Skip to main content

Advertisement

SpringerLink
Log in

Postoperative Prognosis of Non-alcoholic Fatty Liver Disease-Associated Intrahepatic Cholangiocarcinoma: a Multi-center Propensity Score Matching Analysis

  • Original Article
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background and Aims

The incidence of intrahepatic cholangiocarcinoma (ICC) in non-alcoholic fatty liver disease (NAFLD) is increasing gradually. The prognosis of NAFLD-ICC has not been well studied. We aim to investigate the prognosis of patients with NAFLD-ICC after curative-intent partial hepatectomy (PH).

Methods

Multi-center data from January 2003 to January 2014 were retrospectively analyzed. The prognosis of ICC was analyzed using PSM and compared with hepatitis B virus (HBV)–related ICC.

Results

A total of 898 patients with ICC were included in this study. Of them, 199 (22.2%) were NAFLD-ICC, and 699 (77.8%) were HBV-ICC. Multivariate analysis showed that CA19-9 ≥ 37 U/mL, microvascular invasion, tumor size > 5 cm, multiple tumors, and lymph node (LN) metastasis were independent risk factors for early recurrence (ER) in ICC patients. After a 1:1 PSM, NAFLD-ICC has worse 5-year overall survival (OS) (24.0% vs. 48.9%), 5-year recurrence (80.9% vs. 55.0%), and ER (58.5% vs. 30.0%) than that of HBV-ICC (all P < 0.01). Multivariable analysis showed NAFLD was an independent risk factor for OS (hazard ratio [HR] 2.26, 95% CI 1.63–3.13, P < 0.001), tumor recurrence (HR 2.24, 95%CI 1.61–3.10, P < 0.001) and ER (HR 2.23, 95%CI 1.60–3.09, P < 0.001) in patients with ICC after PH. The sensitivity analysis indicated that NAFLD-ICC patients were more likely to experience ER.

Conclusion

Compared with HBV-ICC, NAFLD-ICC has a worse prognosis and was more likely to relapse early. More frequent surveillance should be considered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

All data relevant to the study are included in the article or uploaded as online supplemental information.

Abbreviations

ICC:

Intrahepatic cholangiocarcinoma

HBV:

Hepatitis B virus

NAFLD:

Non-alcoholic fatty liver disease

HCV:

Hepatitis C virus

PH:

Partial hepatectomy

PSM:

Propensity score matching

ER:

Early recurrence

OS:

Overall survival

TTR:

Time to recurrence

HR:

Hazard ratio

CI:

Confidence interval

CA19-9:

Carbohydrate antigen 19–9

AFP:

Alpha fetoprotein

CEA:

Carcinoembryonic antigen

TBIL:

Total bilirubin

ALB:

Albumin

ALT:

Alanine aminotransferase

PLT:

Platelet

PT:

Prothrombin time

LN:

Lymph node

References

  1. Massarweh, N. N.; El-Serag, H. B., Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Control 2017, 24 (3), 1073274817729245.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mavros, M. N.; Economopoulos, K. P.; Alexiou, V. G.; Pawlik, T. M., Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg 2014, 149 (6), 565-74.

    Article  PubMed  Google Scholar 

  3. Sirica, A. E.; Gores, G. J.; Groopman, J. D.; Selaru, F. M.; Strazzabosco, M.; Wei Wang, X.; Zhu, A. X., Intrahepatic cholangiocarcinoma: continuing challenges and translational advances. Hepatology 2019, 69 (4), 1803-1815.

    Article  PubMed  Google Scholar 

  4. Wirth, T. C.; Vogel, A., Surveillance in cholangiocellular carcinoma. Best Pract Res Clin Gastroenterol 2016, 30 (6), 987-999.

    Article  PubMed  Google Scholar 

  5. Khan, S. A.; Thomas, H. C.; Davidson, B. R.; Taylor-Robinson, S. D., Cholangiocarcinoma. Lancet 2005, 366 (9493), 1303-14.

