Prognostic impact of recurrent laryngeal nerve palsy after esophagectomy: a systematic review and reconstructed individual patient data meta-analysis

Introduction

Esophageal carcinoma ranks as the 11^th most commonly diagnosed cancer worldwide and is the 7^th leading cause of cancer-related mortality (1). Multimodal therapy, including esophagectomy with lymphadenectomy, remains the cornerstone of treatment (2-4). Despite progress in prehabilitation programs, surgical techniques, and perioperative care, esophagectomy is still associated with considerable morbidity and mortality (5,6).

The incidence of recurrent laryngeal nerve (RLN) lymph node metastasis in thoracic esophageal cancer ranges from 30% to 50%, depending on tumor location, stage, and histological type (7). While RLN lymph node metastasis is associated with decreased overall survival (OS), bilateral RLN lymphadenectomy has been reported to possibly improve long-term survival and reduce the likelihood of local recurrence (8-11). However, surgical dissection around the RLN (station 106Rec) may increase the risk for RLN palsy (RLNP) related to inadvertent thermal injury, stretching, compression, or vascular impairment. The incidence of RLNP after esophagectomy has been reported up to 59% with an increased risk for postoperative pneumonia, reintubation, pulmonary complications, and anastomotic leakage (7,12-17). Previous research has suggested that postoperative RLNP may negatively impact patients’ long-term survival (11). Nonetheless, the prognostic value of RLNP is still debated, as existing studies have concluded inconsistent results (18-21).

Hence, although evidence on the effects of RLNP on long-term prognosis is limited, addressing this issue is important as it challenges the rationale for extensive RLN lymphadenectomy. In this reconstructed individual patient data (IPD) meta-analysis from Kaplan-Meier curves, we aimed to assess the impact of RLNP on patients’ long-term OS. We present this article in accordance with the PRISMA reporting checklist (22) (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1220/rc).

Methods

As the study involved the synthesis of previously published data, ethical approval was not required. A comprehensive literature search was performed across PubMed, Scopus, Web of Science, ClinicalTrials.gov, Cochrane Central Library, and Google Scholar (23). The search strategy was initially implemented in March 2025, repeated in September 2025, and subsequently updated on 15 December 2025. Search terms were derived from medical subject headings (MeSH) and included “esophageal cancer”, “esophageal neoplasm”, “esophageal carcinoma”, “esophagectomy”, “recurrent laryngeal nerve”, “palsy”, “paralysis”, “injury”, “survival”, and “overall survival”. These terms were combined using the Boolean operators AND and OR (Appendix 1). Following database retrieval, article titles were screened, potentially eligible abstracts were reviewed, and the reference lists of relevant publications were examined independently by three investigators (A.A., G.B., and M.E.). The review protocol was prospectively registered in the PROSPERO international database under registration number CRD420261287613.

Eligibility criteria

Studies were considered eligible if they met the following criteria: (I) they evaluated the impact of RLNP on survival outcomes following esophagectomy for esophageal cancer; (II) OS data were presented through Kaplan-Meier survival curves; (III) in cases of multiple publications originating from the same institution, research cohort, or database, only the most recent study or the publication with the largest patient population was included; and (IV) the article was published from 2000 onwards. Studies were excluded if they: (I) did not provide long-term survival outcomes; (II) lacked Kaplan-Meier survival analyses and reported only hazard ratios (HRs); (III) failed to include a direct comparison between patients with and without RLNP; or (IV) were published in languages other than English.

Data extraction

The following variables were extracted from each eligible study: first author, publication year, country of origin, sample size, patient demographics [including sex, age, and body mass index (BMI)], American Society of Anesthesiologists (ASA) physical status classification, tumor-related characteristics and location, operative approach, follow-up duration, perioperative outcomes, occurrence of RLNP, and survival outcomes.

Data extraction was performed independently by three investigators (A.A., A.B., and G.B.). Upon completion of the extraction process, the collected datasets were compared and consolidated. Any inconsistencies were subsequently reviewed by a fourth investigator (L.B.), who adjudicated discrepancies and verified the accuracy of the final database.

