Prediction of Recurrence Patterns from Hepatic Parenchymal Disease After Resection of Colorectal Liver Metastases



Obesity and metabolic syndrome are associated with inflammatory hepatic parenchymal disease (HPD) and increased risk for recurrence after resection of colorectal liver metastases (CRLM). The independent impact of HPD on recurrence patterns has not been well defined.


The nonalcoholic fatty liver disease activity score (NAS) was used to quantify HPD including steatosis and fibrosis for all patients with completely resected CRLM between April 2003 and March 2007. Clinicopathologic factors, perioperative history, and outcomes were compared with the NAS. Fisher’s exact test was used to examine the association between severe HPD (NAS ≥ 3) with clinical and perioperative characteristics. Kaplan–Meier methods were used to estimate recurrence-free survival (RFS). The cumulative incidences of recurrence [any intrahepatic recurrence (IHR), extrahepatic recurrence only (EHR), and death without recurrence (DWR)] were estimated using competing risks methods.


Among the 357 patients included in this study, microsteatosis was noted in 124 (35%) patients, severe HPD in 31 (9%), steatohepatitis in 14 (4%), and sinusoidal injury in 36 (10%). After median follow-up of 127 months (range 4–175 months), 10-year RFS was 22% [95% confidence interval (CI) 17–27%]. Ten-year cumulative incidence for IHR, EHR, and DWR was 37%, 30%, and 12%, respectively. After controlling for confounders, NAS ≥ 3 was independently associated with higher risk of IHR [hazard ratio (HR) 1.76, 95% CI 1.07–2.90, p = 0.027] and lower risk of EHR (HR 0.18, 95% CI 0.04–0.75, p = 0.019) on multivariable analysis.


Severe HPD was associated with increased IHR risk and decreased EHR risk. Future investigation into whether improving HPD from reversible etiologies can reduce the risk for IHR is warranted.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250(3):440–448.

    PubMed  Google Scholar 

  3. 3.

    Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–318; discussion 318-321.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer. 1996;77(7):1254–1262.

    CAS  PubMed  Google Scholar 

  5. 5.

    Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg. 1999;189(3):291–299.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Margonis GA, Buettner S, Andreatos N, et al. Association of BRAF mutations with survival and recurrence in surgically treated patients with metastatic colorectal liver cancer. JAMA Surg. 2018;153(7):e180996.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Margonis GA, Sasaki K, Gholami S, et al. Genetic and morphological evaluation (GAME) score for patients with colorectal liver metastases. Br J Surg. 2018;105(9):1210–1220.

    CAS  PubMed  Google Scholar 

  8. 8.

    Margonis GA, Spolverato G, Kim Y, Karagkounis G, Choti MA, Pawlik TM. Effect of KRAS mutation on long-term outcomes of patients undergoing hepatic resection for colorectal liver metastases. Ann Surg Oncol. 2015;22(13):4158–4165.

    PubMed  Google Scholar 

  9. 9.

    Stadlmayr A, Aigner E, Steger B, et al. Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia. J Intern Med. 2011;270(1):41–49.

    CAS  PubMed  Google Scholar 

  10. 10.

    Wong VW, Wong GL, Tsang SW, et al. High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut. 2011;60(6):829–836.

    PubMed  Google Scholar 

  11. 11.

    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221–1231.

    CAS  PubMed  Google Scholar 

  12. 12.

    Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;377(21):2063–2072.

    CAS  PubMed  Google Scholar 

  13. 13.

    Parikh ND, Marrero WJ, Wang J, et al. Projected increase in obesity and non-alcoholic-steatohepatitis-related liver transplantation waitlist additions in the United States. Hepatology. 2019;70(2):487–495.

    PubMed  Google Scholar 

  14. 14.

    Murono K, Kitayama J, Tsuno NH, et al. Hepatic steatosis is associated with lower incidence of liver metastasis from colorectal cancer. Int J Colorectal Dis. 2013;28(8):1065–1072.

    PubMed  Google Scholar 

  15. 15.

    Hamady ZZ, Rees M, Welsh FK, et al. Fatty liver disease as a predictor of local recurrence following resection of colorectal liver metastases. Br J Surg. 2013;100(6):820–826.

    CAS  PubMed  Google Scholar 

  16. 16.

    Molla NW, Hassanain MM, Fadel Z, et al. Effect of non-alcoholic liver disease on recurrence rate and liver regeneration after liver resection for colorectal liver metastases. Curr Oncol. 2017;24(3):e233–e243.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wolf PS, Park JO, Bao F, et al. Preoperative chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience. J Am Coll Surg. 2013;216(1):41–49.

    PubMed  Google Scholar 

  18. 18.

    Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321.

    PubMed  Google Scholar 

  19. 19.

    Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15(3):460–466.

    CAS  PubMed  Google Scholar 

  20. 20.

    Rubbia-Brandt L, Lauwers GY, Wang H, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology. 2010;56(4):430–439.

    PubMed  Google Scholar 

  21. 21.

    Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496–509.

    Google Scholar 

  22. 22.

    Cholankeril G, Wong RJ, Hu M, et al. Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes. Dig Dis Sci. 2017;62(10):2915–2922.

    PubMed  Google Scholar 

  23. 23.

    Rashid A, Pizer ES, Moga M, et al. Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am J Pathol. 1997;150(1):201–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Zaytseva YY, Harris JW, Mitov MI, et al. Increased expression of fatty acid synthase provides a survival advantage to colorectal cancer cells via upregulation of cellular respiration. Oncotarget. 2015;6(22):18891–18904.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Pizer ES, Chrest FJ, DiGiuseppe JA, Han WF. Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res. 1998;58(20):4611–4615.

    CAS  PubMed  Google Scholar 

  26. 26.

    Murata S, Yanagisawa K, Fukunaga K, et al. Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice. Cancer Sci. 2010;101(8):1861–1865.

    CAS  PubMed  Google Scholar 

  27. 27.

    Zaytseva YY, Rychahou PG, Le AT, et al. Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer. Oncotarget. 2018;9(37):24787–24800.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Zaytseva YY, Rychahou PG, Gulhati P, et al. Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res. 2012;72(6):1504–1517.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Wen YA, Xing X, Harris JW, et al. Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis. 2017;8(2):e2593.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Zeiss J, Merrick HW, Savolaine ER, Woldenberg LS, Kim K, Schlembach PJ. Fatty liver change as a result of hepatic artery infusion chemotherapy. Am J Clin Oncol. 1990;13(2):156–160.

    CAS  PubMed  Google Scholar 

  31. 31.

    Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24(13):2065–2072.

    CAS  PubMed  Google Scholar 

  32. 32.

    Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006;24(31):4983–4990.

    CAS  PubMed  Google Scholar 

  33. 33.

    Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 2008;247(1):118–124.

    PubMed  Google Scholar 

  34. 34.

    Cleary JM, Tanabe KT, Lauwers GY, Zhu AX. Hepatic toxicities associated with the use of preoperative systemic therapy in patients with metastatic colorectal adenocarcinoma to the liver. Oncologist. 2009;14(11):1095–1105.

    PubMed  Google Scholar 

  35. 35.

    Andreou A, Kopetz S, Maru DM, et al. Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases. Ann Surg. 2012;256(4):642–650.

    PubMed  Google Scholar 

  36. 36.

    Araujo R, Gonen M, Allen P, et al. Comparison between perioperative and postoperative chemotherapy after potentially curative hepatic resection for metastatic colorectal cancer. Ann Surg Oncol. 2013;20(13):4312–4321.

    PubMed  Google Scholar 

  37. 37.

    Passot G, Chun YS, Kopetz SE, et al. Prognostic factors after resection of colorectal liver metastases following preoperative second-line chemotherapy: Impact of RAS mutations. Eur J Surg Oncol. 2016;42(9):1378–1384.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999;341(27):2039–2048.

    CAS  PubMed  Google Scholar 

  39. 39.

    Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med. 2005;352(7):734–735.

    CAS  PubMed  Google Scholar 

  40. 40.

    Bolton JS, O’Connell MJ, Mahoney MR, et al. Hepatic arterial infusion and systemic chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic to the liver: a North Central Cancer Treatment Group (NCCTG) phase II study, 92-46-52. Clin Colorectal Cancer. 2012;11(1):31–37.

    CAS  PubMed  Google Scholar 

  41. 41.

    Barth RJ, Jr., Mills JB, Suriawinata AA, et al. Short-term preoperative diet decreases bleeding after partial hepatectomy: results from a multi-institutional randomized controlled trial. Ann Surg. 2019;269(1):48–52.

    PubMed  Google Scholar 

Download references


This work was supported in part by the NIH/NCI P30 CA008748 Cancer Center Support Grant.

Author information



Corresponding author

Correspondence to Michael I. D’Angelica MD.

Ethics declarations


The authors have no conflicts of interest to report.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 15 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Narayan, R.R., Harris, J.W., Chou, J.F. et al. Prediction of Recurrence Patterns from Hepatic Parenchymal Disease After Resection of Colorectal Liver Metastases. Ann Surg Oncol 27, 188–195 (2020).

Download citation