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Impact of increasing lymph node yield on staging, morbidity and survival after esophagectomy for esophageal adenocarcinoma

  • Sofie P.G. Henckens
    Correspondence
    Corresponding author. Department of Surgery, Amsterdam UMC, location University of Amsterdam, PO Box 22660, 1100, DD, Amsterdam, the Netherlands.
    Affiliations
    Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands

    Amsterdam UMC, Location University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
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  • Eliza R.C. Hagens
    Affiliations
    Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands

    Amsterdam UMC, Location University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
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  • Mark I. van Berge Henegouwen
    Affiliations
    Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands

    Amsterdam UMC, Location University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
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  • Sybren L. Meijer
    Affiliations
    Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands

    Amsterdam UMC, Location University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands

    Amsterdam UMC, Location University of Amsterdam, Department of Pathology, Meibergdreef 9, Amsterdam, the Netherlands
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  • Wietse J. Eshuis
    Affiliations
    Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands

    Amsterdam UMC, Location University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
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  • Suzanne S. Gisbertz
    Correspondence
    Corresponding author. Department of Surgery, Amsterdam UMC, location University of Amsterdam, PO Box 22660, 1100, DD, Amsterdam, the Netherlands.
    Affiliations
    Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands

    Amsterdam UMC, Location University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
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Open AccessPublished:July 14, 2022DOI:https://doi.org/10.1016/j.ejso.2022.07.012

      Abstract

      Background

      Extended lymphadenectomy during esophagectomy for esophageal cancer may increase survival, but also increase morbidity. This study analyses the influence of lymph node yield after transthoracic esophagectomy for esophageal adenocarcinoma on the number of positive lymph nodes, pathological N-stage, complications and survival.

      Materials and methods

      Consecutive patients undergoing transthoracic esophagectomy for esophageal adenocarcinoma between 2010 and 2020 were prospectively recorded (follow-up until January 2022). Lymph node yield was analyzed as continuous and dichotomous variable (≤30 vs. ≥31 nodes). The effect of lymph node yield on number of positive lymph nodes, complications, disease-free (DFS) and overall survival (OS) was assessed in multivariable regression analyses.

      Results

      585 patients were included. Median lymph node yield increased from 25 (IQR 20–34) in 2010 to 39 (IQR 32–50) in 2020. Higher lymph node yield was associated with more positive lymph nodes (≥31 vs. ≤30 IRR 1.39, 95%CI 1.11–1.75). In 258 (y)pN + patients, the percentage of (y)pN3-stage increased with 14% between patients with ≤30 and ≥ 31 lymph nodes examined (p 0.014). Higher lymph node yield was not associated with more complications. Superior survival was seen in patients with ≥31 vs. ≤30 lymph nodes examined [DFS: HR 0.73, 95%CI 0.58–0.93, OS: HR 0.71, 95%CI 0.55–0.93)].

      Conclusions

      A lymph node yield of 31 or higher was associated with upstaging and superior survival after esophagectomy for esophageal adenocarcinoma, without increasing morbidity. Extended lymphadenectomy may therefore be regarded as an important part of the multimodal treatment of esophageal cancer.