Outcomes of interest and definitions

The primary endpoint of the review was OS. OS was defined as the interval between surgical treatment and either death or the most recent follow-up assessment. Individual patient-level survival data were reconstructed using published Kaplan-Meier survival curves in conjunction with numerical information provided within the included studies. Where necessary, supplementary information was obtained from associated publications and accompanying supplementary materials to support data extraction and analysis. RLNP was characterized in accordance with the criteria described in the included articles, which differ in terms of diagnostic modalities, timing, and definitions. Generally, RLNP was defined as any kind of damage inflicted during surgery to the left, the right, or both of the RLN(s), resulting in paresis or paralysis (Table S1). Secondary outcomes included short-term outcomes such as pneumonia, reintubation, pulmonary complications, anastomotic leak, 90-day mortality, operative time (minutes), intraoperative blood loss (mL), total number of harvested lymph nodes, and hospital length of stay (HLOS) (days). Esophageal cancer was defined as any primary histopathologically confirmed neoplasm situated in the cervical, thoracic, or abdominal esophagus.

Quality assessment and assessment of certainty of evidence

The methodological quality of the included studies was independently assessed by two reviewers (A.A. and G.B.). Risk of bias was evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool (24), which examines potential sources of bias across seven domains: confounding, participant selection, intervention classification, deviations from intended interventions, missing data, outcome measurement, and selective reporting. For each domain, signaling questions were rated as “yes”, “probably yes”, “probably no”, or “no”, leading to an overall judgment of low, moderate, serious, or critical risk of bias for each study. The overall certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework (25). Evidence profiles were generated with GRADEpro software (https://www.gradepro.org; accessed 30 December 2025) to evaluate the certainty of evidence for each outcome and comparison. The final certainty ratings were based on several domains, including risk of bias, inconsistency of results, indirectness of evidence, imprecision of effect estimates, publication bias, and other considerations deemed relevant to the body of evidence (26).

Statistical analysis

The findings of the systematic review were synthesized qualitatively and subsequently analyzed using a Frequentist meta-analytic framework based on restricted mean survival time difference (RMSTD) (27-29). Individual patient-level time-to-event data were reconstructed from published Kaplan-Meier survival curves according to established methodologies (30), using GetData Graph Digitizer software (https://automeris.io/; accessed 15 November 2025). Pooled RMSTD estimates were derived through a random-effects multivariate meta-analysis that accounted for within-study covariance across multiple time points. To further explore survival patterns, reconstructed IPD were analyzed using a flexible hazard-based regression model incorporating a normally distributed random intercept to address between-study variability. The baseline hazard function was modeled using a third-degree exponential B-spline without internal knots, with the optimal model specification selected on the basis of the Akaike Information Criterion (AIC) (31). Time-dependent effects of RLNP were assessed by introducing interaction terms between RLNP status and the baseline hazard function, and their significance was evaluated using likelihood ratio testing. Hazard functions were estimated through marginal prediction and presented graphically. Statistical significance was defined as a two-sided P value <0.05, and effect estimates were reported with corresponding 95% confidence intervals (CIs). All statistical analyses were performed using R statistical software (version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria) (32).

Results

Systematic review

The selection process flow chart is reported in Figure 1. Overall, 489 publications were identified, and 459 titles were screened after duplicates were removed. After abstracts screening, 29 full-text articles were found possibly relevant. After evaluation, five studies met the inclusion/exclusion criteria and were incorporated in the quantitative analysis (33-37). All included papers were retrospective; four (33-36) were single center and one was a multicenter design (37). The quality of included studies ranged from moderate to serious risk of bias (Table 1). Overall, 2,115 patients with esophageal cancer undergoing esophagectomy were included for quantitative analysis (Table 1). RLNP was diagnosed 24.4% (n=510). The patient’s age ranged from 56 to 75 years and the majority were males (69.1%). The preoperative BMI was reported in one study (36) while the ASA score was reported in two studies (33,36). Tumor histology was defined in all papers with the majority being esophageal squamous cell carcinoma (SCC) (96.3%). Tumor location was reported in all papers and distributed in the upper (13.4%), middle (51%), and lower (35.6%) esophagus. Pathological tumor staging was defined according to the 7^th and 8^th edition of American Joint Commission on Cancer (AJCC); stage 0–I: 21.5%, stage II: 28.3%; stage III: 42.5%, and stage IV: 7.7%. McKeown esophagectomy with cervical anastomosis was performed in 90.8% while Ivor-Lewis esophagectomy with thoracic anastomosis was completed in 9.2% of patients. Two studies presented data on different surgical approaches (33,37), including open, hybrid, minimally invasive esophagectomy (MIE), and robotic esophagectomy. One study focused exclusively on MIE (35), while another provided data solely for robotic esophagectomy (36). Only one study reported routine three-field lymphadenectomy (34) while the other reported both two- and three-field lymphadenectomy depending on tumor location, surgeon preference, and clinical evidence of enlarged RLN lymph nodes at preoperative examinations. Data on neoadjuvant treatments were reported in five studies; overall 40.6% of patients underwent preoperative chemotherapy or chemoradiation therapy. Adjuvant treatment was described in three articles (33,35,37) and completed in 23.3% of patients.

