title: Primary Tumor-Secreted Lymphangiogenic Factors Induce Pre-Metastatic Lymphvascular Niche Formation at Sentinel Lymph Nodes in Oral Squamous Cell Carcinoma.
abstract: OBJECTIVE
  The objectives of this study were to evaluate the formation of lymphvascular niches in lymph nodes of patients with oral squamous cell carcinoma (OSCC), and investigate the roles of lymphangiogenic and angiogenic factors, such as vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D, expressed in the primary tumors.
  
  
  METHODS
  Forty-four patients with previously untreated clinically late T2 or T3 OSCC of cN0 were evaluated for primary tumors and 166 sentinel lymph nodes (SLNs). Primary tumors were immunohistochemically analyzed for expressions of VEGFs. Densities of lymphatic vessels (LVDpodoplanin) and high endothelial venules (HEVD) in the SLNs were also calculated using antibodies for each marker, podoplanin and MECA-79, respectively.
  
  
  RESULTS
  In 25 patients, all lymph nodes were metastasis-negative, whereas, in 19 patients, metastasis was positive for at least one lymph node (either at SLN, non-SLN, or nodal recurrence). From the analyses of 140 SLNs without metastasis, LVDpodoplanin in 50 SLNs of metastasis-positive cases was significantly higher than that in 90 SLNs of metastasis-negative cases (p = 0.0025). HEVD was not associated with lymph node metastasis. The patients with VEGF-A-High or VEGF-D-High tumors had significantly higher LVDpodoplanin than patients with their Low counterparts (p = 0.0233 and p = 0.0209, respectively). In cases with lymph node metastasis, the VEGF-D-expression score was significantly higher than in those without lymph node metastasis (p = 0.0006).
  
  
  CONCLUSIONS
  These results suggest that lymph node lymphangiogenesis occurs before metastasis in OSCC. VEGF-A and VEGF-D play critical roles in this process. VEGF-D is a potential predictive marker of positive lymph node metastasis in cN0 patients.
authors.affiliation: Division of Otolaryngology, and Head & Neck Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Wakisaka
authors.affiliation: Department of Head and Neck Surgery, Aichi Cancer Center, Nagoya, Aichi, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Head and Neck Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Yoshimoto
authors.affiliation: Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Minato-ku, Tokyo, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shiotani
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Junkichi
authors.initials: J
authors.lastname: Yokoyama
authors.affiliation: Department of Head and Neck Surgery and Otolaryngology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sugasawa
authors.affiliation: Division of Otolaryngology, and Head & Neck Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Moriyama-Kita
authors.affiliation: Division of Otolaryngology, and Head & Neck Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Kazuhira
authors.initials: K
authors.lastname: Endo
authors.affiliation: Division of Otolaryngology, and Head & Neck Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshizaki
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D021701:Sentinel Lymph Node Biopsy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; C579459:VEGFD protein, human; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D