The impact of negative lymph nodes in the survival outcomes of pN+ patients following radical gastrectomy: the inverse lymph node ratio as a better score to study negative lymph nodes

Abstract

The impact of negative lymph nodes (LNs) on survival of pN+ patients has been recognized. The weight of negative LNs in an inverse lymph node ratio (nR) should be related to its prognostic impact. Five hundred and two consecutive gastric cancer patients, who underwent radical gastrectomy, were included. Patients were split into groups according to the number of harvested nodes and a cross-tabulation with pTNM stages was performed to test differences in the tumor burden. pN+ patients (n = 296) were split into groups of negative LNs harvested. We tested an alternative formula for computing a lymph node ratio: nR = total number of harvested nodes/total number of positive nodes. The median number of negative LNs was significantly different (p < 0.01) between dissection groups, but not the median of positive nodes (p > 0.05). No difference in pTNM percentage distribution was found between these groups (p > 0.05). When tested, the overall survival improved significantly for groups with larger numbers of negative LNs (p < 0.001). A cutoff of nR ≥ 6 was an independent prognostic factor for survival (p = 0.001), and the survival of pN+ patients with nR ≥ 6 was not different from pN0 patients. The impact of the number of negative LNs on the survival of the pN+ patients was demonstrated. The higher numbers in the numerator of the nR was due to the disproportion between harvested negative LNs and metastatic LNs. Larger ratios imply more negative lymph nodes in relation to positive lymph nodes, which was significantly associated with survival. We believe that the proposed nR is a friendlier to use format because of its intuitive interpretation.

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

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

References

  1. 1.

    Shi R, Chen Q, Ding JB, Yang Z, Pan G, Jiang D et al (2016) Increased number of negative lymph nodes is associated with improved survival outcome in node positive gastric cancer following radical gastrectomy. Oncotarget 7(23):35084–35091

    Article  Google Scholar 

  2. 2.

    Zheng W, Ji T, Lin Y, Li R (2016) The prognostic value of lymph nodes count on survival of patients with node-negative gastric cancer. Oncotarget 7(28):43680–43688

    Article  Google Scholar 

  3. 3.

    Ji X, Bu Z-D, Li Z-Y, Wu A-W, Zhang L-H, Zhang J et al (2017) Prognostic significance of the total number of harvested lymph nodes for lymph node-negative gastric cancer patients. BMC Cancer 17(1):558

    Article  Google Scholar 

  4. 4.

    Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209

    Article  Google Scholar 

  5. 5.

    Martinez VD, Enfield KS, Rowbotham DA, Lam WL (2016) An atlas of gastric PIWI-Interacting RNA transcriptomes and their utility for identifying signatures of gastric cancer recurrence. Gastric Cancer 19(2):660–665

    CAS  Article  Google Scholar 

  6. 6.

    Kanda M, Kodera Y (2015) Recent advances in the molecular diagnostics of gastric cancer. World J Gastroenterol 21(34):9838–9852

    CAS  Article  Google Scholar 

  7. 7.

    Marrelli D, Polom K, Neri A, Roviello F (2018) Clinical impact of molecular classifications in gastric cancer. Updates Surg 70(2):225–232

    Article  Google Scholar 

  8. 8.

    Barros FM, Carneiro F, Machado JC, Melo SA (2018) exosomes and immune response in cancer: friends or foes? Frontiers in Immunology [Internet]. https://journal.frontiersin.org/article/10.3389/fimmu.2018.00730/fullAccessed 14 May 2019

  9. 9.

    Zhu T, Hu X, Wei P, Shan G (2018) Molecular background of the regional lymph node metastasis of gastric cancer (Review). Oncology Letters [Internet]. https://www.spandidos-publications.com/10.3892/ol.2018.7813Accessed 14 May 2019

  10. 10.

    Song Y, Wang J, Cheng Z, Gao P, Sun J, Chen X et al (2017) Quantitative global proteome and lysine succinylome analyses provide insights into metabolic regulation and lymph node metastasis in gastric cancer. Scientific Reports [Internet]. https://www.nature.com/articles/srep42053Accessed 14 May 2019

  11. 11.