      Keywords

      1. Introduction

      Esophageal cancer is the seventh most commonly occurring cancer worldwide, with over 604.000 new patients in 2020 [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • et al.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. The prognosis of esophageal cancer patients is slowly improving from a 5-year survival rate of only 5% in 1970, to 20% today [
      Approved by the Cancer.Net editorial board. Esophageal cancer: statistics.
      ]. After curative therapy, consisting of neoadjuvant chemo(radio)therapy and a surgical resection, 5-year survival rate is nowadays approximately 50% [
      • Van Heijl M.
      • Van Lanschot Jjb
      • Koppert L.B.
      • et al.
      Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS).
      ,
      • Shapiro J.
      • van Lanschot Jjb
      • Hulshof M.C.C.M.
      • et al.
      Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.
      ,
      • Eyck B.M.
      • van Lanschot Jjb
      • Hulshof M.C.C.M.
      • et al.
      Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial.
      ].
      An important prognostic factor after esophagectomy is the pathological lymph node status. Lymph node status can be classified as N1, N2 or N3 (when 1–2, 3–6 and ≥7 lymph nodes are involved, respectively) [
      • Rice T.W.
      • Patil D.T.
      • Blackstone E.H.
      8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice.
      ,
      • Rice T.W.
      • Blackstone E.H.
      • Rusch V.W.
      7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction.
      ]. A higher number of positive lymph nodes is associated with an impaired prognosis [
      • Phillips A.W.
      • Lagarde S.M.
      • Navidi M.
      • Disep B.
      • Griffin S.M.
      Impact of extent of lymphadenectomy on survival, post neoadjuvant chemotherapy and transthoracic esophagectomy.
      ,
      • Mariette C.
      • Piessen G.
      • Briez N.
      • Triboulet J.P.
      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.
      ,
      • Peyre C.G.
      • Hagen J.A.
      • DeMeester S.R.
      • et al.
      The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection.
      ].
      Although there are guidelines from the East on the extent of lymphadenectomy for squamous cell esophageal carcinoma, the exact extent to which lymph nodes should be dissected for esophageal adenocarcinoma (EAC) remains controversial. Several studies have established a minimum lymph node yield, varying from 15 to 30 [
      • Peyre C.G.
      • Hagen J.A.
      • DeMeester S.R.
      • et al.
      The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection.
      ,
      • Yeung J.C.
      • Bains M.S.
      • Barbetta A.
      • et al.
      How many nodes need to be removed to make esophagectomy an adequate cancer operation, and does the number change when a patient has chemoradiotherapy before surgery?.
      ,
      • Ho H.-J.
      • Chen H.-S.
      • Hung W.-H.
      • et al.
      Survival impact of total resected lymph nodes in esophageal cancer patients with and without neoadjuvant chemoradiation.
      ,
      • Samson P.
      • Puri V.
      • Broderick S.
      • Patterson G.A.
      • Meyers B.
      • Crabtree T.
      Extent of lymphadenectomy is associated with improved overall survival after esophagectomy with or without induction therapy.
      ,
      • Hanna J.M.
      • Erhunmwunsee L.
      • Berry M.
      • D'Amico T.
      • Onaitis M.
      The prognostic importance of the number of dissected lymph nodes after induction chemoradiotherapy for esophageal cancer.
      ,
      • Yuan F.
      • Qingfeng Z.
      • Jia W.
      • et al.
      Influence of metastatic status and number of removed lymph nodes on survival of patients with squamous esophageal carcinoma.
      ,
      • Groth S.S.
      • Virnig B.A.
      • Whitson B.A.
      • et al.
      Determination of the minimum number of lymph nodes to examine to maximize survival in patients with esophageal carcinoma: data from the Surveillance Epidemiology and End Results database.
      ]. Besides, the consequences of extended lymphadenectomy on staging, morbidity and survival are reported contradictory in literature [
      • Ho H.-J.
      • Chen H.-S.
      • Hung W.-H.
      • et al.
      Survival impact of total resected lymph nodes in esophageal cancer patients with and without neoadjuvant chemoradiation.
      ,
      • Hagens E.R.C.
      • van Berge Henegouwen M.I.
      • Cuesta M.A.
      • Gisbertz S.S.
      The extent of lymphadenectomy in esophageal resection for cancer should be standardized.
      ,
      • Visser E.
      • Markar S.R.
      • Ruurda J.P.
      • Hanna G.B.
      • van Hillegersberg R.
      Prognostic value of lymph node yield on overall survival in esophageal cancer patients: a systematic review and meta-analysis.
      ,
      • Xia W.
      • Liu S.
      • Mao Q.
      • et al.
      Effect of lymph node examined count on accurate staging and survival of resected esophageal cancer.
      ,
      • Lagergren J.
      • Mattsson F.
      • Zylstra J.
      • et al.
      Extent of lymphadenectomy and prognosis after esophageal cancer surgery.
      ,
      • Hulscher J.B.F.
      • Van Sandick J.W.
      • De Boer A.G.E.M.
      • et al.
      Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus.
      ,
      • Boshier P.R.
      • Anderson O.
      • Hanna G.B.
      Transthoracic versus transhiatal esophagectomy for the treatment of esophagogastric cancer: a meta-analysis.
      ,
      • Mertens A.C.
      • Kalff M.C.
      • Eshuis W.J.
      • Van Gulik T.M.
      • Van Berge Henegouwen M.I.
      • Gisbertz S.S.
      Transthoracic versus transhiatal esophagectomy for esophageal cancer: a nationwide propensity score-matched cohort analysis.
      ]. The objective of this study was to analyze changes in lymph node yield over time in a tertiary referral center, and to investigate the impact of lymph node yield on number of positive lymph nodes, pathological N-stage, postoperative complications and survival in patients following esophagectomy for EAC.

      2. Materials and methods

      This retrospective study was conducted from a prospectively maintained database at the Amsterdam UMC in the Netherlands.

      2.1 Patients

      Consecutive patients who underwent transthoracic esophagectomy with gastric conduit reconstruction for EAC between January 2010 and December 2020, were eligible. Patients were excluded if they underwent non-elective or transhiatal resection, resection for other disease than EAC or if reconstruction was not performed by a gastric conduit. Patients were given the opportunity to opt-out if they didn't agree with the usage of their medical data for research. The STROBE guidelines were used to ensure correct reporting of study results [
      • Pocock S.J.
      • Vandenbroucke J.P.
      Strengthening the reporting of observational studies in epidemiology (StroBE) statement: guidelines for reporting observational studies.
      ].

