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Clinical Studies

Integrating lymphovascular invasion and ypTNM staging system for esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy and surgery: a multi-institutional analysis

British Journal of Cancer volume 134, pages 608–617 (2026)Cite this article

Subjects

Abstract

Purpose

Evidence on the prognostic and staging effects of lymphovascular invasion (LVI) after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (ESCC) is limited. We aimed to determine the prognostic value of LVI and develop a modified post-neoadjuvant pathologic staging (ypStage) system integrating LVI and ypTNM stage to improve risk stratification.

Methods

This multi-institutional study included patients with ESCC receiving neoadjuvant chemoradiotherapy and R0 resection. Recursive partitioning analysis (RPA) was conducted to derive prognostic groupings. A modified ypStage system was developed, validated, and compared with ypTNM stage.

Results

A total of 931 patients were divided into training (n = 565) and external validation (n = 366) cohorts. LVI was present in 115 patients (12.4%). LVI was an independent predictor of survival and disease recurrence, with hazard ratios of 1.70 for overall survival and 1.74 for recurrence-free survival. By integrating LVI status and ypTNM stage, nonmetastatic ESCC were classified into three stages with distinct prognoses. The proposed RPA stage provided superior hazard consistency, hazard discrimination, sample size balance, and outcome prediction over ypTNM stage.

Conclusions

LVI was a strong prognostic factor, independent of the current ypTNM stage in ESCC. We developed an RPA-based ypStage system integrating LVI status and ypTNM stage that exhibited good prognostic performance.

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Fig. 1: Representative histological images of hematoxylin and eosin-stained esophageal tumor.
Fig. 2: Kaplan–Meier curves stratified by lymphovascular invasion status in the entire cohort.
Fig. 3: Recursive partitioning analysis for stratifying prognostic risk.
Fig. 4: Kaplan–Meier curves stratified by RPA stage and the comparison of RPA stage and ypTNM stage in training and validation cohorts.

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Data availability

Deidentified patient data will be available by reasonable request to the corresponding author after institutional approval and with signed access agreement, with no time limits after publication.

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Acknowledgements

We thank Prof. Jibin Li for statistical consultation.

Funding

This work was supported by the grants from the National Natural Science Foundation of China (No.82172669; 82373214), Basic Public Welfare Research Program of Zhejiang Province (LGF21H160005), Beijing Xisike Clinical Oncology Research Foundation (Y-MSDZD2022-0878), Guangdong Basic and Applied Basic Research Foundation (2025B1515020090), and Young Talents Program of Sun Yat-sen University Cancer Center (PT22121101).

Author information

Author notes

  1. These authors contributed equally: Shiliang Liu, Yujin Xu, Xufeng Guo, Wencheng Zhang, Geng Wang.

  2. These authors jointly supervised this work: Qiaoqiao Li, Hong Yang, Mian Xi.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangdong Esophageal Cancer Institute, Guangzhou, China

    Shiliang Liu, Yihong Ling, Li Zhang, Baoqing Chen, Qiaoqiao Li, Hong Yang & Mian Xi

  2. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Shiliang Liu, Li Zhang, Baoqing Chen, Qiaoqiao Li & Mian Xi

  3. Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China

    Yujin Xu & Ruiqi Wang

  4. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Xufeng Guo

  5. Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Wencheng Zhang

  6. Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China

    Geng Wang

  7. Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Gang Zhao

  8. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Yihong Ling

  9. Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Hong Yang

  10. United Laboratory of Frontier Radiotherapy Technology of Sun Yat-sen University & Chinese, Academy of Sciences Ion Medical Technology Co. Ltd, Guangzhou, China

    Mian Xi

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  1. Shiliang Liu
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Contributions

Conception and design: Qiaoqiao Li, Hong Yang, and Mian Xi. Provision of study material or patients: Yujin Xu, Xufeng Guo, Wencheng Zhang, Geng Wang, Qiaoqiao Li, Hong Yang, and Mian Xi. Collection and assembly of data: Shiliang Liu, Gang Zhao, Ruiqi Wang, Yihong Ling, Baoqing Chen, and Mian Xi. Data analysis and interpretation: Shiliang Liu, Li Zhang, Baoqing Chen, Qiaoqiao Li, and Mian Xi. Manuscript writing and final approval: All authors. All authors had full access to the data, participated in reviewing and editing of the manuscript, and approved the final version before submission. Three principal investigators (QL, HY, and MX) verified the raw data of the study and had final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Mian Xi.

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The authors declare no competing interests.

Ethics approval and consent to participate

No patient’s personal identifying information is included in this manuscript. This study was approved by the Institutional Review Boards of each participating center and informed consent was waived owing to its retrospective design. The study was performed in accordance with the Declaration of Helsinki.

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Liu, S., Xu, Y., Guo, X. et al. Integrating lymphovascular invasion and ypTNM staging system for esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy and surgery: a multi-institutional analysis. Br J Cancer 134, 608–617 (2026). https://doi.org/10.1038/s41416-025-03314-9

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