Clinical significance of cytokeratin 19 expression in hepatocellular carcinoma

Abstract

Aim: This study aimed to compare the prognostic outcomes of cytokeratin (CK) 19-positive and CK19-negative hepatocellular carcinoma (HCC), focusing on clinicopathological features and the impact of targeted therapy in CK19-positive patients.

Methods: A retrospective analysis was performed on 310 HCC patients who underwent curative resection between 2010 and 2020 at the First Affiliated Hospital of Nanjing Medical University. Among them, 102 were CK19-positive and 168 were CK19-negative. Multivariate Cox regression was used to identify independent predictors of overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier survival curves were generated from the Cox model.

Results: CK19-positive patients exhibited significantly poorer tumor differentiation (P < 0.001), increased microvascular invasion (P = 0.010), elevated α-fetoprotein (AFP) (P = 0.0001) and were more often asymptomatic at diagnosis (P = 0.014). The median survival time (MST) was 22.1 months in CK19-positive versus 60.3 months in CK19-negative patients. Among those with recurrence, MST was 56.4 months for CK19-positive and 101.6 months for CK19-negative patients. CK19 status significantly impacted OS (P < 0.001) and RFS (P = 0.006) in advanced-stage cases. Independent prognostic factors for RFS included cirrhosis, tumor size, number of tumors, macrovascular invasion, poor differentiation, and CK19 expression. Microvascular invasion and Child-Pugh classification were additional predictors of OS. Targeted therapies did not significantly improve outcomes in CK19-positive patients.

Conclusions: CK19-positive HCC is associated with more aggressive tumor behavior, higher recurrence, and poorer survival. Targeted therapy provided no significant survival benefit in this study.

Keywords

Hepatocellular carcinoma / cytokeratin 19 / overall survival / recurrence-free survival / targeted therapy

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.CA Cancer J Clin2018;68:394-424

[2] Sung H,Siegel RL.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[3] Bray F,Sung H.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2024;74:229-63

[4] Lai CL,Yuen MF.Viral hepatitis B.Lancet2003;362:2089-94

[5] Zhuo JY,Tan WY,Shen YQ.CK19-positive hepatocellular carcinoma is a characteristic subtype.J Cancer2020;11:5069-77

[6] Singal AG,Tiro J.Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.PLoS Med2014;11:e1001624

[7] Ghazanfar H,Qasim A.Metabolic dysfunction-associated steatohepatitis and progression to hepatocellular carcinoma: a literature review.Cancers2024;16:1214

[8] Yoon JK,Rhee H.MRI features of histologic subtypes of hepatocellular carcinoma: correlation with histologic, genetic, and molecular biologic classification.Eur Radiol2022;32:5119-33

[9] Fulgenzi CAM,Murray SM.Immunotherapy in hepatocellular carcinoma.Curr Treat Options Oncol2021;22:87

[10] Komatsu S,Kido M.Hepatectomy versus sorafenib for advanced hepatocellular carcinoma with macroscopic portal vein tumor thrombus: a bi-institutional propensity-matched cohort study.J Hepatobiliary Pancreat Sci2023;30:303-14

[11] Sun P,Yan Z.Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression.BMC Cancer2024;24:922

[12] Boyault S,de Reyniès A.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology2007;45:42-52

[13] Lee JS,Libbrecht L.A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.Nat Med2006;12:410-6

[14] Chiang DY,Hoshida Y.Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.Cancer Res2008;68:6779-88

[15] Mehrpouya M,Yardehnavi N.Evaluation of cytokeratin 19 as a prognostic tumoral and metastatic marker with focus on improved detection methods.J Cell Physiol2019;234:21425-35

[16] Moll R,Schiller DL,Krepler R.The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells.Cell1982;31:11-24

[17] Haruna Y,Spaulding S,Gerber MA.Identification of bipotential progenitor cells in human liver development.Hepatology1996;23:476-81

[18] Durnez A,Nevens F.The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin.Histopathology2006;49:138-51