      2.2 Treatment

      Patients were diagnosed and clinically staged according to the Dutch national guideline [
      • Rice T.W.
      • Patil D.T.
      • Blackstone E.H.
      8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice.
      ,
      • Rice T.W.
      • Blackstone E.H.
      • Rusch V.W.
      7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction.
      ,
      Nederlandse Vereniging van Maag-Darm-Leverartsen
      Dutch national guidelines esophageal cancer.
      ]. Neoadjuvant chemoradiotherapy was routinely administered and usually consisted of chemoradiotherapy since the implementation of the CROSS scheme in 2004 (carboplatin AUC and paclitaxel 50 mg/m2 chemotherapy on day 1, 8, 15, 22 and 29 with concurrent 41.4 Gy radiotherapy 23 fractions) [
      • Van Heijl M.
      • Van Lanschot Jjb
      • Koppert L.B.
      • et al.
      Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS).
      ,
      • Shapiro J.
      • van Lanschot Jjb
      • Hulshof M.C.C.M.
      • et al.
      Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.
      ,
      • Eyck B.M.
      • van Lanschot Jjb
      • Hulshof M.C.C.M.
      • et al.
      Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial.
      ]. Since 2010, ≥80% of all patients in the current center received neoadjuvant chemoradiotherapy [
      • Slaman A.E.
      • Pirozzolo G.
      • Eshuis W.J.
      • et al.
      Improved clinical and survival outcomes after esophagectomy for cancer over 25 years.
      ]. Perioperative chemotherapy was administered in patients with tumors with large gastric involvement.
      All patients underwent either open or minimally invasive transthoracic esophagectomy with gastric conduit reconstruction, either intrathoracic or cervical anastomosis and two-field lymphadenectomy. Two-field lymphadenectomy included stations 4R/L (lower paratracheal), 5 (aortopulmonary window), 7 (subcarinal), 8 M/Lo (middle and lower para esophageal), 9 R/L (pulmonary ligament), 15–20 (diaphragmatic, paracardial, left gastric, common hepatic, splenic and celiac trunk) and lymph nodes along the hepatoduodenal ligament. In case of McKeown esophagectomy, station 8U (upper para esophageal) was additionally resected. When indicated based on preoperative imaging or in case of biopsy-proven lymph node involvement, station 2 R/L (upper paratracheal) was additionally resected.
      During the study period, several changes have been made to the surgical management of esophageal cancer patients in this tertiary referral center (Fig. 1). In 2010, a shift from open to minimally invasive McKeown took place, followed by the gradual replacement of minimally invasive McKeown esophagectomy by minimally invasive Ivor Lewis esophagectomy in 2013. Hereafter, McKeown esophagectomy was reserved for proximal or mid-esophageal tumors, and for patients with paratracheal lymph node metastases or radiation fields above the carina. Transhiatal esophagectomy remained reserved for frail patients, unfit to undergo transthoracic surgery. The extent of lymphadenectomy has also expanded over the years. In 2013, standard supracarinal lymphadenectomy was introduced (station 4R and 5). Also in 2013, a minimum lymph node yield of 15 was implemented as quality indicator of upper gastrointestinal surgery in the nationwide Dutch Upper Gastrointestinal Cancer Audit (DUCA), and ex vivo back table dissection of the specimen for lymph nodes was implemented in the context of the TIGER study [
      Home - DICA.
      ,
      • Hagens E.
      • Van Berge Henegouwen M.I.
      • Gisbertz S.
      Distribution of lymph node metastases in esophageal carcinoma [tiger study]: a multinational observational study.
      ]. Lastly in 2014, paratracheal lymphadenectomy was extended to station 4L, and the ‘flap and wrap’ reconstruction was introduced to protect intrathoracic anastomoses against severe leakage [
      • Slaman A.E.
      • Pirozzolo G.
      • Eshuis W.J.
      • et al.
      Improved clinical and survival outcomes after esophagectomy for cancer over 25 years.
      ].
      Fig. 1
      Fig. 1Changes in the extent of lymphadenectomy visualized in time.
      Abbreviations: MI = Minimally Invasive, nCRT = Neoadjuvant ChemoRadioTherapy, DUCA = Dutch Upper Gastrointestinal Cancer Audit.

      2.3 Pathology

      For histopathologic examination, both the esophageal resection specimens and separately sent lymph node stations were processed by the pathology department. The specimen was embedded in paraffin, fixated in formalin overnight and carefully analyzed for remaining lymph nodes. The separately submitted lymph nodes were embedded in paraffin as well (nodes less than 5 mm completely, larger ones in slices of 3–4 mm thick). With microscopic evaluation, both the lymph nodes on the resection specimen, as well as the separately sent lymph nodes were counted. Initial microscopic evaluation was performed by standard H&E staining, or on indication with additional keratin stains. Subsequently, the total lymph node yield as well as the number of positive lymph nodes and their location was registered in the pathology report.

      2.4 Follow up

      Patients were followed up until 5 years postoperatively. The first year after surgery, patients were seen every 3 months, the 2nd-4th year after surgery every 6 months, and once yearly until the 5th postoperative year. Radiology imaging and/or endoscopy was performed when indicated based on signs and symptoms. Follow-up data was collected until January 2022.

