Skip to main content

Advertisement

SpringerLink
Log in

The value of lymphadenectomy in surgical resection of perihilar cholangiocarcinoma: a systematic review and meta-analysis

  • Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Surgical resection is the only potentially curative treatment for patients with resectable perihilar cholangiocarcinoma (PHC). There is still no consensus on the value of lymphadenectomy despite evidence indicating lymph node (LN) status is an important prognostic indicator for postoperative long-term survival. We sought to perform a meta-analysis to summarize the current evidence on the value of lymphadenectomy among patients undergoing surgery for PHC. The PubMed (OvidSP), Embase and Cochrane Library were systematically searched for studies published before July 2020 that reported on lymphadenectomy at the time of surgery for PHC after curative surgery. 7748 patients from 28 studies were included in the meta-analysis. No survival benefit was identified with increased number of LN resected (all P > 0.05). Meanwhile, overall LN status was an important prognostic factor. Patients with lymph node metastasis had a pooled estimate hazard ratio of death that was over two-fold higher than patients without lymph node metastasis (HR 2.07, 95% CI 1.65–2.59, P < 0.001). The examination of 5 LNs on histology was associated with better staging of lymph node status and stratification of patients into positive or negative LN groups. While the extent of LN dissection was not associated with a survival benefit, examination of more than 5 LNs better staged patients into positive or negative LN groups with a lower risk of nodal understaging.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

PHC:

Perihilar cholangiocarcinoma

LN:

Lymph node

LN (+):

Positive lymph node

LN (-):

Negative lymph node

R0:

Negative resection margin

R1/2:

Positive resection margin

NCCN:

National Comprehensive Cancer Network

AJCC:

American Joint Committee on Cancer

HRs:

Hazard ratios

OS:

Overall survival

PD:

Pancreaticoduodenectomy

dBDCA:

Distal bile duct cancer

mBDCA:

Middle bile duct cancer

exHBDCA:

Extrahepatic bile duct cancer

References

  1. Razumilava N, Gores GJ (2014) Cholangiocarcinoma. Lancet 383(9935):2168–2179

    Article  PubMed  PubMed Central  Google Scholar 

  2. DeOliveira ML, Cunningham SC, Cameron JL et al (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245(5):755–762

    Article  PubMed  PubMed Central  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A (2015): Cancer statistics. CA: a cancer journal for clinicians, 65(1):5–29.

  4. Dodson RM, Weiss MJ, Cosgrove D et al (2013) Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 217(4):736-750.e4

    Article  PubMed  Google Scholar 

  5. Brito AF, Abrantes AM, Encarnacao JC et al (2015) Cholangiocarcinoma: from molecular biology to treatment. Med Oncol 32(11):245

    Article  PubMed  CAS  Google Scholar 

  6. Pichlmayr R, Lamesch P, Weimann A et al (1995) Surgical treatment of cholangiocellular carcinoma. World J Surg 19(1):83–88

    Article  CAS  PubMed  Google Scholar 

  7. Matsuo K, Rocha FG, Ito K et al (2012) The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg 215(3):343–355

    Article  PubMed  Google Scholar 

  8. Groot Koerkamp B, Wiggers JK, Allen PJ et al (2014) American Joint Committee on Cancer staging for resected perihilar cholangiocarcinoma: a comparison of the 6th and 7th editions. HPB (Oxford) 16(12):1074–1082

    Article  Google Scholar 

  9. Murakami Y, Uemura K, Sudo T et al (2011) Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol 18(3):651–658

    Article  PubMed  Google Scholar 

  10. Sano T, Shimada K, Sakamoto Y et al (2008) Prognosis of perihilar cholangiocarcinoma: hilar bile duct cancer versus intrahepatic cholangiocarcinoma involving the hepatic hilus. Ann Surg Oncol 15(2):590–599

    Article  PubMed  Google Scholar 

  11. Kitagawa Y, Nagino M, Kamiya J et al (2001) Lymph node metastasis from hilar cholangiocarcinoma: audit of 110 patients who underwent regional and paraaortic node dissection. Ann Surg 233(3):385–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kosuge T, Yamamoto J, Shimada K et al (1999) Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 230(5):663–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Blom D, Schwartz SI (2001) Surgical treatment and outcomes in carcinoma of the extrahepatic bile ducts: the University of Rochester experience. Arch Surg 136(2):209–215

    Article  CAS  PubMed  Google Scholar 

  14. Cheng Q, Luo X, Zhang B et al (2007) Distal bile duct carcinoma: prognostic factors after curative surgery. A series of 112 cases. Ann Surg Oncol 14(3):1212–1219

    Article  PubMed  Google Scholar 

  15. Sasaki R, Takahashi M, Funato O et al (2001) Prognostic significance of lymph node involvement in middle and distal bile duct cancer. Surgery 129(6):677–683

    Article  CAS  PubMed  Google Scholar 

  16. Kondo S, Hirano S, Ambo Y et al (2004) Forty consecutive resections of hilar cholangiocarcinoma with no postoperative mortality and no positive ductal margins: results of a prospective study. Ann Surg 240(1):95–101

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dinant S, Gerhards MF, Rauws EA et al (2006) Improved outcome of resection of hilar cholangiocarcinoma (Klatskin tumor). Ann Surg Oncol 13(6):872–880

    Article  PubMed  Google Scholar 

  18. Jutric Z, Johnston WC, Hoen HM et al (2016) Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database. HPB (Oxford) 18(1):79–87

    Article  Google Scholar 

  19. Vitale A, Moustafa M, Spolverato G et al (2016) Defining the possible therapeutic benefit of lymphadenectomy among patients undergoing hepatic resection for intrahepatic cholangiocarcinoma. J Surg Oncol 113(6):685–691

    Article  PubMed  Google Scholar 

  20. Panic N, Leoncini E, de Belvis G et al (2013) Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement on the quality of published systematic review and meta-analyses. PLoS ONE 8(12):e83138

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Tierney JF, Stewart LA, Ghersi D et al (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16

    Article  PubMed  PubMed Central  Google Scholar 

  22. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17(24):2815–2834

    Article  CAS  PubMed  Google Scholar 

  23. Ofek Shlomai N, Rao S, Patole S (2015) Efficacy of interventions to improve hand hygiene compliance in neonatal units: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis: Off Publ Eur Soc Clin Microbiol 34(5):887–897

    Article  CAS  Google Scholar 

  24. Guyatt GH, Oxman AD, Vist GE et al (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336(7650):924–926

    Article  PubMed  PubMed Central  Google Scholar 

  25. Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  PubMed Central  Google Scholar 

  26. Schwarz RE, Smith DD (2007) Lymph node dissection impact on staging and survival of extrahepatic cholangiocarcinomas, based on US population data. J Gastrointest Surg: Off J Soc Surg Aliment Tract 11(2):158–165

    Article  Google Scholar 

  27. Buettner S, van Vugt JLA, Gaspersz MP et al (2017) Survival after resection of perihilar cholangiocarcinoma in patients with lymph node metastases. HPB (Oxford) 19(8):735–740

    Article  PubMed Central  Google Scholar 

  28. Bagante F, Tran T, Spolverato G et al (2016) Perihilar cholangiocarcinoma: number of nodes examined and optimal lymph node prognostic scheme. J Am Coll Surg 222(5):750-759.e2

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rocha FG, Matsuo K, Blumgart LH et al (2010) Hilar cholangiocarcinoma: the Memorial Sloan-Kettering Cancer Center experience. J Hepatobiliary Pancreat Sci 17(4):490–496

    Article  PubMed  Google Scholar 

  30. Ebata T, Mizuno T, Yokoyama Y et al (2018) Surgical resection for Bismuth type IV perihilar cholangiocarcinoma. Br J Surg 105(7):829–838

    Article  CAS  PubMed  Google Scholar 

  31. Mao K, Liu J, Sun J et al (2016) Patterns and prognostic value of lymph node dissection for resected perihilar cholangiocarcinoma. J Gastroenterol Hepatol 31(2):417–426

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mizuno T, Ebata T, Yokoyama Y et al (2017) Adjuvant gemcitabine monotherapy for resectable perihilar cholangiocarcinoma with lymph node involvement: a propensity score matching analysis. Surg Today 47(2):182–192

    Article  CAS  PubMed  Google Scholar 

  33. Morine Y, Shimada M, Utsunomiya T et al (2012) Clinical impact of lymph node dissection in surgery for peripheral-type intrahepatic cholangiocarcinoma. Surg Today 42(2):147–151

    Article  PubMed  Google Scholar 

  34. Ito K, Ito H, Allen PJ et al (2010) Adequate lymph node assessment for extrahepatic bile duct adenocarcinoma. Ann Surg 251(4):675–681

    Article  PubMed  Google Scholar 

  35. Guglielmi A, Ruzzenente A, Campagnaro T et al (2013) Patterns and prognostic significance of lymph node dissection for surgical treatment of perihilar and intrahepatic cholangiocarcinoma. J Gastrointest Surg: Off J Soc Surg Aliment Tract 17(11):1917–1928

    Article  Google Scholar 

  36. Hakeem AR, Marangoni G, Chapman SJ et al (2014) Does the extent of lymphadenectomy, number of lymph nodes, positive lymph node ratio and neutrophil-lymphocyte ratio impact surgical outcome of perihilar cholangiocarcinoma? Eur J Gastroenterol Hepatol 26(9):1047–1054

    Article  CAS  PubMed  Google Scholar 

  37. Giuliante F, Ardito F, Guglielmi A et al (2016) Association of lymph node status with survival in patients after liver resection for hilar cholangiocarcinoma in an Italian multicenter analysis. JAMA Surg 151(10):916–922

    Article  PubMed  Google Scholar 

  38. Guglielmi A, Ruzzenente A, Campagnaro T et al (2011) Prognostic significance of lymph node ratio after resection of peri-hilar cholangiocarcinoma. HPB (Oxford) 13(4):240–245

    Article  Google Scholar 

  39. Murakami Y, Uemura K, Sudo T et al (2011) Is para-aortic lymph node metastasis a contraindication for radical resection in biliary carcinoma? World J Surg 35(5):1085–1093

    Article  PubMed  Google Scholar 

  40. Oshiro Y, Sasaki R, Kobayashi A et al (2011) Prognostic relevance of the lymph node ratio in surgical patients with extrahepatic cholangiocarcinoma. Eur J Surg Oncol: J Eur Soc Surg Oncol British Assoc Surg Oncol 37(1):60–64

    Article  CAS  Google Scholar 

  41. Patel SH, Kooby DA, Staley CA 3rd et al (2011) The prognostic importance of lymphovascular invasion in cholangiocarcinoma above the cystic duct: a new selection criterion for adjuvant therapy? HPB (Oxford) 13(9):605–611

    Article  Google Scholar 

  42. Ruys AT, Kate FJ, Busch OR et al (2011) Metastatic lymph nodes in hilar cholangiocarcinoma: does size matter? HPB (Oxford) 13(12):881–886

    Article  Google Scholar 

  43. de Jong MC, Marques H, Clary BM et al (2012) The impact of portal vein resection on outcomes for hilar cholangiocarcinoma: a multi-institutional analysis of 305 cases. Cancer 118(19):4737–4747

    Article  PubMed  Google Scholar 

  44. Kow AW, Wook CD, Song SC et al (2012) Role of caudate lobectomy in type III A and III B hilar cholangiocarcinoma: a 15-year experience in a tertiary institution. World J Surg 36(5):1112–1121

    Article  PubMed  Google Scholar 

  45. Noji T, Miyamoto M, Kubota KC et al (2012) Evaluation of extra capsular lymph node involvement in patients with extra-hepatic bile duct cancer. World J Surg Oncol 10:106

