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Extranodal extension of lymph node metastasis is a marker of poor prognosis in oesophageal cancer: a systematic review with meta-analysis
  1. Claudio Luchini1,2,3,
  2. Laura D Wood4,
  3. Liang Cheng5,
  4. Alessia Nottegar1,
  5. Brendon Stubbs6,
  6. Marco Solmi7,
  7. Paola Capelli1,
  8. Antonio Pea8,
  9. Giuseppe Sergi9,
  10. Enzo Manzato9,
  11. Matteo Fassan9,
  12. Fabio Bagante8,
  13. Elfriede Bollschweiler10,
  14. Simone Giacopuzzi11,
  15. Takuma Kaneko12,
  16. Giovanni de Manzoni11,
  17. Mattia Barbareschi3,
  18. Aldo Scarpa1,2,
  19. Nicola Veronese9
  1. 1Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
  2. 2ARC-NET Research Center, University and Hospital Trust of Verona, Verona, Italy
  3. 3Department of Pathology, Santa Chiara Hospital, Trento, Italy
  4. 4Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, USA
  5. 5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
  6. 6Health Service and Population Research Department, King's College London, London, UK
  7. 7Department of Neuroscience, University of Padua, Padua, Italy
  8. 8Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
  9. 9Department of Medicine, DIMED, University of Padua, Padua, Italy
  10. 10Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
  11. 11Upper G.I. Surgery Division, University and Hospital Trust of Verona, Verona, Italy
  12. 12Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan
  1. Correspondence to Dr Claudio Luchini, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy; claudio.luchini{at}, claudio.luchini{at}


The extranodal extension (ENE) of nodal metastasis is the extension of neoplastic cells through the nodal capsule into the perinodal adipose tissue. This histological feature has recently been indicated as an important prognostic factor in different types of malignancies; in this manuscript, we aim at defining its role in the prognosis of oesophageal cancer with the tool of meta-analysis. Two independent authors searched SCOPUS and PubMed until 31 August 2015 without language restrictions. The studies with available data about prognostic parameters in subjects with oesophageal cancer, comparing patients with the presence of ENE (ENE+) versus only intranodal extension (ENE−), were considered as eligible. Data were summarised using risk ratios (RRs) for number of deaths/recurrences and HRs together with 95% CIs for time-dependent risk related to ENE+, adjusted for potential confounders. Fourteen studies were selected; they followed-up 1437 patients with oesophageal cancer for a median follow-up of 39.4 months. The presence of ENE was associated with a significantly increased risk of all-cause mortality (RR=1.33; 95% CI 1.18 to 1.50, p<0.0001, I2=49%; HR=2.72, 95% CI 2.03 to 3.64, p<0.0001, I2=0%), cancer-specific mortality (RR=1.35; 95% CI 1.14 to 1.59, p=0.001, I2=57%; HR=1.97, 95% CI 1.41 to 2.75, p<0.0001, I2=41%) and of risk of recurrence (RR=1.50, 95% CI 1.20 to 1.88, p<0.0001, I2=9%; HR=2.27, 95% CI 1.72 to 2.90, p<0.0001, I2=0%). On the basis of these results, in oesophageal cancer, ENE should be considered from the gross sampling to the pathology report, and in future oncological staging system.


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  • Handling editor Cheok Soon Lee

  • Contributors CL: study concepts; CL, LDW, LC, NV, AN and AS: study design; CL and NV: meta-analysis, meta-regression analysis; LDW, LC, PC and AS: important intellectual content; CL, NV, AN, BS, LDW, LC and AS: drafting the manuscript; all coauthors: data extraction, elaboration, interpretation, manuscript revision, final manuscript editing and final approval of the submission in its present form.

  • Funding MB was supported by Trentino Biomolecular Oncologic Network—TreBiONet: ‘Fondazione Cassa di Risparmio di Trento e Rovereto’. AS is supported by Ministry of University (FIRB RBAP10AHJB) and AIRC (grant n. 12182).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.