      2.5 Study outcomes

      Study outcomes were the median lymph node yield per year, and the association of lymph node yield with positive lymph node yield, pathological N-stage, complications, disease-free (DFS) and overall survival (OS). DFS was defined as the time from surgery to recurrent disease or death (whichever occurred first), or last follow up. OS was defined as the time from surgery to death or last follow up.

      2.6 Statistical analysis

      For descriptive statistics, variables were compared using independent T, Pearson Chi-square or Fisher's Exact tests when appropriate, and outcomes were reported accordingly as either the mean ± standard deviation (SD) or numbers with corresponding percentages. Trends in lymph node yield over time were visualized in a bar chart and presented as median with interquartile range (IQR). Lymph node yield was in all analyses entered both as continuous variable and dichotomous variable (≤30 and ≥ 31 lymph nodes examined). This particular cut-off was considered because 30 is the minimum recommended lymph node yield in previous literature [
      • Yeung J.C.
      • Bains M.S.
      • Barbetta A.
      • et al.
      How many nodes need to be removed to make esophagectomy an adequate cancer operation, and does the number change when a patient has chemoradiotherapy before surgery?.
      ,
      • Groth S.S.
      • Virnig B.A.
      • Whitson B.A.
      • et al.
      Determination of the minimum number of lymph nodes to examine to maximize survival in patients with esophageal carcinoma: data from the Surveillance Epidemiology and End Results database.
      ,
      Home - DICA.
      ,
      • van der Werf L.R.
      • Dikken J.L.
      • van Berge Henegouwen M.I.
      • Lemmens V.E.P.P.
      • Nieuwenhuijzen G.A.P.
      • Wijnhoven B.P.L.
      A population-based study on lymph node retrieval in patients with esophageal cancer: results from the Dutch upper gastrointestinal cancer Audit.
      ]. To investigate the association between lymph node yield and number of positive lymph nodes, a negative binomial regression model was used (results reported as incidence rate ratio (IRR) with 95% confidence interval (CI)). To correct for confounding, cT-stage, cN-stage, neoadjuvant therapy and surgical approach were added to the multivariate model as these factors may influence the (positive) lymph node yield. To study the effect of lymph node yield on the pathological N-stage, Chi2 test was used. To study the effect of lymph node yield on postoperative complications, binary logistic regression was performed (corrected for ASA score, BMI, cT-stage, cN-stage, neoadjuvant therapy and surgical approach as these factors may impact lymph node yield or the occurrence of complications; results reported as odds ratios (OR) with 95%CI). The influence of lymph node yield on survival was assessed with Kaplan-Meier curves, log-rank test and multivariable Cox regression analyses, corrected for cT-stage, cN-stage, neoadjuvant therapy, surgical approach and operation year (2010–2012/2013-2020), and reported as 3-year survival probabilities and hazard ratios (HR) with 95%CI. Missing data was 1.5% and handled with complete case analysis [
      • Jakobsen J.C.
      • Wetterslev J.
      • Winkel P.
      • Lange T.
      • Gluud C.
      Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods.
      ]. A p-value <0.05 was considered to be statistically significant. Data were analyzed using IBM SPSS Statistics Version 28.0.

      3. Results

      Between 2010 and 2020, 935 patients underwent esophagectomy for cancer. After applying the in- and exclusion criteria, 350 patients were excluded (supplementary A). Table 1 outlines the baseline characteristics of all 585 included patients. Their mean age at surgery was 63.5 ± 9.4 years. The majority of patients was male (85.3%) and most tumors were located in the distal esophagus (79.3%).
      Table 1Characteristics of 585 included patients, stratified by lymph node yield.
      All patients