    Article  PubMed  Google Scholar 

  6. Corrao, S.; Natoli, G.; Argano, C., Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis. Eur J Gastroenterol Hepatol 2021, 33 (1), 62-68.

    Article  CAS  PubMed  Google Scholar 

  7. Petrick, J. L.; Yang, B.; Altekruse, S. F.; Van Dyke, A. L.; Koshiol, J.; Graubard, B. I.; McGlynn, K. A., Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare. PLoS One 2017, 12 (10), e0186643.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Shin, H. R.; Oh, J. K.; Masuyer, E.; Curado, M. P.; Bouvard, V.; Fang, Y. Y.; Wiangnon, S.; Sripa, B.; Hong, S. T., Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci 2010, 101 (3), 579-85.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, H.; Yang, T.; Wu, M.; Shen, F., Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management. Cancer Lett 2016, 379 (2), 198-205.

    Article  CAS  PubMed  Google Scholar 

  10. Rizvi, S.; Gores, G. J., Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013, 145 (6), 1215-29.

    Article  CAS  PubMed  Google Scholar 

  11. Iida, H.; Kaibori, M.; Tanaka, S.; Takemura, S.; Wada, H.; Hirokawa, F.; Nakai, T.; Hayashi, M.; Eguchi, H.; Kubo, S., Low incidence of lymph node metastasis after resection of hepatitis virus-related intrahepatic cholangiocarcinoma. World J Surg 2017, 41 (4), 1082-1088.

    Article  PubMed  Google Scholar 

  12. Wang, Q.; Li, J.; Lei, Z.; Wu, D.; Si, A.; Wang, K.; Wang, Y.; Wan, X.; Lau, W. Y.; Shen, F., Prognosis of intrahepatic cholangiocarcinomas with HBV infection is better than those with hepatolithiasis after R0 liver resection: a propensity score matching analysis. Ann Surg Oncol 2017, 24 (6), 1579-1587.

    Article  PubMed  Google Scholar 

  13. Diehl, A. M.; Day, C., Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med 2017, 377 (21), 2063-2072.

    Article  CAS  PubMed  Google Scholar 

  14. Alexander, M.; Loomis, A. K.; Fairburn-Beech, J.; van der Lei, J.; Duarte-Salles, T.; Prieto-Alhambra, D.; Ansell, D.; Pasqua, A.; Lapi, F.; Rijnbeek, P.; Mosseveld, M.; Avillach, P.; Egger, P.; Kendrick, S.; Waterworth, D. M.; Sattar, N.; Alazawi, W., Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med 2018, 16 (1), 130.

    Article  PubMed  PubMed Central  Google Scholar 

  15. De Lorenzo, S.; Tovoli, F.; Mazzotta, A.; Vasuri, F.; Edeline, J.; Malvi, D.; Boudjema, K.; Renzulli, M.; Jeddou, H.; D'Errico, A.; Turlin, B.; Cescon, M.; Uguen, T.; Granito, A.; Lièvre, A.; Brandi, G., Non-Alcoholic Steatohepatitis as a Risk Factor for Intrahepatic Cholangiocarcinoma and Its Prognostic Role. Cancers (Basel). 2020, 12 (11), 3182. https://doi.org/10.3390/cancers12113182

  16. Reddy, S. K.; Hyder, O.; Marsh, J. W.; Sotiropoulos, G. C.; Paul, A.; Alexandrescu, S.; Marques, H.; Pulitano, C.; Barroso, E.; Aldrighetti, L.; Geller, D. A.; Sempoux, C.; Herlea, V.; Popescu, I.; Anders, R.; Rubbia-Brandt, L.; Gigot, J. F.; Mentha, G.; Pawlik, T. M., Prevalence of nonalcoholic steatohepatitis among patients with resectable intrahepatic cholangiocarcinoma. J Gastrointest Surg 2013, 17 (4), 748-55.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Chalasani, N.; Younossi, Z.; Lavine, J. E.; Charlton, M.; Cusi, K.; Rinella, M.; Harrison, S. A.; Brunt, E. M.; Sanyal, A. J., The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018, 67 (1), 328-357.

