Skip to main content
SpringerLink
Log in

Identifying intense inflammatory subtype of esophageal squamous cell carcinoma using clustering approach

  • Original Article
  • Published:
General Thoracic and Cardiovascular Surgery Aims and scope Submit manuscript

Abstract

Objective

To establish a risk-stratification system for predicting the postoperative recurrence of esophageal squamous cell carcinoma, this study aimed to evaluate the prognostic value of clusters based on blood inflammation and coagulation markers and investigate their correlation with serum cytokines and genetic alteration.

Method

This single-center, retrospective cohort study enrolled 491 patients with esophageal cancer who underwent subtotal esophagectomy between 2004 and 2012. For cluster exploration, nonhierarchical cluster analysis and k-means were applied using serum C-reactive protein, albumin, fibrinogen, and platelet–lymphocyte ratio as variables. Then, multivariate survival analysis was conducted to investigate the association of clusters with recurrence-free survival. To characterize the clusters, serum interleukin-6, interleukin-8, and genetic alteration in primary tumors, the PleSSision-Rapid panel, which can evaluate 160 representative driver genes, was used.

Results

Patients were classified into clusters 1, 2, and 3, which included 24 (5%), 161 (33%), and 306 (62%) patients, respectively. Compared with cluster 3, cluster 1 or 2 had significantly worse recurrence-free survival. Based on the multivariable analysis using cluster, pStage, and age as covariates, cluster was an independent prognostic factor for recurrence-free survival (hazard ratio, 1.55; 95% confidence interval, 1.08–2.21; P = 0.02). The percentage of serum interleukin-6 and interleukin-8 levels was the highest in cluster 1, followed by clusters 2 and 3. In 23 patients with available genomic profiles, no significant difference in representative genomic alterations was observed.

Conclusions

Non-biased clustering using inflammation and coagulation markers identified the intense inflammatory subtype, which had an independent prognostic effect on recurrence-free survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Takeuchi H, Fujii H, Ando N, Ozawa S, Saikawa Y, Suda K, et al. Validation study of radio-guided sentinel lymph node navigation in esophageal cancer. Ann Surg. 2009;249:757–63.

    Article  PubMed  Google Scholar 

  2. Akutsu Y, Kato K, Igaki H, Ito Y, Nozaki I, Daiko H, et al. The prevalence of overall and initial lymph node metastases in clinical T1N0 thoracic esophageal cancer: from the results of JCOG0502, a prospective multicenter study. Ann Surg. 2016;264:1009–15.

    Article  PubMed  Google Scholar 

  3. Tsuji T, Matsuda S, Takeuchi M, Kawakubo H, Kitagawa Y. Updates of perioperative multidisciplinary treatment for surgically resectable esophageal cancer. Jpn J Clin Oncol. 2023;53:645–52.

    Article  PubMed  Google Scholar 

  4. Ozawa S, Uchi Y, Ando T, Hayashi K, Aoki T. Essential updates 2020/2021: recent topics in surgery and perioperative therapy for esophageal cancer. Ann Gastroenterol Surg. 2023;7:346–57.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Tanaka Y, Yoshida K, Suetsugu T, Imai T, Matsuhashi N, Yamaguchi K. Recent advancements in esophageal cancer treatment in Japan. Ann Gastroenterol Surg. 2018;2:253–65.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kitagawa Y, Ishihara R, Ishikawa H, Ito Y, Oyama T, Oyama T, et al. Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus. 2023;20:343–72.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kitagawa Y, Ishihara R, Ishikawa H, Ito Y, Oyama T, Oyama T, et al. Esophageal cancer practice guidelines 2022 edited by the Japan Esophageal Society: part 2. Esophagus. 2023;20:373–89.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Matsuda S, Takeuchi H, Fukuda K, Nakamura R, Takahashi T, Wada N, et al. Clinical significance of plasma fibrinogen level as a predictive marker for postoperative recurrence of esophageal squamous cell carcinoma in patients receiving neoadjuvant treatment. Dis Esophagus. 2014;27:654–61.

    Article  CAS  PubMed  Google Scholar 

  9. Matsuda S, Takeuchi H, Kawakubo H, Fukuda K, Nakamura R, Takahashi T, et al. Cumulative prognostic scores based on plasma fibrinogen and serum albumin levels in esophageal cancer patients treated with transthoracic esophagectomy: comparison with the Glasgow prognostic score. Ann Surg Oncol. 2015;22:302–10.

