Work-in-progress report: a prospective, multi-institutional observational study on intraoperative lymph node dissection for thymic epithelial malignancies with radiologically invasive features

Introduction

Recommendations for intraoperative lymph node dissection (LND) during the resection of thymic epithelial malignancies vary across the guidelines of the Japan Lung Cancer Society, the European Society of Medical Oncology, and the National Comprehensive Cancer Network (1-3). Recently, the International Thymic Malignancy Interest Group recommended routine systematic removal of lymph nodes (LNs) in both the anterior (N1-level) and deep (N2-level) regions (4) probably because previous retrospective studies suggested that LN metastasis may be an adverse prognostic factor for survival outcomes in patients undergoing resection of thymic epithelial malignancies (5-7). Thymic (neuroendocrine) carcinoma and/or a higher T stage, as recent studies suggested, are among the relevant factors associated with LN metastasis (8,9), and intraoperative LND plays an important role in nodal staging for thymic epithelial malignancies with those factors. However, the feasibility and characteristics of LND are largely unknown, likely because of the retrospective nature of these studies. Since a histological diagnosis is typically not available preoperatively for resectable thymic malignancies, we focused on the radiological invasive features that would be associated with thymic carcinoma or neuroendocrine carcinoma. This prospective observational study aimed to investigate the feasibility and characteristics of LND, including surgical approaches, detailed LN stations, and postoperative complications, in patients undergoing LND during resection of thymic epithelial malignancies with radiological invasive features. We present this article in accordance with the STROBE reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-24-42/rc).

Methods

This prospective, multi-institutional, observational cohort study was initiated in June 2021 at Kyoto University Hospital, Nara Medical University, Nishi Kobe Medical Center, Shiga General Hospital, Kyoto City Hospital, Tenri Hospital, Shizuoka City Shizuoka Hospital, Osaka Red Cross Hospital, Nagara Medical Center, Otsu Red Cross Hospital, St. Luke’s International Hospital, and Kyoto-Katsura Hospital. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved on June 21, 2021 by the Institutional Review Board of Kyoto University Hospital (reference number: R2996). Written informed consent was obtained from all the patients. All participating institutions were informed and agreed to the study. The number of dissected stations and the extent of LND were determined at the discretion of attending surgeons. Patients undergoing therapeutic resection for thymic epithelial malignancies >5 cm on preoperative computed tomography, whose standardized uptake value max on positron emission tomography was >5, or who were suspected of invading surrounding organs such as the lung, pericardium, heart, or great vessels were included. Patients who underwent surgical biopsy only and those diagnosed with malignancies other than thymic epithelial malignancies on final pathology were excluded. The recently introduced nodal map of the International Thymic Malignancy Interest Group/International Association for the Study of Lung Cancer and the Tumor, Node, Metastasis stage classification was used to group and stage the LNs (4).

Statistical analysis

Descriptive statistics for categorical variables are reported as frequencies and percentages, whereas continuous variables are reported as medians (ranges), as appropriate. The proportions of patients who underwent N1-level and N2-level LND were compared between the open and minimally invasive approaches using the Chi-square test. The number of dissected LN stations was compared between the open and minimally invasive approaches using the Mann-Whitney U test. All analyses were performed using JMP^® 14 and SAS@ 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

A total of 25 patients were enrolled in this study. The background and characteristics of the enrolled patients were summarized in Table 1. The median size was 5.7 cm on preoperative computed tomography and the median standardized uptake value max was 5.13 on positron emission tomography. All patients underwent complete resection of the primary lesion along with LND. Grade 3 postoperative complication was noted in 4 patients (16%). The final pathology was thymoma in 18 (72%) patients and thymic carcinoma in 7 (28%) patients. Twenty-two (88%) patients had N1-level LNs evaluated and 20 (80%) patients had N2-level LNs evaluated among all patients. The median number of dissected LN stations was 2. Frequencies of LND in each station were shown for all patients in Figure 1, which suggested that stations 3a, 5, and 6 appeared to be the most frequently dissected among all the stations. Figure 2 showed that frequencies of LND in each station in in open approach and minimally invasive approach. In Figure 3, frequencies of N1-level and N2-level LND were compared between open approach and minimally invasive approach, which resulted in no significant differences in N1-level LND (P=0.49), or N2-level LND (P=0.69). In Figure 4, the number of dissected stations was compared between open approach and minimally invasive approach, which resulted in no significant differences (P=0.71).

Figure 1 Frequencies of lymph node dissection in each station were shown in all patients.

Figure 2 Frequencies of lymph node dissection in each station were shown in open approach and minimally invasive approach.

Figure 3 Frequencies of N1-level and N2-level lymph node dissection were compared between open approach and minimally invasive approach.

Figure 4 The number of dissected stations was compared between open approach and minimally invasive approach.

Discussion

Intraoperative LND during the resection of thymic epithelial malignancies are recommended by the guidelines from the Japan Lung Cancer Society, the European Society of Medical Oncology, and the National Comprehensive Cancer Network Guidelines, indications or details of LND were not specified (1-3).

Our previous study showed that preoperative radiological investigations appear to play a limited role in detecting pathological LN metastases (10), therefore, in this study, we focused on radiological invasive features of the primary lesions.

The major findings of this work-in-progress report were that both N1-level and N-2 level LND were feasible both in open approach and minimally invasive approach and that intraoperative LND would contribute to nodal staging. It is challenging to estimate the time required for the LND, however, presumably it would be less than ten minutes because the procedure was performed in the same approach. We speculate that none of the postoperative complications were specifically attributed to LND, whereas we cannot completely deny that chylothorax was not associated with LND.

Of interest, Figure 3 suggested that open approach appeared to have an advantage of a slightly more comprehensive access to N2-level LNs over minimally invasive approach, therefore, LND via open approach may be preferred in thymic carcinoma and/or higher T stage, which recent studies suggested as independent factors associated with LN metastasis (8,9). Because histological information is frequently unavailable preoperatively in resectable thymic malignancies, we added greater than 5 of standardized uptake value max on positron emission tomography as one of criteria for enrollment in this study, given the fact that a higher standardized uptake value may be associated with thymic carcinoma (11).

The limitations of our study included its observational design and the small number of patients. Owing to the small sample size (with a small number of patients from each institution) and the only one case with LN metastasis, we were unable to perform multivariable analyses of factors associated with LN metastasis. The low positive rate (4%) in our preliminary data would be presumably due to the small sample size, which suggests it is too early to conclude that LND is not required in our cohort. The procedure of LND was not performed in a standardized manner, which should be investigated in a next study. Our patients were limited to surgical patients, and it remains unknown whether our findings can be applied to more advanced diseases or metastatic diseases.

Despite the above limitations, this work-in-progress report appears to contribute to current literature regarding LND during resection of thymic epithelial malignancies. We will continue to enroll eligible patients in this study in order to investigate any potentially relevant factors, other than tumor size and being FDG-avid, associated with LN metastasis.

Conclusions

In this work-in-progress report, we conclude that intraoperative LND may be feasible in both approaches and in resectable thymic malignancies with radiological invasive features.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-24-42/rc

Data Sharing Statement: Available at https://med.amegroups.com/article/view/10.21037/med-24-42/dss

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-42/prf

Funding: This study was partially funded by Daiwa Securities Foundation (No. 2115).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-42/coif). M.H. serves as an unpaid editorial board member of Mediastinum from May 2024 to December 2025. The other 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Kyoto University Hospital Institutional Review Board (reference number: R2996) and written consent was obtained from each patient. All participating institutions were informed and agreed to the study.

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/.

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