    Article  PubMed  Google Scholar 

  18. Amin, M. B.; Greene, F. L.; Edge, S. B.; Compton, C. C.; Gershenwald, J. E.; Brookland, R. K.; Meyer, L.; Gress, D. M.; Byrd, D. R.; Winchester, D. P., The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017, 67 (2), 93-99.

    Article  PubMed  Google Scholar 

  19. Ohira, M.; Kobayashi, T.; Hashimoto, M.; Tazawa, H.; Abe, T.; Oshita, A.; Kohashi, T.; Irei, T.; Oishi, K.; Ohdan, H.; Hiroshima Surgical study group of Clinical, O., Prognostic factors in patients with recurrent intrahepatic cholangiocarcinoma after curative resection: a retrospective cohort study. Int J Surg 2018, 54 (Pt A), 156-162.

    Article  PubMed  Google Scholar 

  20. Zhao, L.; Ma, X.; Liang, M.; Li, D.; Ma, P.; Wang, S.; Wu, Z.; Zhao, X., Prediction for early recurrence of intrahepatic mass-forming cholangiocarcinoma: quantitative magnetic resonance imaging combined with prognostic immunohistochemical markers. Cancer Imaging 2019, 19 (1), 49.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhu, Y.; Mao, Y.; Chen, J.; Qiu, Y.; Guan, Y.; Wang, Z.; He, J., Radiomics-based model for predicting early recurrence of intrahepatic mass-forming cholangiocarcinoma after curative tumor resection. Sci Rep 2021, 11 (1), 18347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cotter, T. G.; Rinella, M., Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology 2020, 158 (7), 1851-1864.

    Article  CAS  PubMed  Google Scholar 

  23. Brown, J. C.; Harhay, M. O.; Harhay, M. N., Nonalcoholic fatty liver disease and mortality among cancer survivors. Cancer Epidemiol 2017, 48, 104-109.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cariou, B., The metabolic triad of non-alcoholic fatty liver disease, visceral adiposity and type 2 diabetes: implications for treatment. Diabetes Obes Metab 2022, 24 Suppl 2, 15-27.

    Article  CAS  PubMed  Google Scholar 

  25. Michelotti, G. A.; Machado, M. V.; Diehl, A. M., NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013, 10 (11), 656-65.

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, H. B.; Hu, J. Y.; Hu, H. P., Hepatitis B virus infection and intrahepatic cholangiocarcinoma. World J Gastroenterol 2014, 20 (19), 5721-9.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nguyen, M.H.; Wong, G.; Gane, E.; Kao, J.H.; Dusheiko, G., Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy. Clin Microbiol Rev. 2020, 33 (2), e00046-19. https://doi.org/10.1128/CMR.00046-1

  28. Ding, F. X.; Wang, F.; Lu, Y. M.; Li, K.; Wang, K. H.; He, X. W.; Sun, S. H., Multiepitope peptide-loaded virus-like particles as a vaccine against hepatitis B virus-related hepatocellular carcinoma. Hepatology 2009, 49 (5), 1492-502.

    Article  CAS  PubMed  Google Scholar 

  29. Kim, K. M.; Na, J. E.; Shim, S. G.; Sinn, D. H., Comparison of ICC patients with hepatitis B infection to those with no major risk factors for HCC. HPB (Oxford) 2021, 23 (6), 945-953.

    Article  PubMed  Google Scholar 

  30. Yu, T. H.; Chen, X.; Zhang, X. H.; Zhang, E. C.; Sun, C. X., Clinicopathological characteristics and prognostic factors for intrahepatic cholangiocarcinoma: a population-based study. Sci Rep 2021, 11 (1), 3990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yasui, K.; Hashimoto, E.; Tokushige, K.; Koike, K.; Shima, T.; Kanbara, Y.; Saibara, T.; Uto, H.; Takami, S.; Kawanaka, M.; Komorizono, Y.; Okanoue, T.; Japan, N. S. G., Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. Hepatol Res 2012, 42 (8), 767-73.

