Tumor Biology

, Volume 37, Issue 2, pp 2449–2459 | Cite as

Presence of tumour high-endothelial venules is an independent positive prognostic factor and stratifies patients with advanced-stage oral squamous cell carcinoma

  • Anna M. Wirsing
  • Oddveig G. Rikardsen
  • Sonja E. Steigen
  • Lars Uhlin-Hansen
  • Elin Hadler-Olsen
Original Article


Staging of oral squamous cell carcinoma is based on the tumour-node-metastasis (TNM) system, which has been deemed insufficient for prognostic purposes. Hence, better prognostic tools are needed to reflect the biological diversity of these cancers. Previously, high numbers of specialized blood vessels called high-endothelial venules have been reported to be associated with prolonged survival in patients with breast cancer. In this study, we analysed the prognostic value and morphological characteristics of tumour-associated high-endothelial venules in oral cancer. The presence of tumour-associated high-endothelial venules was evaluated by immunohistochemistry in 75 patients with oral squamous cell carcinoma and analysed with correlation to clinicopathological parameters, patients’ survival and vessel morphology. Ten of the samples were analysed at multiple levels to evaluate intratumoural heterogeneity. The presence of tumour-associated high-endothelial venules was found to be associated with lower disease-specific death in multivariate regression analyses (P = 0.002). High-endothelial venules were present in all (n = 53) T1-T2 tumours, but only in two thirds (n = 14) of the T3-T4 tumours. The morphology of high-endothelial venules was heterogeneous and correlated with lymphocyte density. High-endothelial venules were found to be distributed homogeneously within the tumours. We found the presence of tumour-associated high-endothelial venules to be an easy-to-use, robust, and independent positive prognostic factor for patients with oral cancer. Absence of these vessels in advanced-stage tumours might identify patients with more aggressive disease. Evaluating the presence of tumour-associated high-endothelial venules might help to tailor the treatment of oral cancer patients to their individual needs.


Oral squamous cell carcinoma Prognostic factor High-endothelial venules Peripheral node addressin Inflammation Lymphocyte trafficking 



This work was supported by grants from The North Norwegian Regional Health Authorities and The Erna and Olav Aakre Foundation for Cancer Research. We are also grateful for advice from Dr. Kristin A. Fenton, Professor Elin Mortensen and M.Sc. Stine Figenschau at the Department of Medical Biology, University of Tromsø—The Arctic University of Norway (UiT), and for excellent technical help from Anne-Lise Klodiussen at the Department of Clinical Pathology, University Hospital of North Norway (UNN), and Bente Mortensen as well as Marit Nina Nilsen at the Department of Medical Biology, UiT. We would also like to show our gratitude to Professor Tom Wilsgård at the Department of Community Medicine, UiT, for statistical advice. We further want to express our sincere thanks to Carol-Immanuel Geppert and the Department of Pathology at Friedrich-Alexander University Erlangen-Nuremberg, Germany, for providing the scanning facilities. We also thank Dr. Gunbjørg Svineng, Dr. Peter McCourt and M.Sc. Maarten Beerepoot for advice and critical revision of the manuscript.

Ethical approval

All procedures performed in this study involving human material were in accordance with the ethical standards of the Regional Committee for Medical and Health Research Ethics, Northern Norway (REK-number 22/2007) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required. This article does not contain any studies with animals performed by any of the authors.

Compliance with ethical standards

Conflicts of interest


Research involving human participants and/or animals

All procedures performed in this study involving human material were in accordance with the ethical standards of the Regional Committee for Medical and Health Research Ethics, Northern Norway (REK-number 22/2007) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not present any animal studies.

Informed consent

The Regional Committee for Medical and Health Research Ethics, Northern Norway approved the study without requiring informed consent from the patients, as many of them were dead when the study was initiated.

Supplementary material

13277_2015_4036_Fig4_ESM.gif (79 kb)
Figure S1

Log minus log plots for proportional hazards checking; (A) T stage; (B) N stage, (C) tumour site, (D) high-endothelial venules (HEVs). (GIF 79 kb)

13277_2015_4036_MOESM1_ESM.tif (268 kb)
High Resolution Image (TIFF 268 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Anna M. Wirsing
    • 1
  • Oddveig G. Rikardsen
    • 1
    • 2
  • Sonja E. Steigen
    • 1
    • 3
  • Lars Uhlin-Hansen
    • 1
    • 3
  • Elin Hadler-Olsen
    • 1
    • 3
  1. 1.Department of Medical Biology, Faculty of Health SciencesUniversity of Tromsø—The Arctic University of NorwayTromsøNorway
  2. 2.Department of OtorhinolaryngologyUniversity Hospital of North NorwayTromsøNorway
  3. 3.Department of Clinical PathologyUniversity Hospital of North NorwayTromsøNorway

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