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Prognostic Significance of Epithelial-Mesenchymal Transition of Extracapsular Spread Tumors in Lymph Node Metastases of Head and Neck Cancer

  • Head and Neck Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background and Purpose

The extracapsular spread (ECS) of lymph node metastasis (LNM) reflects tumor aggressiveness and is associated with poor survival and risk of distant metastasis. In this study, we aimed to explore the prognostic significance of epithelial-mesenchymal transition (EMT) of ECS tumors in LNM of head and neck cancers.

Methods

We collected LNM samples from head and neck cancer patients (follow-up >2 years) and made 20 ECS(−): ECS(+) pairs (1:2) of LNM (N = 60), matched by the primary sites and by T and N classifications. Immunostaining of cytokeratin, E-cadherin, vimentin, and CD31 were performed and quantified to determine the epithelial-mesenchymal transition percent (EMT%), defined as vimentin(+)/cytokeratin(+) area of ECS. Univariate and multivariable analyses of clinic-pathologic factors, including EMT% of ECS, were conducted to identify the significant prognosticators. In addition, the anatomical relationship between CD31 vessels and ECS tumors was analyzed.

Results

Rather than the presence of ECS in LNM, higher EMT% (>50 %) of ECS strongly correlated with the worse overall and disease-free survival and had more frequent recurrence and distant dissemination in their clinical courses. ECS tumors intermingled closely with Ki-67(−) CD31(+) non-proliferating perinodal blood vessels. Particularly, vimentin(+) ECS areas exhibited a higher density of CD31(+) perinodal vessels than did vimentin(−) ECS.

Conclusion

High EMT scores of ECS tumors in LNM predict an unfavorable prognosis and systemic dissemination more accurately than the simple presence of ECS in LNM in head and neck cancer patients.

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Acknowledgment

This work was supported by the National Research Foundation of Korea grant, the Korea government (MEST No. 2012R1A1A2040866), the Samsung Medical Center (Research Development Grant #GL1-B2-291-1), and the KIST-SMC Translational Research Project 2013.

Disclosure

The authors have declared no conflicts of interest.

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Authors and Affiliations

  1. Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Won-Yong Lee MD, Da-Yong Shin MS, Hye Jin Kim MS & Han-Sin Jeong MD, PhD

  2. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Young-Hyeh Ko MD, PhD

  3. Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Republic of Korea

    Sehoon Kim PhD

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  1. Won-Yong Lee MD
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  2. Da-Yong Shin MS
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Corresponding authors

Correspondence to Sehoon Kim PhD or Han-Sin Jeong MD, PhD.

Additional information

Won-Yong Lee and Da-Yong Shin contributed equally as first author.

Electronic supplementary material

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10434_2014_3567_MOESM1_ESM.docx

Matched pairs of study subjects according to extra-capsular spread (ECS) status in lymph node metastasis (2:1 = ECS(+):ECS(-), N = 60) and follow-up outcomes Supplementary material 1 (DOCX 18 kb)

10434_2014_3567_MOESM2_ESM.tif

Enrollment of study subjects. Clinical characteristics of patients diagnosed with head and neck cancer and neck node metastasis (N = 110), including 84 extra-capsular spread (ECS)(+) tumors and 26 ECS(-) tumors. Subjects were divided into twenty 2:1 pairs (N = 60), exactly matched by primary sites, T and N classifications, with or without ECS; lymph node samples were used for analysis Supplementary material 2 (TIFF 1789 kb)

10434_2014_3567_MOESM3_ESM.tif

Quantification of the relative epithelial-mesenchymal transition (EMT)  % in lymph node metastasis tumors.(A) To define the tumor area, we manually delineated a cytokeratin(+) area on slide scan images. For extra-capsular spread (ECS) tumor areas, we defined EMT  % of ECS as the vimentin(+) areas divided by cytokeratin(+) ECS tumor areas, which were also manually determined.(B) EMT of intra-lymph node metastasis. Intra-lymph node metastases had peripheral vimentin(+) tumors around the deep portion of lymph nodes, whereas most of the tumor cells from the lymph node capsule were E-cadherin(+) and vimentin(-) Supplementary material 3 (TIFF 6471 kb)

10434_2014_3567_MOESM4_ESM.tif

Extent of ECS and patient prognosis. Survival curves showed that no significant differences between ECS(-), ECS(+) < 5 mm, and ECS(+) ≥ 5 mm in terms of overall survival Supplementary material 4 (TIFF 1096 kb)

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Lee, WY., Shin, DY., Kim, H.J. et al. Prognostic Significance of Epithelial-Mesenchymal Transition of Extracapsular Spread Tumors in Lymph Node Metastases of Head and Neck Cancer. Ann Surg Oncol 21, 1904–1911 (2014). https://doi.org/10.1245/s10434-014-3567-z

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  • DOI: https://doi.org/10.1245/s10434-014-3567-z

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