    Philippron A, Bollschweiler E, Kunikata A, Plum P, Schmidt C, Favi F et al (2016) Prognostic relevance of lymph node regression after neoadjuvant chemoradiation for esophageal cancer. Semin Thorac Cardiovasc Surg 28(2):549–558

    Article  Google Scholar 

  12. 12.

    Becker K, Langer R, Reim D, Novotny A, Meyer zum Buschenfelde C, Engel J et al (2011) Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. Ann Surg 253(5):934–939

    Article  Google Scholar 

  13. 13.

    Davies AR, Myoteri D, Zylstra J, Baker CR, Wulaningsih W, Van Hemelrijck M et al (2018) Lymph node regression and survival following neoadjuvant chemotherapy in oesophageal adenocarcinoma: lymph node regression in oesophageal cancer. Br J Surg 105(12):1639–1649

    CAS  Article  Google Scholar 

  14. 14.

    Zhu Y-L, Sun Y-K, Xue X-M, Yue J-Y, Yang L, Xue L-Y (2019) Unnecessity of lymph node regression evaluation for predicting gastric adenocarcinoma outcome after neoadjuvant chemotherapy. World J Gastrointest Oncol 11(1):48–58

    Article  Google Scholar 

  15. 15.

    Marchet A, Mocellin S, Ambrosi A, de Manzoni G, Leo AD, Marrelli D et al (2008) The prognostic value of N-ratio in patients with gastric cancer: validation in a large, multicenter series. Eur J Surg Oncol 34(2):159–165

    CAS  Article  Google Scholar 

  16. 16.

    Xiao L-B, Yu J-X, Wu W-H, Xu F-F, Yang S-B (2011) Superiority of metastatic lymph node ratio to the 7th edition UICC N staging in gastric cancer. World J Gastroenterol 17(46):5123–5130

    Article  Google Scholar 

  17. 17.

    Wang J, Dang P, Raut CP, Pandalai PK, Maduekwe UN, Rattner DW et al (2012) Comparison of a lymph node ratio-based staging system with the 7th AJCC system for gastric cancer: analysis of 18,043 patients from the SEER database. Ann Surg 255(3):478–485

    Article  Google Scholar 

  18. 18.

    Wu X-J, Miao R-L, Li Z-Y, Bu Z-D, Zhang L-H, Wu A-W et al (2015) Prognostic value of metastatic lymph node ratio as an additional tool to the TNM stage system in gastric cancer. Eur J Surg Oncol 41(7):927–933

    Article  Google Scholar 

  19. 19.

    Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJH, Nicolson M et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355(1):11–20

    CAS  Article  Google Scholar 

  20. 20.

    Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN et al (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345(10):725–730

    CAS  Article  Google Scholar 

  21. 21.

    Manzoni GD, Marrelli D, Baiocchi GL, Morgagni P, Saragoni L, Degiuli M et al (2017) The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015. Gastric Cancer 20(1):20–30

    Article  Google Scholar 

  22. 22.

    Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D et al (2016) Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 27(suppl 5):v38–49

    CAS  Article  Google Scholar 

  23. 23.

    Siewert JR, Böttcher K, Stein HJ, Roder JD (1998) Relevant prognostic factors in gastric cancer: 10-year results of the German Gastric Cancer Study. Ann Surg 228(4):449–461

    CAS  Article  Google Scholar 

  24. 24.

    The RCPath, https://www.rcpath.org/uploads/assets/d424aaee-6170-4171-ba184326229af027/Dataset-for-the-histopathological-reporting-of-gastric-carcinoma.pdf. Accessed 20 Nov 2019

  25. 25.

    AJCC—Cancer Staging Manual [Internet]. https://cancerstaging.org/references-tools/deskreferences/pages/default.aspx. Accessed 15 May 2019

  26. 26.

    Chen S, Zhao B-W, Li Y-F, Feng X-Y, Sun X-W, Li W et al (2012) The prognostic value of harvested lymph nodes and the metastatic lymph node ratio for gastric cancer patients: results of a study of 1101 patients. PLoS One 7(11):e49424

    CAS  Article  Google Scholar 

  27. 27.

    Kutlu OC, Watchell M, Dissanaike S (2015) Metastatic lymph node ratio successfully predicts prognosis in western gastric cancer patients. Surg Oncol 24(2):84–88

    Article  Google Scholar 

  28. 28.

    Bouliaris K, Rachiotis G, Diamantis A, Christodoulidis G, Polychronopoulou E, Tepetes K (2017) Lymph node ratio as a prognostic factor in gastric cancer patients following D1 resection. Comparison with the current TNM staging system. Eu J Surg Oncol (EJSO) 43(7):1350–1356

    CAS  Article  Google Scholar 

  29. 29.

    Junior C, Da WL, Coimbra FJF, Batista TP, de Ribeiro HSC, Diniz AL et al (2013) Evaluation of N-ratio in selecting patients for adjuvant chemoradiotherapy after D2-gastrectomy. Arq Gastroenterol 50(4):257–263

    Article  Google Scholar 

  30. 30.

    Baiocchi GL, Tiberio GA, Minicozzi AM, Morgagni P, Marrelli D, Bruno L et al (2010) A multicentric Western analysis of prognostic factors in advanced, node-negative gastric cancer patients. Ann Surg 252(1):70–73

    Article  Google Scholar 

  31. 31.

    Xu D, Huang Y, Geng Q, Guan Y, Li Y, Wang W et al (2012) Effect of lymph node number on survival of patients with lymph node-negative gastric cancer according to the 7th edition UICC TNM system. PLoS One 7(6):e38681

    CAS  Article  Google Scholar 

  32. 32.

    Song W, Yuan Y, Wang L, He W, Zhang X, Chen C et al (2014) The prognostic value of lymph nodes dissection number on survival of patients with lymph node-negative gastric cancer [Internet]. Gastroenterol Res Pract. https://www.hindawi.com/journals/grp/2014/603194/

  33. 33.

    Chu X, Yang Z-F (2015) Impact on survival of the number of lymph nodes resected in patients with lymph node-negative gastric cancer. World J Surg Oncol [Internet]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460775/Accessed 2 Nov 2017

  34. 34.

    Feinstein AR, Sosin DM, Wells CK (1985) The will rogers phenomenon. N Engl J Med 312(25):1604–1608

    CAS  Article  Google Scholar 

  35. 35.

    European Chapter of International Gastric Cancer Association, Mariette C, Carneiro F, Grabsch HI, van der Post RS, Allum W et al (2019) Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma. Gastric Cancer 22(1):1–9

    Article  Google Scholar 

  36. 36.

    Gullo I, Carneiro F, Oliveira C, Almeida GM (2018) Heterogeneity in gastric cancer: from pure morphology to molecular classifications. Pathobiology 85(1–2):50–63

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by PC, PL and SO. Statistical analysis was planned and performed by RR. The first draft of the manuscript was written by PC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Paulo Matos da Costa.

Ethics declarations

Conflict of interest

The authors have no conflicting of financial interest or other regarding the present study.

Ethical statement

All procedures in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964. The study was approved by the Ethical Committee of the Lisbon Academic Medical Center. The Centro Hospitalar Lisboa Norte is the academic hospital of this Center and Hospital Garcia de Orta is an Affiliated Hospital to this Academic Center.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

da Costa, P.M., Lages, P., Onofre, S. et al. The impact of negative lymph nodes in the survival outcomes of pN+ patients following radical gastrectomy: the inverse lymph node ratio as a better score to study negative lymph nodes. Updates Surg 72, 1031–1040 (2020). https://doi.org/10.1007/s13304-020-00757-y

Download citation

Keywords

  • Gastrectomy for cancer
  • Lymph nodes (LNs)
  • Negative LNs and outcomes
  • Inverse lymph node ratio
  • Gastric cancer survival