      n = 585

      n (%)
      Lymph node yield <15 n = 26

      n (%)
      Lymph node yield 15–30 n = 251

      n (%)
      Lymph node yield ≥31 n = 308

      n (%)
      p-value
      Age in years, mean ± SD63.5 ± 9.464.8 ± 9.762.5 ± 9.564.2 ± 9.20.254
      Sex
      Female86 (14.7)7 (26.9)41 (16.3)38 (12.3)0.087
      Male449 (85.3)19 (73.1)210 (83.7)270 (87.7)
      ASA score
      I157 (26.8)8 (30.8)86 (34.4)63 (20.5)0.004
      II315 (53.8)15 (57.7)116 (46.2)184 (59.7)
      III113 (19.3)3 (11.5)49 (19.5)61 (19.8)
      Clinical T-stage
      cT138 (6.7)1 (4.0)13 (5.2)24 (8.1)0.008
      cT2112 (19.6)5 (20.0)55 (22.2)52 (17.5)
      cT3410 (71.9)16 (64.0)174 (70.2)220 (74.1)
      cT410 (1.8)3 (12.0)6 (2.4)1 (0.3)
      Clinical N-stage
      cN0194 (33.6)5 (20.0)83 (33.3)106 (35.0)0.066
      cN1263 (45.6)15 (60.0)126 (50.6)122 (40.3)
      cN2111 (19.2)5 (20.0)36 (14.5)70 (23.1)
      cN39 (1.6)0 (0.0)4 (1.6)5 (1.7)
      Localization
      Mid15 (2.6)1 (3.8)8 (3.2)6 (1.9)0.670
      Distal464 (79.3)21 (80.8)201 (80.1)242 (78.6)
      Gastroesophageal Junction106 (18.1)4 (15.4)42 (16.7)60 (19.5)
      Neoadjuvant treatment
      None38 (6.5)1 (3.8)9 (3.6)28 (9.1)0.028
      Chemotherapy28 (4.8)0 (0.0)9 (3.6)19 (6.2)
      Chemoradiotherapy519 (88.7)25 (96.2)233 (92.8)261 (84.7)
      Approach
      Open72 (12.3)8 (30.8)44 (17.5)20 (6.5)<0.001
      Minimally Invasive513 (87.7)18 (69.2)207 (82.5)288 (93.5)
      Anastomosis
      Cervical192 (32.8)19 (73.1)106 (42.2)67 (21.8)<0.001
      Intrathoracic393 (67.2)7 (26.9)145 (57.8)241 (78.2)
      Pathological (y)pT-stage
      (y)pT0113 (19.3)6 (23.1)34 (13.5)73 (23.7)<0.001
      (y)pT1115 (19.7)1 (3.8)53 (21.1)61 (19.8)
      (y)pT285 (14.5)3 (11.5)36 (14.3)46 (14.9)
      (y)pT3245 (41.9)11 (42.3)108 (43.0)126 (40.9)
      (y)pT45 (0.9)0 (0.0)5 (2.0)0 (0.0)
      (y)pTx22 (3.8)5 (19.2)15 (6.0)2 (0.6)
      Pathological (y)pN-stage
      (y)pN0327 (55.9)12 (46.2)141 (56.2)174 (56.5)0.023
      (y)pN1130 (22.2)7 (26.9)64 (25.5)59 (19.2)
      (y)pN283 (14.2)7 (26.9)34 (13.5)42 (13.6)
      (y)pN345 (7.7)0 (0.0)12 (4.8)33 (10.7)
      Abbreviations: ASA = American Society Anesthesiology, SD = Standard Deviation.
      The median lymph node yield in the entire study period was 32 (IQR 24–40). Median lymph node yield increased from 25 lymph nodes (IQR 20–34) in 2010 to 39 lymph nodes (IQR 32–50) in 2020. Fig. 2 visualizes the median lymph node yield over the years in a bar chart.
      Fig. 2
      Fig. 2Median lymph node yield over the years.

      3.1 Positive lymph nodes

      In multivariable analyses with lymph node yield as continuous variable, patients with a higher lymph node yield were more likely to have positive lymph nodes identified at pathological examination. For every extra lymph node examined, the risk of having positive lymph nodes increased by 1.019 times (IRR 1.019, 95%CI 1.01–1.03, p < 0.001) (Table 2).
      Table 2Influence of lymph node yield as continuous variable on the number of positive lymph nodes.
      Independent variableCoefficientsp-valueIRR (95%CI)
      Univariable analysis
      Intercept−0.2260.1530.797(0.585–1.087)
      Lymph node yield0.023<0.0011.024(1.015–1.032)
      Multivariable analysis
      = corrected for cT-stage, cN-stage, neoadjuvant therapy and surgical approach.
      Intercept−1.433<0.0010.239(0.118–0.481)
      Lymph node yield0.019<0.0011.019(1.011–1.028)
      cT-stage
      cT1 (reference)
      cT20.1260.7901.134(0.451–2.852)
      cT31.2060.0083.340(1.374–8.119)
      cT41.0860.0812.908(0.875–9.664)
      cN-stage
      cN0 (reference)
      cN10.3510.0111.421(1.086–1.860)
      cN20.819<0.0012.268(1.656–3.107)
      cN30.8390.0332.313(1.068–5.008)
      Neoadjuvant therapy
      No (reference)
      Yes−0.1210.7870.886(0.369–2.130)
      Surgical approach
      Open (reference)
      Minimally invasive0.1140.5171.121(0.794–1.582)
      Abbreviations: CI = Confidence Interval, IRR = Incidence Rate Ratio.
      a = corrected for cT-stage, cN-stage, neoadjuvant therapy and surgical approach.
      When categorizing lymph node yield, 26 patients (4.4%) had <15 lymph nodes examined, 251 patients (42.9%) had 15-30 lymph nodes examined and 308 patients (52.6%) had 31 or more lymph nodes examined. Because only 4% of the study population had <15 lymph nodes examined, and because this is well-consensus for inadequate lymph node yield in esophageal cancer (a minimum lymph node yield of 15 nodes is one of the DUCA quality indicators), these patients were excluded from further categorized analyses.
      The risk of having positive lymph nodes increased by 1.389 times (IRR 1.389, 95%CI 1.11–1.75) by having a lymph node yield of ≥31 instead of ≤30, p 0.005 (Table 3). In patients with positive lymph nodes at pathological examination (n = 244), the pathological N-stage increases with increasing lymph node yield (p 0.014). When ≤30 lymph nodes were examined, 11% of patients had pN3-stage vs. 25% of patients with ≥31 lymph nodes examined (Table 4).
      Table 3Influence of lymph node yield as categorical variable on the number of positive lymph nodes.
      Independent variableCoefficientsp-valueIRR(95%CI)
      Univariable analysis
      Intercept0.366<0.0011.441(1.225–1.695)
      Lymph node yield
      ≤30 (reference)
      ≥310.404<0.0011.498(1.211–1.854)
      Multivariable analysis
      = corrected for cT-stage, cN-stage, neoadjuvant therapy and surgical approach.
      Intercept−1.1460.0010.318(0.161–0.745)
      Lymph node yield
      ≤30 (reference)
      ≥310.3290.0051.389(1.106–1.745)
      cT-stage
      cT1 (reference)
      cT20.2120.6541.236(0.489–3.128)
      cT31.2890.0053.629(1.485–8.866)
      cT40.9000.1812.460(0.658–9.203)
      cN-stage
      cN0 (reference)
      cN10.4110.0031.508(1.148–1.980)
      cN20.870<0.0012.386(1.738–3.277)
      cN30.9100.0212.484(1.149–5.370)
      Neoadjuvant therapy
      No (reference)
      Yes−0.1990.6570.820(0.341–1.969)
      Surgical approach
      Open (reference)
      Minimally invasive0.2720.1431.312(0.913–1.887)
      Abbreviations: CI = Confidence Interval, IRR = Incidence Rate Ratio.
      a = corrected for cT-stage, cN-stage, neoadjuvant therapy and surgical approach.
      Table 4Pathological N-stages for different lymph node yields.
      pN1pN2pN3
      N%N%N%
      ≤306458.23430.91210.9
      ≥315944.04231.33324.6
      All patients12350.47631.14518.4

