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Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression

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Abstract

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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Acknowledgements

This study was supported by the National Research Foundation of Korea (NRF) funded by the Korean Government (MSIP) (nos. NRF-2017R1A2B4005871, NRF-2017M3A9B6061512, and NRF-2016M3A9D5A01952416).

Author information

Author notes

  1. Taek Chung

    Present address: Department of Biomedical Systems Informatics, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

  2. Hyungjin Rhee and Taek Chung contributed equally.

Authors and Affiliations

  1. Department of Radiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Hyungjin Rhee

  2. Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Taek Chung, Jeong Eun Yoo, Ji Hae Nahm, Ha Young Woo & Young Nyun Park

  3. Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Gi Hong Choi & Dai Hoon Han

  4. BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Young Nyun Park

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  1. Hyungjin Rhee
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Correspondence to Young Nyun Park.

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Conflict of interest

Hyungjin Rhee, Taek Chung, Jeong Eun Yoo, Ji Hae Nahm, Ha Young Woo, Gi Hong Choi, Dai Hoon Han, and Young Nyun Park declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional national research committee (Institutional Review Board of Severance Hospital, IRB number: 4-2019-0172) and as per the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Rhee, H., Chung, T., Yoo, J.E. et al. Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression. Hepatol Int 14, 239–248 (2020). https://doi.org/10.1007/s12072-020-10012-6

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  • DOI: https://doi.org/10.1007/s12072-020-10012-6

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