Figure 1 The PRISMA checklist diagram.

Reconstructed IPD analysis

The clinical appraisal of the RMSTD was based on studies reporting Kaplan-Meier curves for OS (n=5) (Figure S1). The RMSTD and the time horizons are detailed in Table 2 for the comparison RLNP vs. no RLNP. At the 60-month follow-up, the combined effect calculated from multivariate meta-analysis and RMSTD estimation was −0.21 months (95% CI: −2.4, 2.7; P=0.88). This finding suggests that, over a 5-year period, patients with RLNP have comparable survival outcomes to those without RLNP. The estimated pooled OS for RLNP and no RLNP is depicted in Figure 2. Considering the non-proportional hazard model (P<0.001), the time-varying HRs for RLNP and no RLNP were also assessed. No significant differences were found regarding mortality hazard up to 60-month follow-up (HR =0.96; 95% CI: 0.79, 1.10) (Figure S2).

Figure 2 Estimated pooled OS for RLNP (black line) and no RLNP (red line). OS, overall survival; RLNP, recurrent laryngeal nerve palsy.

Secondary outcomes

RLNP was associated with a significantly higher risk for postoperative pneumonia [risk ratio (RR) =1.82], pulmonary complications (RR =1.94), reintubation (RR =3.83), and anastomotic leak (RR =1.52). Further, HLOS [standardized mean difference (SMD) =5.4 days] and total number of harvested lymph nodes (SMD =1.29) were higher for RLNP. No significant differences were found for 90-day mortality and intraoperative blood loss (Table 3). Sensitivity analyses demonstrated that the observed results remained consistent, with stable effect estimates, comparable CIs, and minimal variation in heterogeneity measures. According to the GRADE framework, the overall certainty of evidence for OS was rated as low (Table S2).

Discussion

This reconstructed IPD analysis from Kaplan-Meier curves presents the latest evidence regarding the prognostic significance of RLNP following esophagectomy for cancer. RLNP was observed in 24% of patients. In the present study, its impact on long-term OS appears limited despite the increased risk for postoperative pneumonia, reintubation, pulmonary complications and anastomotic leak. Because relevant confounders could not be adequately accounted for, the available evidence does not suggest an independent prognostic effect of RLNP.

En bloc transthoracic esophagectomy with lymphadenectomy remains the standard approach for localized esophageal cancer, providing accurate staging, enhanced local control, and superior oncological outcomes. There is ongoing debate regarding the optimal extent of lymph node dissection during surgery (38-40). Recent research, including contributions from the Worldwide Esophageal Cancer Collaboration, recommends varying numbers of lymph nodes to be excised depending on T stage, while the National Comprehensive Cancer Network (NCCN) specifies a minimum of 15 lymph nodes (41-45). In cases of thoracic esophageal SCC, Japanese guidelines advise extensive mediastinal lymphadenectomy, encompassing paratracheal, RLN lymph nodes, and cervical lymph node stations, based on the possibility of metastatic involvement (46-48). This recommendation is supported by evidence from observational studies indicating that extended lymphadenectomy may improve survival outcomes in patients with SCC of the thoracic esophagus (49). The recommendation for an extended lymphadenectomy in the setting of esophageal adenocarcinoma is still discussed and questioned with Western and European surgeons preferring a more conservative lymphadenectomy (40,50). The ongoing TIGER study, a global multicenter prospective trial, is expected to provide valuable insights in the near future concerning patterns of nodal metastases and proper extent of lymphadenectomy considering histology, tumor location, depth of invasion, and neoadjuvant therapy (51).

RLN lymph node metastatic involvement occurs in up to 50% of patients with middle third esophageal SCC. The likelihood of RLN involvement varies according to tumor size, location, pathological stage, and histologic subtype (9,10). Although RLN lymph node metastasis is associated with poorer OS, comprehensive RLN lymphadenectomy has been shown to possibly improve survival outcomes and reduce the risk of local recurrence (18). However, this surgical step is technically challenging due to the close proximity of the RLN which increases the risk of iatrogenic injury and can lead to vocal cord paralysis, aspiration, reintubation, increased risk for anastomotic leak and pulmonary complications all negatively influencing patient survival (7,52,53). In our study the incidence of postoperative RLNP was 24% which is consistent with previous literature. The incidence of RLNP is reported to range from 9% to 22% (1-5,7); notably, some Asian centers have documented rates as high as 59% (54,55). These variations are influenced by multiple factors, including the extent of lymph node dissection (two- vs. three-field) (39), anastomosis location (cervical vs. thoracic), surgical approach (open vs. thoracoscopic vs. robotic) (56-59), surgical technique (transthoracic vs. transhiatal), use of energy devices, tumor size and pathological stage, and definition of RLNP. The implementation of non-invasive intraoperative neurological monitoring and anatomical visual clues can assist surgeons in identifying and preserving RLNs (60-65).

