xia C,Liu X.Noninvasive prediction of HCC with progenitor phenotype based on gadoxetic acid-enhanced MRI..Eur Radiol2020;30:1232-42

[111] Hu XX,Yang L,Liang HY.MR features based on LI-RADS identify cytokeratin 19 status of hepatocellular carcinomas..Eur J Radiol2019;113:7-14

[112] Choi SY,Park CK,Lee JE.Imaging features of gadoxetic acid-enhanced and diffusion-weighted MR imaging for identifying cytokeratin 19-positive hepatocellular carcinoma: a retrospective observational study..Radiology2018;286:897-908

[113] Munz M,Gires O.The emerging role of EpCAM in cancer and stem cell signaling..Cancer Res2009;69:5627-9

[114] Zhou L.The EpCAM overexpression is associated with clinicopathological significance and prognosis in hepatocellular carcinoma patients: a systematic review and meta-analysis..Int J Surg2018;56:274-80

[115] Ji J,Budhu A,Jia HL.Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells..Hepatology2009;50:472-80 PMCID:PMC2721019