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Poor outcome of hepatocellular carcinoma with stemness marker under hypoxia: resistance to transarterial chemoembolization

 Hyungjin Rhee  ;  Ji Hae Nahm  ;  Haeryoung Kim  ;  Gi Hong Choi  ;  Jeong Eun Yoo  ;  Hye Sun Lee  ;  Myoung Ju Koh  ;  Young Nyun Park 
 MODERN PATHOLOGY, Vol.29(9) : 1038-1049, 2016 
Journal Title
Issue Date
Antigens, Neoplasm/metabolism ; Biomarkers, Tumor/metabolism* ; Biopsy ; Carbonic Anhydrase IX/metabolism ; Carcinoma, Hepatocellular/drug therapy* ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/mortality ; Carcinoma, Hepatocellular/pathology ; Chemoembolization, Therapeutic* ; Chemotherapy, Adjuvant ; Drug Resistance, Neoplasm ; Epithelial Cell Adhesion Molecule/metabolism ; Female ; Hepatectomy ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Keratin-19/metabolism ; Liver Neoplasms/drug therapy* ; Liver Neoplasms/metabolism ; Liver Neoplasms/mortality ; Liver Neoplasms/pathology ; Male ; Middle Aged ; Necrosis ; Neoadjuvant Therapy* ; Neoplasm Staging ; Neoplastic Stem Cells/drug effects* ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Predictive Value of Tests ; Proportional Hazards Models ; Time Factors ; Treatment Outcome ; Tumor Hypoxia* ; Tumor Microenvironment*
Hypoxia is known to be important in the generation and maintenance of stemness; however, its clinical significance is yet to be determined in human hepatocellular carcinoma. The expression of stemness (K19, EpCAM) and hypoxia (carbonic anhydrase-IX (CAIX))-related markers were investigated by immunohistochemistry in three hepatocellular carcinoma cohorts. The clinicopathologic features, response to transarterial chemoembolization, and outcomes were compared. In cohort 1 (n=14, biopsy-transarterial chemoembolization-resection-matched hepatocellular carcinoma), all K19-, EpCAM-, or CAIX-positive hepatocellular carcinomas on initial biopsy (6/6, 100%) showed residual tumors after transarterial chemoembolization, whereas 75% (6/8) of all-negative hepatocellular carcinomas on biopsy showed complete necrosis in the post-transarterial chemoembolization-resected specimens. In cohort 2 (n=85, explanted hepatocellular carcinomas with/without transarterial chemoembolization; totally necrotic hepatocellular carcinoma after transarterial chemoembolization was not included), the expression of K19, EpCAM, and CAIX, and their coexpression, was more frequently observed with a greater number of transarterial chemoembolization sessions, and the expression of these markers was also correlated to each other. CAIX expression was shown to be an independent factor for recurrence and survival, and combination of CAIX with Milan criteria significantly increased the time-dependent integrative area under the curve values for recurrence and survival. In cohort 3 (n=339, resected hepatocellular carcinomas without transarterial chemoembolization), CAIX(+) hepatocellular carcinomas exhibited higher K19 and EpCAM expression, and more invasive pathological features. CAIX expression and TNM stage were independent predictors of extrahepatic recurrence, and the addition of CAIX to the TNM stage significantly increased time-dependent integrative area under the curve values. In conclusion, the expression of stemness (K19, EpCAM) and hypoxia (CAIX)-related markers were correlated each other, and hepatocellular carcinoma expressing these markers showed resistance to transarterial chemoembolization and poorer outcome. Evaluation for both markers of stemness and hypoxia may have an additional value in predicting hepatocellular carcinoma outcome, especially for transarterial chemoembolization-treated hepatocellular carcinomas.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Koh, Myoung Ju(고명주)
Nahm, Ji Hae(남지해) ORCID logo https://orcid.org/0000-0003-0902-866X
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Yoo, Jeong Eun(유정은)
Rhee, Hyungjin(이형진) ORCID logo https://orcid.org/0000-0001-7759-4458
Choi, Gi Hong(최기홍) ORCID logo https://orcid.org/0000-0002-1593-3773
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