While the detrimental effect of anastomotic leak and pulmonary complications on patient survival has been described in previous studies (52,53,66), the effect of RLNP on patient survival is debated. In our reconstructed IPD analysis the RMSTD assessment demonstrated no statistically significant dissimilarities for 5-year OS for RLNP vs. no RLNP (−0.21 months; 95% CI: −2.4, 2.7; P=0.88). This is in line with previous studies defining no differences in term of long-term survival for RLNP vs. no RLNP. Specifically, Yang et al. in their retrospective single-center study including 409 patients with esophageal SCC, reported no differences in term of long-term OS (62% vs. 62.4%) and recurrence-free survival for RLNP vs. no RLNP (36). Similarly, Ogawa and colleagues in their recent multicenter retrospective study including 343 stage I–IV patients with esophageal SCC concluded no significant difference in term of 3-year OS for RLNP vs. no RLNP (69.8% vs. 70.5%) and comparable 3-year survival hazard (HR =1.02; P=0.90) (37). Notably, while pneumonia (HR =1.6; P=0.03) was identified as an independent predictor of poor OS in the logistic regression analysis, RLNP was not (HR =0.91; P=0.70). Also Booka et al. reported no significant difference for long-term OS for RLNP vs. no RLNP (P=0.40) (33). The absence effect on 5-year OS may be due to the transient and self-limiting nature of RLNP, which often resolves within three to 6 months, or it may reflect a false negative outcome resulting from the relatively small sample size. Although prior research and also our study have indicated an increased risk of pneumonia and pulmonary complications following RLNP, not all patients experiencing transient RLNP develop pulmonary complications. Aspiration results from inadequate laryngeal closure, which involves glottic closure, laryngeal vestibular closure, and epiglottic inversion. Thus, even with incomplete glottal closure due to RLNP, other laryngeal closure mechanisms may compensate, potentially preventing aspiration. Thus, this risk may be mitigated through ERAS protocols, respiratory rehabilitation strategies, swallowing training, physical exercise, and nutritional therapy (67,68).

Several factors should be considered when interpreting our findings. First, the included studies were conducted at tertiary centers in Eastern regions and focused on esophageal SCC, which may limit the applicability of the results to Western populations where esophageal adenocarcinoma predominates. Second, all included studies were retrospective with a potential for selection, allocation, and reporting bias. Although most studies reported routine mediastinal dissection, there was insufficient detail regarding the criteria for a two- or a three-field lymphadenectomy which was often left to the operating surgeon’s discretion, thereby introducing additional bias. Therefore, RLNP might be considered a surrogate for treatment intensity rather than an independent prognostic factor. Further, no data were available regarding the type of energy device utilized for dissection or intraoperative strategies/visual clues for RLN identification. Third, patient data spanned operations performed from 1997 to 2019, raising the possibility of temporal bias due to advancements in postoperative protocols, enhanced recovery after surgery initiatives, and evolving neoadjuvant or adjuvant chemoradiation strategies (69). Fourth, while neoadjuvant treatments were reported for most patients, information pertaining to adjuvant treatments and specific protocols remained limited. Fifth, although a consensus-derived benchmark definition for instrumental and degree of RLN injury was established in 2019 (70), none of the included studies conformed to this standardized criterion. Particularly, information whether RLNP was temporary or permanent, as well as associated recovery timelines, was insufficient. Finally, the association between RLNP and long-term survival may be mediated by postoperative complications that could not be adequately evaluated in our reconstructed Kaplan-Meier-based dataset. Although RLNP was associated with higher rates of pneumonia, pulmonary complications, reintubation, and anastomotic leakage, the available data did not allow determination of whether these events contributed to subsequent differences in long-term outcomes. RLNP may not directly influence oncological prognosis; however, its clinical sequelae, including aspiration-related morbidity, prolonged hospitalization, nutritional impairment, delayed recovery, and reduced compliance with adjuvant treatment, may still affect survival. Accordingly, the absence of a detectable difference in OS should be interpreted with caution, as clinically relevant indirect effects may have been obscured by the limitations of the available retrospective data.

