Poor outcome of hepatocellular carcinoma with stemness marker under hypoxia: resistance to transarterial chemoembolization.
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.
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Hyungjin
H
Rhee
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Ji Hae
JH
Nahm
Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
Haeryoung
H
Kim
Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
Gi Hong
GH
Choi
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Jeong Eun
JE
Yoo
Biostatistics Collaboration Unit, Department of Research Affairs, Yonsei University College of Medicine, Seoul, Korea.
Hye Sun
0000-0001-6328-6948
HS
Lee
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Myoung Ju
MJ
Koh
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.|Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Young Nyun
YN
Park
D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016461:Chemoembolization, Therapeutic; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism; D005260:Female; D006498:Hepatectomy; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053539:Keratin-19 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D013997:Time Factors; D016896:Treatment Outcome; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D053539:Keratin-19; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX