Pathological predictive factors for late recurrence of hepatocellular carcinoma in chronic liver disease

Ji Hae Nahm, Hye Sun Lee, Haeryoung Kim, Sun Young Yim, Ji hyun Shin, Jeong Eun Yoo, Sang Hoon Ahn, Jin Sub Choi, Ju Seog Lee, Young Nyun Park

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Background & Aims: Late recurrence of hepatocellular carcinoma (HCC) is regarded as de novo HCC from chronic hepatitis. This study investigated clinicopathological and molecular factors to develop a nomogram for predicting late HCC recurrence (>2 years after curative resection). Methods: The training and validation cohorts included HCC patients with a major aetiology of hepatitis B who underwent curative resection. Clinicopathological features including lobular and porto-periportal inflammatory activity, fibrosis and liver cell change were evaluated. Proteins encoded by genes related to late recurrence were identified using a reverse phase protein array of 95 non-tumourous liver tissues. Immunoexpression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), plasminogen activator inhibitor-1, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and spleen tyrosine kinase (SYK) was measured. Results: Late recurrence occurred in 74/402 (18%) and 47/243 (19%) in the training and validation cohorts respectively. Cirrhosis, moderate/severe lobular inflammatory activity, and expression of pSTAT3, pERK1/2, and SYK proteins correlated to the gene signature of hepatocyte injury and regeneration were independently associated with late recurrence, with odds ratios (95% confidence intervals) of 2.0 (1.2-3.3), 21.1 (4.3-102.7) and 6.0 (2.1-17.7) respectively (P <.05 for all). A nomogram based on these variables (histological parameters and immunohistochemical marker combinations) showed high reliability in both the training and validation cohorts (Harrell’s C index: 0.701 and 0.716; 95% confidence intervals: 0.64-0.76 and 0.64-0.79 respectively). Conclusions: The combination of pSTAT3, pERK1/2 and SYK immunoexpression with high lobular inflammatory activity and cirrhosis (fibrosis) predicts late HCC recurrence.

Original languageEnglish
Pages (from-to)1662-1674
Number of pages13
JournalLiver International
Issue number7
Publication statusPublished - 2021 Jul

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF) funded by the Korean Government (MSIP) (No. NRF‐2020R1A2B5B01001646, NRF‐2016M3A9D5A01952416) to YNP and National Institutes of Health (NIH) (CA237327) to JL. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

All Science Journal Classification (ASJC) codes

  • Hepatology


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