A key strength of the current reconstructed IPD analysis lies in its application of the RMSTD for evaluating long-term OS. RMSTD is increasingly recognized in clinical oncology for its robust reliability and clear measurement of survival benefits (71,72). The RMSTD analysis facilitates the assessment of RLNP effects during follow-up through comparative analysis of the area under the Kaplan-Meier survival curves. In contrast to RR and HR, which presume a constant risk over time and are susceptible to misinterpretation, RMSTD offers a more direct and comprehensible interpretation (73). However, several limitations must be acknowledged. Notwithstanding the rigorous application of the statistical methodology, the IPD meta-analysis based on reconstructed Kaplan-Meier curves remain susceptible to possible measurement error. Baseline heterogeneity among patients including differences in demographics and comorbidities as well as inconsistencies in reporting oncologic variables such as tumor grading, compliance with adjuvant treatments, and stratification by tumor stage may affect results. Furthermore, disparities in perioperative multidisciplinary care, variations in surgical techniques, differences in surgeon expertise and hospital volumes, total postoperative complication rates, and diversity in genomic and biological tumor features may influence long-term survival outcomes (74-77). It should also be noted that these findings were derived from Asian patients with esophageal SCC, and thus their applicability to esophageal adenocarcinoma and to Western series remains to be validated in rigorously designed studies. The absence of sufficiently powered prospective investigations and the lack of a standardized definition for RLNP stands as a significant limitation. Finally, interpretation of OS alone may be misleading, as it may be confounded by non-cancer-related mortality. In this setting, disease-free survival and cancer-specific survival would be more informative endpoints; however, these data were not reported in the included studies.

