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Distribution of lymph node metastases in esophageal adenocarcinoma after neoadjuvant chemoradiation therapy: a prospective study

Surgical Endoscopy volume 34, pages 4347–4357 (2020)Cite this article

Abstract

Background

The distribution of lymph node metastases in esophageal adenocarcinoma following neoadjuvant chemoradiation (nCRTx) is unclear, but may have consequences for radiotherapy and surgery. The aim of this study was to define the distribution of lymph node metastases and relation to the radiation field in patients following nCRTx and esophagectomy.

Methods

Between April 2014 and August 2015 esophageal adenocarcinoma patients undergoing transthoracic esophagectomy with 2-field lymphadenectomy following nCRTx were included in this prospective observational study. Lymph node stations according to AJCC 7 were separately investigated. The location of lymph node metastases in relation to the radiation field was determined. The primary endpoint was the distribution of lymph node metastases and relation to the radiation field, the secondary endpoints were high-risk stations and risk factors for lymph node metastases and relation to survival.

Results

Fifty consecutive patients were included. Lymph node metastases were found in 60% of patients and most frequently observed in paraesophageal (28%), left gastric artery (24%), and celiac trunk (18%) stations. Fifty-two percent had lymph node metastases within the radiation field. The incidence of lymph node metastases correlated significantly with ypT-stage (p = 0.002), cT-stage (p = 0.005), lymph angioinvasion (p = 0.004), and Mandard (p = 0.002). The number of lymph node metastases was associated with survival in univariable analysis (HR 1.12, 95% CI 1.068–1.173, p < 0.001).

Conclusions

Esophageal adenocarcinoma frequently metastasizes to both the mediastinal and abdominal lymph node stations. In this study, more than half of the patients had lymph node metastases within the radiation field. nCRTx is therefore not a reason to minimize lymphadenectomy in patients with esophageal adenocarcinoma.

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References

  1. (2017) DICA_Jaarrapportage_2017_-_Registraties

  2. Peyre CG, Hagen JA, DeMeester SR, Altorki NK, Ancona E, Griffin SM, Hölscher A, Lerut T, Law S, Rice TW, Ruol A, Van Lanschot JJB, Wong J, DeMeester TR (2008) The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg 248:549–554. https://doi.org/10.1097/SLA.0b013e318188c474

    Article  PubMed  Google Scholar 

  3. Mariette C, Piessen G, Briez N, Triboulet JP (2008) The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg 247:365–371. https://doi.org/10.1097/SLA.0b013e31815aaadf

    Article  PubMed  Google Scholar 

  4. Rizk N, Venkatraman E, Park B, Flores R, Bains MS, Rusch V (2006) The prognostic importance of the number of involved lymph nodes in esophageal cancer: implications for revisions of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg. https://doi.org/10.1016/j.jtcvs.2006.07.039

    Article  PubMed  Google Scholar 

  5. Koenig AM, Prenzel KL, Bogoevski D, Yekebas EF, Bubenheim M, Faithova L, Vashist YK, Gawad KA, Baldus SE, Pantel K, Schneider PM, Hölscher AH, Izbicki JR (2008) Strong impact of micrometastatic tumor cell load in patients with esophageal carcinoma. Ann Surg Oncol 16:454–462. https://doi.org/10.1245/s10434-008-0169-7

    Article  PubMed  Google Scholar 

  6. Altorki NK, Zhou XK, Stiles B, Port JL, Paul S, Lee PC, Mazumdar M (2008) Total number of resected lymph nodes predicts survival in esophageal cancer. Ann Surg 248:221–226. https://doi.org/10.1097/SLA.0b013e31817bbe59

    Article  PubMed  Google Scholar 

  7. Greenstein AJ, Litle VR, Swanson SJ, Divino CM, Packer S, Wisnivesky JP (2008) Effect of the number of lymph nodes sampled on postoperative survival of lymph node-negative esophageal cancer. Cancer 112:1239–1246. https://doi.org/10.1002/cncr.23309

    Article  PubMed  Google Scholar 

  8. Miyata H, Yamasaki M, Makino T, Miyazaki Y, Takahashi T, Kurokawa Y, Nakajima K, Takiguchi S, Mori M, Doki Y (2015) Therapeutic value of lymph node dissection for esophageal squamous cell carcinoma after neoadjuvant chemotherapy. J Surg Oncol 112:60–65. https://doi.org/10.1002/jso.23965

    Article  PubMed  Google Scholar 

  9. Chen J, Pan J, Zheng X, Zhu K, Li J, Chen M, Wang J, Liao Z (2012) Number and location of positive nodes, postoperative radiotherapy, and survival after esophagectomy with three-field lymph node dissection for thoracic esophageal squamous cell carcinoma. Int J Radiat Oncol Biol Phys 82:475–482. https://doi.org/10.1016/j.ijrobp.2010.08.037