[19] Lee JI,Kim JM,Chung HJ.Prognosis of hepatocellular carcinoma expressing cytokeratin 19: comparison with other liver cancers.World J Gastroenterol2012;18:4751-7

[20] Govaere O,Berkers J.Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.Gut2014;63:674-85

[21] Llovet JM,Lachenmayer A.Advances in targeted therapies for hepatocellular carcinoma in the genomic era.Nat Rev Clin Oncol2015;12:408-24

[22] Qin LX.Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature.J Cancer Res Clin Oncol2004;130:497-513

[23] Yamashita T,Wang W.EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma.Cancer Res2008;68:1451-61

[24] Yamashita T.Cancer stem cells in the development of liver cancer.J Clin Invest2013;123:1911-8

[25] Scheau C,Costache R.The Role of matrix metalloproteinases in the epithelial-mesenchymal transition of hepatocellular carcinoma.Anal Cell Pathol2019;2019:9423907

[26] Zhu Y,Gan R.Wnt signaling in hepatocellular carcinoma: biological mechanisms and therapeutic opportunities.Cells2024;13:1990

[27] Zhu Z,Yan M.Cancer stem/progenitor cells are highly enriched in CD133⁺CD44⁺ population in hepatocellular carcinoma.Int J Cancer2010;126:2067-78

[28] Kim H.Hepatocellular carcinomas expressing ‘stemness’-related markers: clinicopathological characteristics.Dig Dis2014;32:778-85

[29] Idowu SA,Oluwole KA.Cytokeratin 19 (CK19) expression by thyroid neoplasms in a Nigerian tertiary health centre.Pan Afr Med J2023;44:176

[30] Verma V.Cytokeratin 19 expression in intrathoracic neoplasms: first study utilizing cellblocks, evaluating the role of a rarely used cytokeratin for lung cancers.Diagn Cytopathol2022;50:105-11

[31] Jia JJ,Feng MB.Diagnosis and treatment of biliary mucinous cystic neoplasms: a single-center experience.Hepatobiliary Pancreat Dis Int2024;23:495-501

[32] Llovet JM,Mazzaferro V.SHARP Investigators Study GroupSorafenib in advanced hepatocellular carcinoma.N Engl J Med2008;359:378-90

[33] Kudo M,Qin S.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet2018;391:1163-73

[34] Sacco R,Tortora R.AI.G.O. (Italian Association of Hospital Gastroenterologists). Role of etiology in hepatocellular carcinoma patients treated with lenvatinib: a counterfactual event-based mediation analysis.Cancers2023;15:381

[35] Qin S,Gu S.Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase II-III trial.J Clin Oncol2021;39:3002-11

[36] Finn RS,Ikeda M.IMbrave150 InvestigatorsAtezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med2020;382:1894-905

[37] Lee YT,Zhu Y,Tseng HR.Diagnostic criteria and LI-RADS for hepatocellular carcinoma.Clin Liver Dis2021;17:409-13

[38] Shuyao W,Feifei M.CK19 Predicts recurrence and prognosis of HBV positive HCC.J Gastrointest Surg2022;26:341-51

[39] Uenishi T,Yamamoto T.Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence.Cancer Sci2003;94:851-7

[40] Wang ZS,Yi X.CK19 can be used to predict the early recurrence and prognosis of HBV-related hepatocellular carcinoma patients with low AFP serum concentration after R0 radical hepatectomy.Chin J Oncol2012;34:753-8

[41] Badvie S.Hepatocellular carcinoma.Postgrad Med J2000;76:4-11

[42] Chi X,Yuan Y.A comparison of clinical pathologic characteristics between alpha-fetoprotein negative and positive hepatocellular carcinoma patients from Eastern and Southern China.BMC Gastroenterol2022;22:202

[43] Bruix J.American Association for the Study of Liver DiseasesManagement of hepatocellular carcinoma: an update.Hepatology2011;53:1020-2

[44] Forner A,Bruix J.Hepatocellular carcinoma.Lancet2018;391:1301-14

[45] Ariizumi S,Katagiri S,Yamamoto M.Combined hepatocellular-cholangiocarcinoma had poor outcomes after hepatectomy regardless of Allen and Lisa class or the predominance of intrahepatic cholangiocarcinoma cells within the tumor.Ann Surg Oncol2012;19:1628-36