Conclusions

In the present study, RLNP after esophagectomy was not associated with worse long-term OS. However, this finding should be interpreted with caution, as relevant confounders could not be adequately accounted for and an independent prognostic effect of RLNP cannot be excluded. RLNP was associated with increased risks of pneumonia, reintubation, pulmonary complications, and anastomotic leak. Prospective studies using standardized definitions and detailed patient-level data are needed to clarify the impact of RLNP on both short- and long-term outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1220/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1220/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1220/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84. [Crossref] [PubMed]
3. Arnold M, Rutherford MJ, Bardot A, et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol 2019;20:1493-505. [Crossref] [PubMed]
4. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 2015;16:1090-8. [Crossref] [PubMed]
5. Aiolfi A, Cammarata F, Bonitta G, et al. Open, hybrid, minimally invasive, and robotic-assisted transthoracic esophagectomy for cancer: a network meta-analysis of randomized trials. Int J Surg 2025;111:8503-14. [Crossref] [PubMed]
6. Aiolfi A, Bona D, Bonitta G, et al. Short-term Outcomes of Different Techniques for Gastric Ischemic Preconditioning Before Esophagectomy: A Network Meta-analysis. Ann Surg 2024;279:410-8. [Crossref] [PubMed]
7. Scholtemeijer MG, Seesing MFJ, Brenkman HJF, et al. Recurrent laryngeal nerve injury after esophagectomy for esophageal cancer: incidence, management, and impact on short- and long-term outcomes. J Thorac Dis 2017;9:S868-78. [Crossref] [PubMed]
8. Jang HJ, Lee HS, Kim MS, et al. Patterns of lymph node metastasis and survival for upper esophageal squamous cell carcinoma. Ann Thorac Surg 2011;92:1091-7. [Crossref] [PubMed]
9. Taniyama Y, Nakamura T, Mitamura A, et al. A strategy for supraclavicular lymph node dissection using recurrent laryngeal nerve lymph node status in thoracic esophageal squamous cell carcinoma. Ann Thorac Surg 2013;95:1930-7. [Crossref] [PubMed]
10. Ninomiya I, Osugi H, Fujimura T, et al. Thoracoscopic esophagectomy with extended lymph node dissection in the left lateral position: technical feasibility and oncologic outcomes. Dis Esophagus 2014;27:159-67. [Crossref] [PubMed]
11. Kanemura T, Makino T, Miyazaki Y, et al. Distribution patterns of metastases in recurrent laryngeal nerve lymph nodes in patients with squamous cell esophageal cancer. Dis Esophagus 2017;30:1-7. [Crossref] [PubMed]
12. Baba M, Aikou T, Yoshinaka H, et al. Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus. Ann Surg 1994;219:310-6. [Crossref] [PubMed]
13. Nishimaki T, Suzuki T, Suzuki S, et al. Outcomes of extended radical esophagectomy for thoracic esophageal cancer. J Am Coll Surg 1998;186:306-12. [Crossref] [PubMed]
14. Gockel I, Kneist W, Keilmann A, et al. Recurrent laryngeal nerve paralysis (RLNP) following esophagectomy for carcinoma. Eur J Surg Oncol 2005;31:277-81. [Crossref] [PubMed]
15. Gelpke H, Grieder F, Decurtins M, et al. Recurrent laryngeal nerve monitoring during esophagectomy and mediastinal lymph node dissection. World J Surg 2010;34:2379-82. [Crossref] [PubMed]
16. Taniyama Y, Okamoto H, Sato C, et al. Prevention and Management of Recurrent Laryngeal Nerve Palsy in Minimally Invasive Esophagectomy: Current Status and Future Perspectives. J Clin Med 2024;13:7611. [Crossref] [PubMed]
17. Takahashi K, Nishikawa K, Tanishima Y, et al. Risk Stratification of Postoperative Pneumonia in Patients Undergoing Subtotal Esophagectomy for Esophageal Cancer. Anticancer Res 2022;42:3023-8. [Crossref] [PubMed]
18. Wu J, Chen QX, Zhou XM, et al. Does recurrent laryngeal nerve lymph node metastasis really affect the prognosis in node-positive patients with squamous cell carcinoma of the middle thoracic esophagus? BMC Surg 2014;14:43. [Crossref] [PubMed]
19. Hong TH, Kim HK, Lee G, et al. Role of Recurrent Laryngeal Nerve Lymph Node Dissection in Surgery of Early-Stage Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 2022;29:627-39. [Crossref] [PubMed]
20. Xu S, Chen D, Liu Z, et al. Impact of the extent of recurrent laryngeal nerve lymphadenectomy on thoracic esophageal squamous cell carcinoma: a real-world multicentre study. Eur J Cardiothorac Surg 2023;63:ezad168. [Crossref] [PubMed]
21. Hagens ERC, Kingma BF, van Berge Henegouwen MI, et al. The Impact of Paratracheal Lymphadenectomy on Survival After Esophagectomy: A Nationwide Propensity Score Matched Analysis. Cancers (Basel) 2025;17:888. [Crossref] [PubMed]
22. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372: [Crossref] [PubMed]
23. Goossen K, Tenckhoff S, Probst P, et al. Optimal literature search for systematic reviews in surgery. Langenbecks Arch Surg 2018;403:119-29. [Crossref] [PubMed]
24. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919. [Crossref] [PubMed]
25. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-6. [Crossref] [PubMed]
26. Schünemann H, Brożek J, Guyatt G, et al. GRADE Handbook: 5 Quality of Evidence. 2013. Accessed on December 30th, 2025. Available online: https://gdt.gradepro.org/app/handbook/handbook.html#h.9rdbelsnu4iy
27. Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol 2013;13:152. [Crossref] [PubMed]
28. Aiolfi A, Bona D, Cali M, et al. Impact of Thoracic Duct Resection on Long-Term Survival After Esophagectomy: Individual Patient Data Meta-analysis. Ann Surg Oncol 2024;31:6699-709. [Crossref] [PubMed]
29. Jackson D, White IR, Riley RD. A matrix-based method of moments for fitting the multivariate random effects model for meta-analysis and meta-regression. Biom J 2013;55:231-45. [Crossref] [PubMed]
30. Guyot P, Ades AE, Ouwens MJ, et al. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol 2012;12:9. [Crossref] [PubMed]
31. Charvat H, Belot A. Mexhaz: An R package for fitting flexible hazard-based regression models for overall and excess mortality with a random effect. J Stat Softw 2021;98:1-36.
32. R Core Team. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing. Accessed on 10th November 2025. Available online: http://www.R-project.org/
33. Booka E, Takeuchi H, Nishi T, et al. The Impact of Postoperative Complications on Survivals After Esophagectomy for Esophageal Cancer. Medicine (Baltimore) 2015;94:e1369. [Crossref] [PubMed]
34. Koyanagi K, Igaki H, Iwabu J, et al. Recurrent Laryngeal Nerve Paralysis after Esophagectomy: Respiratory Complications and Role of Nerve Reconstruction. Tohoku J Exp Med 2015;237:1-8. [Crossref] [PubMed]
35. Qu R, Tu D, Ping W, et al. The Impact of the Recurrent Laryngeal Nerve Injury on Prognosis After McKeown Esophagectomy for ESCC. Cancer Manag Res 2021;13:1861-8. [Crossref] [PubMed]
36. Yang Y, Li B, Xu X, et al. Short-term and long-term effects of recurrent laryngeal nerve injury after robotic esophagectomy. Eur J Surg Oncol 2023;49:107009. [Crossref] [PubMed]
37. Ogawa K, Toyozumi T, Noma K, et al. The prognostic effect of recurrent laryngeal nerve palsy after esophagectomy in locally advanced esophageal squamous cell carcinoma: A multi-center retrospective study. Eur J Surg Oncol 2025;51:110151. [Crossref] [PubMed]
38. Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg 2010;251:46-50. [Crossref] [PubMed]
39. Bona D, Lombardo F, Matsushima K, et al. Three-field versus two-field lymphadenectomy for esophageal squamous cell carcinoma: A long-term survival meta-analysis. Surgery 2022;171:940-7. [Crossref] [PubMed]
40. Hagens ERC, van Berge Henegouwen MI, Cuesta MA, et al. The extent of lymphadenectomy in esophageal resection for cancer should be standardized. J Thorac Dis 2017;9:S713-23. [Crossref] [PubMed]
41. Herrera LJ. Extent of lymphadenectomy in esophageal cancer: how many lymph nodes is enough? Ann Surg Oncol 2010;17:676-8. [Crossref] [PubMed]
42. Stiles BM, Nasar A, Mirza FA, et al. Worldwide Oesophageal Cancer Collaboration guidelines for lymphadenectomy predict survival following neoadjuvant therapy. Eur J Cardiothorac Surg 2012;42:659-64. [Crossref] [PubMed]
43. Nafteux P, Depypere L, Van Veer H, et al. Principles of esophageal cancer surgery, including surgical approaches and optimal node dissection (2- vs. 3-field). Ann Cardiothorac Surg 2017;6:152-8.
44. Yeung JC, Bains MS, 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? Ann Surg Oncol 2020;27:1227-32. [Crossref] [PubMed]
45. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Esophageal. Available online: https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
46. Kitagawa Y, Ishihara R, Ishikawa H, et al. Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus 2023;20:343-72.
47. Kitagawa Y, Ishihara R, Ishikawa H, et al. Esophageal cancer practice guidelines 2022 edited by the Japan Esophageal Society: part 2. Esophagus 2023;20:373-89.
48. Mine S, Tanaka K, Kawachi H, et al. Japanese Classification of Esophageal Cancer, 12th Edition: Part I. Esophagus 2024;21:179-215.
49. Li B, Hu H, Zhang Y, et al. Esophageal squamous cell carcinoma patients with positive lymph nodes benefit from extended radical lymphadenectomy. J Thorac Cardiovasc Surg 2019;157:1275-1283.e1. [Crossref] [PubMed]
50. Gantxegi A, Kingma BF, Ruurda JP, et al. The Value of Paratracheal Lymphadenectomy in Esophagectomy for Adenocarcinoma of the Esophagus or Gastroesophageal Junction: A Systematic Review of the Literature. Ann Surg Oncol 2022;29:1347-56. [Crossref] [PubMed]
51. Hagens ERC, van Berge Henegouwen MI, van Sandick JW, et al. Distribution of lymph node metastases in esophageal carcinoma TIGER study: study protocol of a multinational observational study. BMC Cancer 2019;19:662. [Crossref] [PubMed]
52. Aiolfi A, Griffiths EA, Sozzi A, et al. Effect of Anastomotic Leak on Long-Term Survival After Esophagectomy: Multivariate Meta-analysis and Restricted Mean Survival Times Examination. Ann Surg Oncol 2023;30:5564-72. [Crossref] [PubMed]
