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Gross Type of Hepatocellular Carcinoma Reflects the Tumor Hypoxia, Fibrosis, and Stemness-Related Marker Expression

 Hyungjin Rhee  ;  Taek Chung  ;  Jeong Eun Yoo  ;  Ji Hae Nahm  ;  Ha Young Woo  ;  Gi Hong Choi  ;  Dai Hoon Han  ;  Young Nyun Park 
 HEPATOLOGY INTERNATIONAL, Vol.14(2) : 239-248, 2020-03 
Journal Title
Issue Date
Early recurrence ; Fibrous tumor stroma ; Gross morphology ; Hepatocellular carcinoma ; Hypoxia ; Immunohistochemistry ; Microvascular invasion ; Stemness ; Tumor microenvironment ; Tumor necrosis
Background: Hepatocellular carcinoma (HCC) is subclassified into five gross types, namely, vaguely nodular (VN), single nodular (SN), single nodular with extranodular growth (SNEG), confluent multinodular (CM), and infiltrative (INF) type. However, the pathological background underlying differences in biological behavior of different gross types of HCC remains unclear.

Methods: The histopathological features, clinical outcomes of HCC gross types, and their relationships with stemness-related marker status and fibrotic/hypoxic tumor microenvironment (TME) were evaluated in 266 resected HCCs. The stemness-related markers (CD24, CD44, CD133, SALL4, YAP1, K19 and EpCAM), fibrous tumor stroma (αSMA), and hypoxia (CAIX) were evaluated with immunohistochemistry.

Results: Poorer differentiation, reduced capsule formation, higher microvascular invasion, larger tumor size and larger area of necrosis were observed in order of VN-SN-SNEG-CM-INF type (p = 0.005 for all, linear-by-linear association). The expression of summed stemness-related markers and hypoxic/fibrotic TME showed an increasing trend in order of VN-SN-SNEG-CM-INF type (p < 0.005), and their expression well correlated with each other. INF type was found only in HCCs with hypoxic/fibrotic TME or high expression of stemness-related markers. CAIX expression and tumor necrosis ≥ 30% were independent prognostic markers for disease-specific survival. Early recurrence-free survival showed a significant difference based on gross types, revealing best outcome with VN type and worst outcome with INF type.

Conclusion: The marker expression of stemness-related and hypoxic/fibrotic TME of HCC showed an increasing trend in order of VN-SN-SNEG-CM-INF gross types, and their cross-talk may be involved in the determination of various gross-morphological features and their distinct biological behavior.
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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 Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
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
Woo, Ha Young(우하영) ORCID logo https://orcid.org/0000-0002-3078-6484
Yoo, Jeong Eun(유정은) ORCID logo https://orcid.org/0000-0001-9990-279X
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
Han, Dai Hoon(한대훈) ORCID logo https://orcid.org/0000-0003-2787-7876
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