    Article  PubMed  Google Scholar 

  10. Oppedijk V, van der Gaast A, van Lanschot JJB, van Hagen P, van Os R, van Rij CM, van der Sangen MJ, Beukema JC, Rutten H, Spruit PH, Reinders JG, Richel DJ, van Berge Henegouwen MI, Hulshof MCCM (2014) Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol 32:385–391. https://doi.org/10.1200/JCO.2013.51.2186

    Article  PubMed  Google Scholar 

  11. Castoro C, Scarpa M, Cagol M, Ruol A, Cavallin F, Alfieri R, Zanchettin G, Rugge M, Ancona E (2011) Nodal metastasis from locally advanced esophageal cancer: how neoadjuvant therapy modifies their frequency and distribution. Ann Surg Oncol 18:3743–3754. https://doi.org/10.1245/s10434-011-1753-9

    Article  PubMed  Google Scholar 

  12. Talsma AK, Ong C-AJ, Liu X, van Hagen P, Van Lanschot JJB, Tilanus HW, Hardwick RH, Carroll NR, Spaander MCW, Fitzgerald RC, Wijnhoven BPL (2014) Location of lymph node involvement in patients with esophageal adenocarcinoma predicts survival. World J Surg 38:106–113. https://doi.org/10.1007/s00268-013-2236-x

    Article  PubMed  Google Scholar 

  13. Phiillips AW, Lagarde SM, Navidi M, Disep B, Griffin SM (2016) Impact of extent of lymphadenectomy on survival, post neoadjuvant chemotherapy and trans-thoracic esophagectomy. Ann Surg. https://doi.org/10.1097/sla.0000000000001737

    Article  Google Scholar 

  14. Rice TW, Ishwaran H, Hofstetter WL, Schipper PH, Kesler KA, Law S, Lerut T, Denlinger CE, Salo JA, Scott WJ, Watson TJ, Allen MS, Chen LQ, Rusch VW, Cerfolio RJ, Luketich JD, Duranceau A, Darling GE, Pera M, Apperson-Hansen C, Blackstone EH (2017) Esophageal cancer: associations with (pN+) lymph node metastases. Ann Surg 265:122–129. https://doi.org/10.1097/SLA.0000000000001594

    Article  PubMed  PubMed Central  Google Scholar 

  15. Visser E, Markar SR, Ruurda JP, Hanna GB, van Hillegersberg R (2018) Prognostic value of lymph node yield on overall survival in esophageal cancer patients: a systematic review and meta-analysis. Ann Surg. https://doi.org/10.1097/SLA.0000000000002824

    Article  PubMed  Google Scholar 

  16. Van De Ven C, De Leyn P, Coosemans W, Van Raemdonck D, Lerut T (1999) Three-field lymphadenectomy and pattern of lymph node spread in T3 adenocarcinoma of the distal esophagus and the gastro-esophageal junction. Eur J Cardio-thoracic Surg 15:769–773. https://doi.org/10.1016/S1010-7940(99)00122-0

    Article  Google Scholar 

  17. Sharma S, Fujita H, Yamana H, Kakegawa T (1994) Patterns of lymph node metastasis in 3-field dissection for carcinoma in the thoracic esophagus. Surg Today 24:410–414

    CAS  Article  Google Scholar 

  18. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP (2007) Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 335:806–808. https://doi.org/10.1136/bmj.39335.541782.AD

    Article  Google Scholar 

  19. Maureen M. de Boer, Bas Wijnhoven, Ate van der Gaast, Tom Rozema, Grard Nieuwenhuijzen GJBH en PDS (2011) Herziene richtlijn ‘Oesofaguscarcinoom.’ Ned Tijdschr Geneeskd 155:

  20. van Hagen P, Hulshof MCCM, van Lanschot JJB, Steyerberg EW, Henegouwen MI, Wijnhoven BPL, Richel DJ, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, ten Kate FJW, Creemers G-J, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074–2084. https://doi.org/10.1056/nejmoa1112088

    Article  PubMed  Google Scholar 

  21. Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, ten Kate FJW, Creemers G-JM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A (2015) Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 16:1090–1098. https://doi.org/10.1016/S1470-2045(15)00040-6

    Article  PubMed  Google Scholar 

  22. Biere SS, Maas KW, Bonavina L, Garcia JR, Van Berge Henegouwen MI, Rosman C, Sosef MN, De Lange ES, Bonjer HJ, Cuesta MA, Van Der Peet DL (2011) Traditional invasive vs. minimally invasive esophagectomy: a multi-center, randomized trial (TIME-trial). BMC Surg 11:1–7. https://doi.org/10.1186/1471-2482-11-2