53. Manara M, Bona D, Bonavina L, et al. Impact of pulmonary complications following esophagectomy on long-term survival: multivariate meta-analysis and restricted mean survival time assessment. Updates Surg 2024;76:757-67. [Crossref] [PubMed]
54. Wright CD, Zeitels SM. Recurrent laryngeal nerve injuries after esophagectomy. Thorac Surg Clin 2006;16:23-33. v. [Crossref] [PubMed]
55. Fujita H, Kakegawa T, Yamana H, et al. Mortality and morbidity rates, postoperative course, quality of life, and prognosis after extended radical lymphadenectomy for esophageal cancer. Comparison of three-field lymphadenectomy with two-field lymphadenectomy. Ann Surg 1995;222:654-62.
56. Na KJ, Kang CH, Park S, et al. Robotic esophagectomy versus open esophagectomy in esophageal squamous cell carcinoma: a propensity-score matched analysis. J Robot Surg 2022;16:841-8. [Crossref] [PubMed]
57. Takeuchi H, Miyata H, Ozawa S, et al. Comparison of Short-Term Outcomes Between Open and Minimally Invasive Esophagectomy for Esophageal Cancer Using a Nationwide Database in Japan. Ann Surg Oncol 2017;24:1821-7. [Crossref] [PubMed]
58. Taniyama Y, Miyata G, Kamei T, et al. Complications following recurrent laryngeal nerve lymph node dissection in oesophageal cancer surgery. Interact Cardiovasc Thorac Surg 2015;20:41-6. [Crossref] [PubMed]
59. Yang Y, Li B, Yi J, et al. Robot-assisted Versus Conventional Minimally Invasive Esophagectomy for Resectable Esophageal Squamous Cell Carcinoma: Early Results of a Multicenter Randomized Controlled Trial: the RAMIE Trial. Ann Surg 2022;275:646-53. [Crossref] [PubMed]
60. Saito Y, Takeuchi H, Fukuda K, et al. Size of recurrent laryngeal nerve as a new risk factor for postoperative vocal cord paralysis. Dis Esophagus 2018;
61. Ohi M, Toiyama Y, Yasuda H, et al. Preoperative computed tomography predicts the risk of recurrent laryngeal nerve paralysis in patients with esophageal cancer undergoing thoracoscopic esophagectomy in the prone position. Esophagus 2021;18:228-38. [Crossref] [PubMed]
62. Hayami M, Watanabe M, Mine S, et al. Steam induced by the activation of energy devices under a wet condition may cause thermal injury. Surg Endosc 2020;34:2295-302. [Crossref] [PubMed]
63. Hikage M, Kamei T, Nakano T, et al. Impact of routine recurrent laryngeal nerve monitoring in prone esophagectomy with mediastinal lymph node dissection. Surg Endosc 2017;31:2986-96. [Crossref] [PubMed]
64. Huang CL, Chen CM, Hung WH, et al. Clinical Outcome of Intraoperative Recurrent Laryngeal Nerve Monitoring during Thoracoscopic Esophagectomy and Mediastinal Lymph Node Dissection for Esophageal Cancer. J Clin Med 2022;11:4949. [Crossref] [PubMed]
65. Chen B, Yang T, Wang W, et al. Application of Intraoperative Neuromonitoring (IONM) of the Recurrent Laryngeal Nerve during Esophagectomy: A Systematic Review and Meta-Analysis. J Clin Med 2023;12:565. [Crossref] [PubMed]
66. Bona D, Manara M, Bonitta G, et al. Long-Term Impact of Severe Postoperative Complications after Esophagectomy for Cancer: Individual Patient Data Meta-Analysis. Cancers (Basel) 2024;16:1468. [Crossref] [PubMed]
67. Shen Y, Chen X, Hou J, et al. The effect of enhanced recovery after minimally invasive esophagectomy: a randomized controlled trial. Surg Endosc 2022;36:9113-22. [Crossref] [PubMed]
68. Takatsu J, Higaki E, Abe T, et al. Critical swallowing functions contributing to dysphagia in patients with recurrent laryngeal nerve paralysis after esophagectomy. Esophagus 2024;21:111-9. [Crossref] [PubMed]
69. Hoeppner J, Brunner T, Schmoor C, et al. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. N Engl J Med 2025;392:323-35. [Crossref] [PubMed]
70. Low DE, Kuppusamy MK, Alderson D, et al. Benchmarking Complications Associated with Esophagectomy. Ann Surg 2019;269:291-8. [Crossref] [PubMed]
71. Wei Y, Royston P, Tierney JF, et al. Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data. Stat Med 2015;34:2881-98. [Crossref] [PubMed]
72. Weir IR, Marshall GD, Schneider JI, et al. Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment. Ann Oncol 2019;30:96-102. [Crossref] [PubMed]
73. Saad ED, Tannock IF. Avoiding the hazards of misinterpreting treatment effects. Ann Oncol 2019;30:16-8. [Crossref] [PubMed]
74. Aiolfi A, Bona D, De Bernardi S, et al. Impact of Centralizing Esophageal Cancer Surgery at High-Volume Centers on Long-Term Survival: Individual Patient Data Meta-Analysis. Ann Surg Oncol 2025;32:7891-900. [Crossref] [PubMed]
75. Cui H, Zhu Z, Xu E, et al. The consensus molecular subtypes of esophageal squamous cell carcinoma. Signal Transduct Target Ther 2026;11:65. [Crossref] [PubMed]
76. Salem ME, Puccini A, Xiu J, et al. Comparative Molecular Analyses of Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, and Gastric Adenocarcinoma. Oncologist 2018;23:1319-27. [Crossref] [PubMed]
77. Chen XX, Zhong Q, Liu Y, et al. Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing. Nat Commun 2017;8:524. [Crossref] [PubMed]