[46] Connell LC,Shia J.Combined intrahepatic cholangiocarcinoma and hepatocellular carcinoma.Chin Clin Oncol2016;5:66

[47] Gong SC,Lee SW,Kim MY.The meaning of gross tumor type in the aspects of cytokeratin 19 expression and resection margin in patients with hepatocellular carcinoma.J Gastroenterol Hepatol2016;31:206-12

[48] Morgan TR,Jamal MM.Alcohol and hepatocellular carcinoma.Gastroenterology2004;127:S87-96

[49] El-Serag HB.Hepatocellular carcinoma.N Engl J Med2011;365:1118-27

[50] Chuang SC,Hashibe M,Zheng T.Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis.Cancer Epidemiol Biomarkers Prev2010;19:1261-8

[51] Huang A,Chung WY,Zhou J.Targeted therapy for hepatocellular carcinoma.Signal Transduct Target Ther2020;5:146

[52] Zhuo J,Lin Z.The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib.Cell Death Dis2021;12:1084

[53] Wu MS,Chen K.Association of CK19 expression with the efficacy of adjuvant transarterial chemoembolization after hepatic resection in hepatocellular carcinoma patients at high risk of recurrence.J Clin Transl Res2022;8:71-9

[54] Ercolani G,Ravaioli M.The role of lymphadenectomy for liver tumors: further considerations on the appropriateness of treatment strategy.Ann Surg2004;239:202-9

[55] Sun HC,Qin LX.Incidence and prognostic values of lymph node metastasis in operable hepatocellular carcinoma and evaluation of routine complete lymphadenectomy.J Surg Oncol2007;96:37-45

[56] Uenishi T,Shuto T.The clinical significance of lymph node metastases in patients undergoing surgery for hepatocellular carcinoma.Surg Today2000;30:892-5

[57] Zhuang PY,Zhu XD.Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor.Cancer2008;112:2740-8

[58] Xiang YJ,Yu HM.Transarterial chemoembolization plus a PD-1 inhibitor with or without lenvatinib for intermediate-stage hepatocellular carcinoma.Hepatol Res2022;52:721-9

[59] Juengpanich S,Lu C.Role of cellular, molecular and tumor microenvironment in hepatocellular carcinoma: Possible targets and future directions in the regorafenib era.Int J Cancer2020;147:1778-92

[60] Granito A,Marinelli S.Experience with regorafenib in the treatment of hepatocellular carcinoma.Therap Adv Gastroenterol2021;14:17562848211016959

[61] Liang L,Gao RZ.Development and validation of a combined radiomic and clinical model based on contrast-enhanced ultrasound for preoperative prediction of CK19-positive hepatocellular carcinoma.Abdom Radiol2025;

[62] Huang K,Liang T.Analysis of clinicopathologic and imaging features of dual-phenotype hepatocellular carcinoma.Sci Rep2024;14:3314

[63] Hu X,Huang G.Gadoxetic Acid-Enhanced MRI-Based Radiomics Signature: A Potential Imaging Biomarker for Identifying Cytokeratin 19-Positive Hepatocellular Carcinoma.Comput Math Methods Med2023;2023:5424204

[64] Lv J,Yu H.The added value of ¹⁸F-FDG PET/MRI multimodal imaging in hepatocellular carcinoma for identifying cytokeratin 19 status.Abdom Radiol2023;48:2331-9.

[65] Gu Y,Gao S.A preoperative nomogram with MR elastography in identifying cytokeratin 19 status of hepatocellular carcinoma.Br J Radiol2025;98:210-9

[66] Chen Y,Zhang Y.Preoperative Prediction of Cytokeratin 19 Expression for Hepatocellular Carcinoma with Deep Learning Radiomics Based on Gadoxetic Acid-Enhanced Magnetic Resonance Imaging.J Hepatocell Carcinoma2021;8:795-808