    Article  PubMed  Google Scholar 

  10. Matsuda S, Takeuchi H, Kawakubo H, Takemura R, Maeda Y, Hirata Y, et al. Validation study of fibrinogen and albumin score in esophageal cancer patients who underwent esophagectomy: multicenter prospective cohort study. Ann Surg Oncol. 2021;28:774–84.

    Article  PubMed  Google Scholar 

  11. Ishibashi Y, Tsujimoto H, Yaguchi Y, Kishi Y, Ueno H. Prognostic significance of systemic inflammatory markers in esophageal cancer: systematic review and meta-analysis. Ann Gastroenterol Surg. 2020;4:56–63.

    Article  PubMed  Google Scholar 

  12. Rice TW, Patil DT, Blackstone EH. 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice. Ann Cardiothorac Surg. 2017;6:119–30.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kaburagi T, Takeuchi H, Fujii H, Saikawa Y, Murakami K, Fukada J, et al. Initial experience of individualized chemoradiotherapy for superficial esophageal cancers based on the sentinel lymph node concept. Esophagus. 2012;9:147–52.

    Article  Google Scholar 

  14. Matsuda S, Kawakubo H, Takeuchi H, Hayashi M, Mayanagi S, Takemura R, et al. Minimally invasive oesophagectomy with extended lymph node dissection and thoracic duct resection for early-stage oesophageal squamous cell carcinoma. Br J Surg. 2020;107:705–11.

    Article  CAS  PubMed  Google Scholar 

  15. Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19:68–74.

    Article  PubMed  Google Scholar 

  16. Hara H, Tahara M, Daiko H, Kato K, Igaki H, Kadowaki S, et al. Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma. Cancer Sci. 2013;104:1455–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mackie IJ, Kitchen S, Machin SJ, Lowe GD. Haemostasis and thrombosis task force of the british committee for standards in haematology. Guidelines on fibrinogen assays. Br J Haematol. 2003;121:396–404.

    Article  PubMed  Google Scholar 

  18. Okamura A, Takeuchi H, Matsuda S, Ogura M, Miyasho T, Nakamura R, et al. Factors affecting cytokine change after esophagectomy for esophageal cancer. Ann Surg Oncol. 2015;22:3130–5.

    Article  PubMed  Google Scholar 

  19. Kudo D, Goto T, Uchimido R, Hayakawa M, Yamakawa K, Abe T, et al. Coagulation phenotypes in sepsis and effects of recombinant human thrombomodulin: an analysis of three multicentre observational studies. Crit Care. 2021;25:114.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tsumura K, Arai E, Tian Y, Shibuya A, Nishihara H, Yotani T, et al. Establishment of permutation for cancer risk estimation in the urothelium based on genome-wide DNA methylation analysis. Carcinogenesis. 2019;40:1308–19.

    Article  CAS  PubMed  Google Scholar 

  21. Saotome K, Chiyoda T, Aimono E, Nakamura K, Tanishima S, Nohara S, et al. Clinical implications of next-generation sequencing-based panel tests for malignant ovarian tumors. Cancer Med. 2020;9:7407–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hoshino S, Matsuda S, Kawakubo H, Yamaguchi S, Nakamura K, Aimono E, et al. Elevation of the prognostic factor plasma fibrinogen reflects the immunosuppressive tumor microenvironment in esophageal squamous cell carcinoma. Ann Surg Oncol. 2022;29:6894–904.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the Japanese Association for Thoracic Surgery Award for Young Investigators and Takeda Science foundation.

Author information

Author notes

  1. Satoru Matsuda, Shota Hoshino and Tadahiro Goto equally contributed to this article.

Authors and Affiliations

  1. Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Satoru Matsuda, Shota Hoshino, Hirofumi Kawakubo, Masashi Takeuchi, Ryota Kobayashi & Yuko Kitagawa

  2. Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Tadahiro Goto

  3. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan

    Kohei Nakamura & Hiroshi Nishihara

  4. Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Hiroya Takeuchi

Authors
  1. Satoru Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shota Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tadahiro Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hirofumi Kawakubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masashi Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ryota Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kohei Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroya Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroshi Nishihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuko Kitagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satoru Matsuda.

Ethics declarations

Conflict of interest

There are no other relationships or activities that could appear to have influenced the submitted work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 442 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsuda, S., Hoshino, S., Goto, T. et al. Identifying intense inflammatory subtype of esophageal squamous cell carcinoma using clustering approach. Gen Thorac Cardiovasc Surg 72, 417–425 (2024). https://doi.org/10.1007/s11748-023-02006-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11748-023-02006-6

Keywords

Search

Navigation