    Article  CAS  PubMed  Google Scholar 

  32. Choi, W. J.; Williams, P. J.; Claasen, M.; Ivanics, T.; Englesakis, M.; Gallinger, S.; Hansen, B.; Sapisochin, G., Systematic Review and Meta-Analysis of Prognostic Factors for Early Recurrence in Intrahepatic Cholangiocarcinoma After Curative-Intent Resection. Ann Surg Oncol 2022. https://doi.org/10.1245/s10434-022-11463-x

  33. Tsilimigras, D. I.; Sahara, K.; Moris, D.; Hyer, J. M.; Paredes, A. Z.; Bagante, F.; Merath, K.; Farooq, A. S.; Ratti, F.; Marques, H. P.; Soubrane, O.; Azoulay, D.; Lam, V.; Poultsides, G. A.; Popescu, I.; Alexandrescu, S.; Martel, G.; Guglielmi, A.; Hugh, T.; Aldrighetti, L.; Endo, I.; Pawlik, T. M., Effect of surgical margin width on patterns of recurrence among patients undergoing R0 hepatectomy for T1 hepatocellular carcinoma: an international multi-institutional analysis. J Gastrointest Surg 2020, 24 (7), 1552-1560.

    Article  PubMed  Google Scholar 

  34. Xu, X. F.; Xing, H.; Han, J.; Li, Z. L.; Lau, W. Y.; Zhou, Y. H.; Gu, W. M.; Wang, H.; Chen, T. H.; Zeng, Y. Y.; Li, C.; Wu, M. C.; Shen, F.; Yang, T., Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China. JAMA Surg 2019, 154 (3), 209-217.

    Article  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China [81871988 to C.Z.J. and 82002584 to L.Z.Q], and the Jiangsu Province Key Research and Development Program [BE2019747 to C.Z.J.].

Author information

Author notes

  1. Qiushi Yu, Zhengqing Lei, and Weihu Ma are equally contributed to the study.

Authors and Affiliations

  1. School of Medicine, Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University, Nanjing, 210009, China

    Qiushi Yu, Zhengqing Lei, Weihu Ma, Facai Yang, Haolan Tang, Qianru Xiao, Xuewu Tang & Zhangjun Cheng

  2. Department of Surgical Oncology, Qin Huai Medical District of Jinling Hospital, Nanjing Medical University, Nanjing, 210009, China

    Anfeng Si

  3. Department of Minimally Invasive Surgery, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China

    Pinghua Yang

  4. Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, 210009, China

    Nan Zhou

Authors
  1. Qiushi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhengqing Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weihu Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Facai Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haolan Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qianru Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xuewu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anfeng Si
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pinghua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhangjun Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZQL, ZJC: study design, financial support, critical revision of the manuscript for important intellectual content, and study supervision; QSY, WHM: study design, patient screening, data collection, data analysis and interpretation, and manuscript writing; FCY, HLT, QRX, XWT, AFS, PHY: patient screening, data collection; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhangjun Cheng.

Ethics declarations

Ethics Approval

This study was approved by the Ethics Committee of each hospital, and all patients signed an informed consent form before surgery.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Lay Summary

• The prevalence of NAFLD-related ICC is gradually increasing.

• Compared to HBV-ICC, NAFLD-ICC has a worse prognosis and is more likely to relapse early.

• For NAFLD-ICC patients, more frequent surveillance should be considered.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, Q., Lei, Z., Ma, W. et al. Postoperative Prognosis of Non-alcoholic Fatty Liver Disease-Associated Intrahepatic Cholangiocarcinoma: a Multi-center Propensity Score Matching Analysis. J Gastrointest Surg 27, 2403–2413 (2023). https://doi.org/10.1007/s11605-023-05794-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-023-05794-7

Keywords

Search

Navigation