      3.2 Complications

      Among all 559 patients, 333 patients (59.6%) had one or more complications during admission or within 30 days after discharge. Pneumonia, pneumothorax, cardiac, urologic and thromboembolic complications, recurrent nerve injury and chyle leakage were equally common within the two groups. The incidence of pulmonary and gastrointestinal complications in general, and anastomotic leakage was higher in patients with ≤30 lymph nodes examined than in patients with ≥31 lymph nodes examined (supplementary B). Patients with a higher lymph node yield were not more likely to have postoperative complications, neither with lymph node yield as continuous variable (OR 1.01, 95%CI 0.99–1.02, p 0.475), nor as dichotomous variable (≥31 vs. ≤30: OR 0.859, 95%CI 0.60–1.24, p 0.412) (supplementary C).

      3.3 Survival

      3-year DFS rate for patients with ≤30 lymph nodes examined was 41.4%; this was 49.5% for patients with ≥31 lymph nodes examined (p 0.034) (Fig. 3A). Median DFS was 24 months (95%CI 17.44–29.7) for patients with a lymph node yield of ≤30 vs. 36 months (95%CI 21.66–49.80) for patients with a lymph node yield of 31 or more, p 0.034. In multivariable analysis, superior DFS was seen in patients with ≥31 lymph nodes examined compared to patients with ≤30 lymph nodes examined [HR 0.73, 95%CI 0.58–0.93, p 0.010]).
      Fig. 3
      Fig. 3Impact of lymph node yield on survival in 559 esophageal adenocarcinoma patients treated with esophagectomy in the period 2010–2018.
      3-year OS was 49.7% for patients with ≤30 lymph nodes examined and 61.5% for patients with 31 or more lymph nodes examined (p 0.011) (Fig. 3B). Median OS was 36 months (95%CI 26.61–45.06) for patients with a lymph node yield of ≤30 vs. 58 months (95%CI 50.10–62.90) for patients with a lymph node yield of 31 or more, p 0.011. In multivariable analysis, superior OS was seen in patients with ≥31 lymph nodes examined compared to patients with ≤30 lymph nodes examined [HR 0.71, 95%CI 0.55–0.93, p 0.011].