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ocuin LM, Bagci P, Fisher SB et al (2013) Discordance between conventional and detailed lymph node analysis in resected biliary carcinoma at or above the cystic duct: are we understaging patients? Ann Surg Oncol 20(13):4298–4304

    Article  PubMed  Google Scholar 

  47. Zhang XF, Beal EW, Chakedis J et al (2018) Defining early recurrence of hilar cholangiocarcinoma after curative-intent surgery: a multi-institutional study from the US extrahepatic biliary malignancy consortium. World J Surg 42(9):2919–2929

    Article  PubMed  Google Scholar 

  48. Conci S, Ruzzenente A, Sandri M et al (2017) What is the most accurate lymph node staging method for perihilar cholangiocarcinoma? Comparison of UICC/AJCC pN stage, number of metastatic lymph nodes, lymph node ratio, and log odds of metastatic lymph nodes. Eur J Surg Oncol: J Eur Soc Surg Oncol British Assoc Surg Oncol 43(4):743–750

    Article  CAS  Google Scholar 

  49. Hu HJ, Mao H, Shrestha A et al (2016) Prognostic factors and long-term outcomes of hilar cholangiocarcinoma: a single-institution experience in China. World J Gastroenterol 22(8):2601–2610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kelly KJ, Dukleska K, Kuk D et al (2014) Prognostic significance of the highest peripancreatic lymph node in biliary tract adenocarcinoma. Ann Surg Oncol 21(3):979–985

    Article  PubMed  Google Scholar 

  51. Aoba T, Ebata T, Yokoyama Y et al (2013) Assessment of nodal status for perihilar cholangiocarcinoma: location, number, or ratio of involved nodes. Ann Surg 257(4):718–725

    Article  PubMed  Google Scholar 

  52. Bogoevski D, Onken F, Koenig A et al (2008) Is it time for a new TNM classification in esophageal carcinoma? Ann Surg 247(4):633–641

    Article  PubMed  Google Scholar 

  53. Mitchell PJ, Ravi S, Grifftiths B et al (2009) Multicentre review of lymph node harvest in colorectal cancer: are we understaging colorectal cancer patients? Int J Colorectal Dis 24(8):915–921

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (No. 81472284 and 81672699).

Author information

Authors and Affiliations

  1. Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, No. 158, Shangtang Road, Hangzhou, 310014, Zhejiang, China

    Lei Liang, Cheng-Wu Zhang & Tian Yang

  2. Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China

    Lei Liang, Cheng-Wu Zhang, Dong-Sheng Huang & Tian Yang

  3. Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China

    Chao Li, Ming-Da Wang, Hao Xing, Yong-Kang Diao, Hang-Dong Jia, Wan Yee Lau, Feng Shen & Tian Yang

  4. Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, ShatinHong Kong SAR, N.T, China

    Wan Yee Lau

  5. Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Timothy M. Pawlik

  6. School of Clinical Medicine, Hangzhou Medical College No, 481, Binwen Road, Hangzhou, 310014, Zhejiang, China

    Dong-Sheng Huang

Authors
  1. Lei Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming-Da Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong-Kang Diao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hang-Dong Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wan Yee Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Timothy M. Pawlik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cheng-Wu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Feng Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dong-Sheng Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LL, CL and MW: contributed equally to this study. LL, CL, MW, FS and TY: conceived and designed the study. LL and CL: searched the literature and extracted the data. LL, MW and HX: wrote the manuscript. YD, HJ, FS and TY: proofread the manuscript. TMP and WYL: made critical revision of the manuscript. TY: obtained funding.

Corresponding authors

Correspondence to Dong-Sheng Huang or Tian Yang.

Ethics declarations

Conflicts of interest

The authors declare no competing financial interests.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 51 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, L., Li, C., Wang, MD. et al. The value of lymphadenectomy in surgical resection of perihilar cholangiocarcinoma: a systematic review and meta-analysis. Int J Clin Oncol 26, 1575–1586 (2021). https://doi.org/10.1007/s10147-021-01967-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-021-01967-z

Keywords

Search

Navigation