    Article  Google Scholar 

  23. Biere SS, van Berge Henegouwen MI, Maas KW, Bonavina L, Rosman C, Garcia JR, Gisbertz SS, Klinkenbijl JH, Hollmann MW, de Lange ES, Bonjer HJ, van der Peet DL, Cuesta MA (2012) Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet 379:1887–1892. https://doi.org/10.1016/S0140-6736(12)60516-9

    Article  PubMed  Google Scholar 

  24. Rice TW, Blackstone EH, Rusch VW (2010) Editorial: 7th edition of the AJCC cancer staging manual: esophagus and esophagogastric junction. Ann Surg Oncol 17:1721–1724. https://doi.org/10.1245/s10434-010-1024-1

    Article  PubMed  Google Scholar 

  25. Mandard A-M, Dalibard F, Mandard J-C, Marnay J, Henry-Amar M, Petiot J-F, Roussel A, Jacob J-H, Segol P, Samama G, Ollivier J-M, Bonvalot S, Gignoux M (1994) Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 73:2680–2686. https://doi.org/10.1002/1097-0142(19940601)73:11%3c2680:AID-CNCR25%3e3.0.CO;2-C

    CAS  Article  PubMed  Google Scholar 

  26. Cheng J, Kong L, Huang W, Li B, Li H, Wang Z, Zhang J, Zhou T, Sun H (2013) Explore the radiotherapeutic clinical target volume delineation for thoracic esophageal squamous cell carcinoma from the pattern of lymphatic metastases. J Thorac Oncol 8:359–365. https://doi.org/10.1097/JTO.0b013e31827e1f6d

    Article  PubMed  Google Scholar 

  27. Shin S, Kim HK, Choi YS, Kim K, Shim YM (2014) Clinical stage T1-T2N0M0 oesophageal cancer: accuracy of clinical staging and predictive factors for lymph node metastasis. Eur J Cardiothorac Surg 46:274–279. https://doi.org/10.1093/ejcts/ezt607discussion 279

    Article  PubMed  Google Scholar 

  28. Dubecz A, Kern M, Solymosi N, Schweigert M, Stein HJ (2015) Predictors of Lymph Node Metastasis in Surgically Resected T1 Esophageal Cancer. Ann Thorac Surg 99:1879–1885. https://doi.org/10.1016/j.athoracsur.2015.02.112discussion 1886

    Article  PubMed  Google Scholar 

  29. Schurink B, Seesing MFJ, Goense L, Mook S, Brosens LAA, Mohammad NH, Ruurda JP, Roeling TAP, Bleys RLAW, van Hillegersberg R (2019) ypT0N+ status in oesophageal cancer patients: location of residual metastatic lymph nodes with regard to the neoadjuvant radiation field. Eur J Surg Oncol 45:454–459. https://doi.org/10.1016/j.ejso.2018.11.011

    CAS  Article  PubMed  Google Scholar 

  30. Ando N, Ozawa S, Kitagawa Y, Shinozawa Y, Kitajima M (2000) Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg 232:225–232

    CAS  Article  Google Scholar 

  31. Prenzel KL, Hölscher AH, Drebber U, Agavonova M, Gutschow CA, Bollschweiler E (2012) Prognostic impact of nodal micrometastasis in early esophageal cancer. Eur J Surg Oncol 38:314–318. https://doi.org/10.1016/j.ejso.2012.01.007

    CAS  Article  PubMed  Google Scholar 

  32. Tachimori Y, Nagai Y, Kanamori N, Hokamura N, Igaki H (2011) Pattern of lymph node metastases of esophageal squamous cell carcinoma based on the anatomical lymphatic drainage system. Dis Esophagus 24:33–38. https://doi.org/10.1111/j.1442-2050.2010.01086.x

    CAS  Article  PubMed  Google Scholar 

  33. Saito H, Sato T, Miyazaki M (2007) Extramural lymphatic drainage from the thoracic esophagus based on minute cadaveric dissections: fundamentals for the sentinel node navigation surgery for the thoracic esophageal cancers. Surg Radiol Anat 29:531–542. https://doi.org/10.1007/s00276-007-0257-6

    Article  PubMed  Google Scholar 

  34. Kuge K, Murakami G, Mizobuchi S, Hata Y, Aikou T, Sasaguri S (2003) Submucosal territory of the direct lymphatic drainage system to the thoracic duct in the human esophagus. J Thorac Cardiovasc Surg 125:1343–1349. https://doi.org/10.1016/S0022-5223(03)00036-9

    Article  PubMed  Google Scholar 

  35. Cense HA, Sloof GW, Klaase JM, Bergman JJ, van Hemert FJ, Fockens P, van Lanschot JJB (2004) Lymphatic drainage routes of the gastric cardia visualized by lymphoscintigraphy. J Nucl Med 45:247–252