      4. Discussion

      This study analyzed trends in lymph node yield after esophagectomy for EAC in a tertiary referral center over time, and investigated the impact of lymph node yield on the number of positive lymph nodes, pathological N-stage, complications and survival. Lymph node yield has increased significantly during the study period. A higher lymph node yield was associated with a higher number of positive lymph nodes, and the disease of patients with a lymph node yield of ≥31 was 14% more often classified as pN3-stage compared to the disease of patients with a lymph node yield of ≤30. A lymph node yield of ≥31 was associated with superior survival, without leading to higher complication rates.
      The median lymph node yield increased with 14 lymph nodes (56%) between 2010 and 2020. The changes in the technique of lymphadenectomy and the start of standard dissection of supracarinal lymph nodes, have almost certainly made a major contribution to this. Another contributing factor is undoubtedly the method of lymph node submission to pathology. Previously, specimens were submitted to the pathologist en-bloc, with lymph nodes still attached. Ex vivo dissection of the lymph nodes by the surgeon helps the pathologist in identifying lymph node tissue and determining its location. A previous study showed that ex vivo lymphadenectomy increases lymph node yield in gastric cancer surgery, and the current study suggests that this is also the case in esophageal cancer surgery [
      • Afaneh C.
      • Levy A.
      • Selby L.
      • et al.
      Ex vivo lymphadenectomy during gastrectomy for adenocarcinoma optimizes lymph node yield.
      ,
      • Cichowitz A.
      • Burton P.
      • Brown W.
      • et al.
      Ex vivo dissection increases lymph node yield in oesophagogastric cancer.
      ]. Furthermore, the implementation of the DUCA quality parameter of resecting a minimum of 15 lymph nodes has probably led to higher awareness by both surgeons and pathologists for the importance of dissection, identification and pathological evaluation of lymph nodes [
      Home - DICA.
      ]. All of the above shows that the increasing focus on adequate lymphadenectomy and pathological examination of lymph nodes resulted in a higher lymph node yield after esophageal cancer surgery.
      The added value of a high lymph node yield has been a topic of discussion amongst esophageal cancer surgeons for several years. The lymphatic distribution pattern of esophageal cancer is unpredictable due to the very complex lymphatic system surrounding the esophagus, and seems to depend on multiple factors such as tumor location, histology, invasion depth and neoadjuvant treatment. Most efficiently is probably a lymphadenectomy strategy for each individual patient, which this is currently being established in the prospective observational multicenter TIGER study [
      • Hagens E.
      • Van Berge Henegouwen M.I.
      • Gisbertz S.
      Distribution of lymph node metastases in esophageal carcinoma [tiger study]: a multinational observational study.
      ]. The TIGER study aims to identify the lymph node stations that should be resected in relation to patient, tumor and treatment characteristics. As long as the evidence is not conclusive, we need to provide adequate lymphadenectomy in all patients to ensure optimal pathological staging, especially since clinical staging has been proven to be unreliable and often not in accordance with pathological staging [
      • Markar S.R.
      • Gronnier C.
      • Pasquer A.
      • et al.
      Discrepancy between clinical and pathologic nodal status of esophageal cancer and impact on prognosis and therapeutic strategy.
      ]. We hypothesized that the more lymph nodes are dissected, the lower the possibility of missing positive lymph nodes and therewith an underestimation of pathological stage and incorrect prognostication. In this study, a higher lymph node yield was associated with a higher opportunity to identify positive lymph nodes, which is consistent with findings in previous literature [
      • Xia W.
      • Liu S.
      • Mao Q.
      • et al.
      Effect of lymph node examined count on accurate staging and survival of resected esophageal cancer.
      ,
      • Kamel M.K.
      • Harrison S.
      • Lee B.
      • Port J.L.
      • Stiles B.M.
      • Altorki N.K.
      Extended lymphadenectomy improves survival after induction chemoradiation for esophageal cancer.
      ,
      • Gottlieb-Vedi E.
      • Kauppila J.H.
      • Mattsson F.
      • et al.
      Extent of lymphadenectomy and long-term survival in esophageal cancer.
      ]. Another aspect emphasizing the importance of optimal pathological staging is evident from the adjuvant treatment options for esophageal cancer patients with residual pathological disease (at least ypT1 or ypN1). Recently, adjuvant nivolumab was found to double disease-free survival and reduce the risk of recurrence or death with 31%, in patients with pathological lymph node positive disease [
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      ]. The indication for adjuvant nivolumab for patients with residual pathological disease could possibly be withheld if patients are operated by esophagectomy with limited lymphadenectomy, reducing the chance of tumor positive lymph nodes in the resection specimen.
      It has been often suggested that the increased surgical trauma of an extended lymph node dissection results in more complications [
      • Hulscher J.B.F.
      • Van Sandick J.W.
      • De Boer A.G.E.M.
      • et al.
      Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus.
      ,
      • Boshier P.R.
      • Anderson O.
      • Hanna G.B.
      Transthoracic versus transhiatal esophagectomy for the treatment of esophagogastric cancer: a meta-analysis.
      ,
      • Mertens A.C.
      • Kalff M.C.
      • Eshuis W.J.
      • Van Gulik T.M.
      • Van Berge Henegouwen M.I.
      • Gisbertz S.S.
      Transthoracic versus transhiatal esophagectomy for esophageal cancer: a nationwide propensity score-matched cohort analysis.
      ]. In the present study, extended lymphadenectomy did not result in increased morbidity. The incidence of several specific complications even decreased with increasing lymph node yield, which is probably due to the implementation of minimally invasive Ivor Lewis esophagectomy in the more recent years of this study, with accompanying increasing lymph node yield. The fact that a higher lymph node yield did not result in more complications, shows that extended lymphadenectomy can be performed safely in expert centers.
      Besides the prognostic value of a high lymph node yield in terms of more reliable staging, the therapeutic value of removing more lymph nodes is also frequently debated. Especially results of studies investigating lymph node yield and survival in patients treated with neoadjuvant chemo(radio)therapy are conflicting [
      • Visser E.
      • Markar S.R.
      • Ruurda J.P.
      • Hanna G.B.
      • van Hillegersberg R.
      Prognostic value of lymph node yield on overall survival in esophageal cancer patients: a systematic review and meta-analysis.
      ,
      • Koen Talsma A.
      • Shapiro J.
      • Looman C.W.N.
      • et al.
      Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival.
      ]. One study concluded that a threshold of 52 lymph nodes was requisite to achieve improved DFS in patients treated with neoadjuvant therapy [
      • Markar S.R.
      • Noordman B.J.
      • Mackenzie H.
      • et al.
      Multimodality treatment for esophageal adenocarcinoma: multi-center propensity-score matched study.
      ].
      The current study found a 3-year OS benefit of almost 12% when comparing a lymph node yield of ≤30 with ≥31 when carefully regarding important confounders. This difference in survival is substantial, and also larger than survival differences reported in previous oncological trials comparing multimodal therapy with surgery alone, e.g., the adenocarcinoma subpopulation of the CROSS trial, comparing neoadjuvant chemoradiotherapy vs. surgery alone for esophageal cancer [
      • Van Heijl M.
      • Van Lanschot Jjb
      • Koppert L.B.
      • et al.
      Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS).
      ,
      • Shapiro J.
      • van Lanschot Jjb
      • Hulshof M.C.C.M.
      • et al.
      Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.
      ]. This underlines that the quality of lymphadenectomy in esophageal adenocarcinoma might be as important as any additional oncological therapy. The improved survival of patients with a lymph node yield of ≥31 found in the current study, should however be interpreted with some caution, as there might be several explanations for this. Primarily, it is presumable a result of improved cancer control by adequate removal of the lymphatics draining the esophageal tumor. This oncological safety reduces the possibility of leaving potential pathological tissue behind and therewith the possibility of (early) recurrent disease. Secondarily, the improvement in high lymph node yield patients' prognosis could be partly explained by time lead bias. In the past few years, synchronous with the increasing lymph node yield, several other improvements have been accomplished in the management of esophageal cancer patients (e.g. the introduction of minimally invasive Ivor Lewis esophagectomy and better complication management). These factors have also significantly improved esophageal cancer patients’ outcomes. However, it is unlikely that this largely explains the survival benefit of a high lymph node yield because we corrected survival analyses for, amongst others, neoadjuvant therapy, surgical approach and operation year.
      This study has some limitations. The specific locations of examined lymph nodes were not available for analysis. As a consequence, it is unknown whether the same lymph nodes were staged as positive in the cN and (y)pN staging, nor could we separately analyze the influence of dissection of specific lymph node stations or thoracic versus abdominal lymph node yield on survival. Another limitation is that the final lymph node yield does not directly correspond with the extent of lymphadenectomy, as lymph node yield is not only affected by the surgeon, but also by the use of neoadjuvant therapy and the identification methodology by the pathologist.
      In this study we used the pathological lymph node yield to quantify the extent of lymphadenectomy, however, this is in fact a proxy of the surgical radicality. In essence, the value of cancer surgery is merely what is left behind in the patient instead of what is resected. Future research should aim to provide an intraoperative metric by capturing photos/videos during surgery, and to use these photo and video assessments to determine the quality of esophageal cancer surgery.
      In conclusion, a vast increase in lymph node yield after esophagectomy for EAC is demonstrated between 2010 and 2020 in this tertiary referral center. A lymph node yield of ≥31 led to higher pathological N-stages and superior survival, without leading to higher complication rates. Extended lymphadenectomy in esophagectomy is therefore a valuable adjunct to multimodal treatment, and should be standard of care in esophageal cancer surgery, irrespectively of choice of neoadjuvant therapy.

