January 2012, Vol. 41 No. 1 21 2011 Young Surgeon's Award Winner: High Endothelial Venules: A Novel Prognostic Marker in Cancer Metastasis and the Missing Link? Ser Yee Lee, 1,2,3 MBBS, MMed (General Surgery), MSc, FRCS (Ed), Chao Nan Qian, 4,5 MD, PhD, Aik Seng Ooi, 6 PhD, Peiyi Chen, 7 MSc, Veronique KM Tan, 1 MBBS, MMed (General Surgery), MRCS, Claramae S Chia, 1 MBBS, MRCS, Jacqueline SG Hwang, 8 MBBS, FRCPA, Bin Tean Teh, 2, 9 BMedSc, MD, PhD, Khee Chee Soo, 1,3 MBBS, FRCS(Ed), MD Abstract Introduction: The extent of lymph nodes (LNs) metastasis is a major determinant for the staging and the most reliable adverse prognostic factor. Primary tumours can induce lymphatics and vasculature reorganisations within sentinel LN before the arrival of cancer cells and these key blood vessels are identiied as high endothelial venules (HEV). The alterations of HEV in the presence of cancer, coupled with the increased proliferation rate of the endothelial cells, results in a functional shift of HEV from immune response mediator to blood low carrier. We aim to evaluate tumour-induced vascularisation in regional LN of cancer patients by studying the morphological and functional alterations of HEV and its correlation to clinico-pathological features. Materials and Methods: This multi-centre study with a prospective database identiied 65 consecutive patients with tongue squamous cell carcinoma (SCC) who underwent primary surgical treatment from 2001 to 2005. Immunohistochemical staining for HEV and image analysis were performed and analysed with correlation to the patients’ clinico-pathological features. Results: The total number of HEV is signiicantly associated to disease-free interval when controlling for the group (P = 0.022) as well as combining both groups as one cohort (P = 0.023). There is also a similar association comparing the HEV parameters to overall survival. Conclusion: Our results suggest that HEV possibly plays a key role in the pathogenesis of lymphatic and subsequent distant metastases and may provide the missing link in cancer metastasis. Conirmation of this hypothesis would offer a novel therapeutic approach to preventing metastasis by blocking the remodeling processes of HEV in LN. Ann Acad Med Singapore 2012;41:21-28 Key words: High endothelial venules, Cancer metastasis, Angioegenesis 1 Department of General Surgery, Singapore General Hospital, Singapore 2 National Cancer Centre Singapore-Van Andel Research Institute, Translational Cancer Research Laboratory, National Cancer Centre, Singapore 3 Department of Surgical Oncology, National Cancer Centre, Singapore 4 Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA 5 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PRC 6 Center for Cancer Genomics and Computational Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA 7 Department of Statistics & Applied Probability, Faculty of Science, National University of Singapore 8 Department of Pathology, Singapore General Hospital, Singapore 9 Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan, USA Address for Correspondence: Dr Ser Yee Lee, Department of Surgical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore 169610. Email: seryee@yahoo.com are remodeled are identiied as high endothelial venules (HEV). 5,6 Tumour-reactive lymphadenopathy in SLN has been observed for decades, but alterations of the lymphatic channels and vasculature in these nodes before the arrival of metastatic tumour cells remain unexplored and not well characterised. The presence of metastatic cells in regional LN along with extracapsular spread of the cervical LN are the most important prognostic factors in patients with squamous cell carcinoma (SCC) of the tongue. 7-10 The lymphatic metastatic cascade is a series of complex interrelated steps and processes. The relationship between angiogenesis and lymphangiogenesis is extensively studied in cancer Introduction Oral and pharyngeal cancer is ranked as the eighth most common cancer diagnosed in men in the United States, and tongue is the most prevalent site. 1 Despite advances in surgery and radiation therapy, the 5-year survival rate has not improved signiicantly over the past several decades and remains at 50-55%. 2,3 Sentinel lymph node (SLN) metastasis is the initial step in cancer metastasis and is the doorway to the regional node basin. 4 The SLN undergoes changes induced by the primary tumour and there are vasculature and lymph channel reorganisations even before the arrival of cancer cells. The key blood vessels in lymph nodes (LN) that High Endothelial Venules—Ser Yee Lee et al Original Article