    PubMed  Google Scholar 

  36. Prenzel KL, Bollschweiler E, Schroder W, Monig SP, Drebber U, Vallboehmer D, Holscher AH (2010) Prognostic relevance of skip metastases in esophageal cancer. Ann Thorac Surg 90:1662–1667. https://doi.org/10.1016/j.athoracsur.2010.07.008

    Article  PubMed  Google Scholar 

  37. Peters CJ, Hardwick RH, Vowler SL, Fitzgerald RC (2009) Generation and validation of a revised classification for oesophageal and junctional adenocarcinoma. Br J Surg. https://doi.org/10.1002/bjs.6584

    Article  PubMed  Google Scholar 

  38. Lagarde SM, Reitsma JB, De Castro SMM, Ten Kate FJW, Busch ORC, Van Lanschot JJB (2007) Prognostic nomogram for patients undergoing oesophagectomy for adenocarcinoma of the oesophagus or gastro-oesophageal junction. Br J Surg 94:1361–1368. https://doi.org/10.1002/bjs.5832

    CAS  Article  PubMed  Google Scholar 

  39. Lagarde SM, Reitsma JB, Ten Kate FJW, Busch ORC, Obertop H, Zwinderman AH, Moons J, Van Lanschot JJB, Lerut T (2008) Predicting individual survival after potentially curative esophagectomy for adenocarcinoma of the esophagus or gastroesophageal junction. Ann Surg 248:1006–1012. https://doi.org/10.1097/SLA.0b013e318190a0a2

    Article  PubMed  Google Scholar 

  40. Shen W, Shen Y, Tan L, Jin C, Xi Y (2018) A nomogram for predicting lymph node metastasis in surgically resected T1 esophageal squamous cell carcinoma. J Thorac Dis 10:4178–4185. https://doi.org/10.21037/jtd.2018.06.51

    Article  PubMed  PubMed Central  Google Scholar 

  41. Duan X-F, Tang P, Shang X-B, Jiang H-J, Yu Z-T (2018) The prevalence of lymph node metastasis for pathological T1 esophageal cancer: a retrospective study of 143 cases. Surg Oncol 27:1–6. https://doi.org/10.1016/j.suronc.2017.11.002

    Article  PubMed  Google Scholar 

  42. Jin P, van der Horst A, de Jong R, van Hooft JE, Kamphuis M, van Wieringen N, Machiels M, Bel A, Hulshof MCCM, Alderliesten T (2015) Marker-based quantification of interfractional tumor position variation and the use of markers for setup verification in radiation therapy for esophageal cancer. Radiother Oncol 117:412–418. https://doi.org/10.1016/j.radonc.2015.10.005

    Article  PubMed  Google Scholar 

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Affiliations

  1. Department of Surgery, Amsterdam UMC (Location AMC), University of Amsterdam, Cancer Center Amsterdam, 1105 AZ, Amsterdam, The Netherlands

    Eliza R. C. Hagens, Anne-Sophie van Rijswijk, Mark I. van Berge Henegouwen & Suzanne S. Gisbertz

  2. Department of Gastroenterology and Hepatology, Amsterdam UMC (Location AMC), University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands

    Hannah T. Künzli & Bas L. A. M. Weusten

  3. Department of Pathology, Amsterdam UMC (Location AMC), University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands

    Sybren L. Meijer & R. Clinton D. Mijnals

  4. Department of Radiotherapy, Amsterdam UMC (Location AMC), University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands

    E. Debby Geijsen

  5. Department of Medical Oncology, Amsterdam UMC (Location AMC), University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands

    Hanneke W. M. van Laarhoven

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  1. Eliza R. C. Hagens
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Correspondence to Suzanne S. Gisbertz.

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Disclosure

Drs Hagens, Künzli, van Rijswijk, Meijer, Mijnals, Geijsen, and Gisbertz have no conflicts of interest of financial ties to disclose. van Berge Henegouwen has served as consultant for Medtronic and has received unrestricted research funding from Olympus and Stryker. Hanneke W. M. van Laarhoven has served as a consultant for BMS, Celgene, Lilly, and Nordic and has received unrestricted research funding from Bayer, Celgene, Lilly, Merck Serono, MSD, Nordic, Philips, and Roche. Bas Weusten received research support for IRB approved studies from GI Solutions Covidien, Erbe, and C2 Therapeutics. He received a honorarium consultancy speakers fee of Boston Scientific and C2Therapeutics.

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Hagens, E.R.C., Künzli, H.T., van Rijswijk, AS. et al. Distribution of lymph node metastases in esophageal adenocarcinoma after neoadjuvant chemoradiation therapy: a prospective study. Surg Endosc 34, 4347–4357 (2020). https://doi.org/10.1007/s00464-019-07205-y

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Keywords

  • Esophageal adenocarcinoma
  • Lymphadenectomy
  • Lymph node metastases
  • Neoadjuvant therapy
  • Survival