      Disclosures

      None of the authors declared to have competing interests. M.I.v.B.H. is consultant for Mylan, Johnson & Johnson, Alesi Surgical, BBraun and Medtronic, and received research grants from Stryker. None of these companies were involved in the design, conduct, nor analysis of this study. The remaining authors have nothing to declare.

      CRediT authorship contribution statement

      Sofie P.G. Henckens: Conceptualization, Data curation, Formal analysis, Methodology, Visualization, Writing - original draft, Writing - review & editing. Eliza R.C. Hagens: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Mark I. van Berge Henegouwen: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing. Sybren L. Meijer: Conceptualization, Data curation, Formal analysis, Methodology, Writing – review & editing. Wietse J. Eshuis: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing. Suzanne S. Gisbertz: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing.

      Declaration of competing interest

      None of the authors declared to have competing interests. M.I.v.B.H. is consultant for Mylan, Johnson & Johnson, Alesi Surgical, BBraun and Medtronic, and received research grants from Stryker. None of these companies were involved in the design, conduct, nor analysis of this study. The remaining authors have nothing to declare.

      Acknowledgments

      The authors would like to express their gratitude to Dr. Susan van Dieren (Epidemiologist, Amsterdam UMC, location University of Amsterdam) for her assistance with statistical analysis.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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