title: Lymphangiogenesis occurs in upper tract urothelial carcinoma and correlates with lymphatic tumour dissemination and poor prognosis.
abstract: OBJECTIVE
  To describe the lymphatic vessel density and to determine the functional and prognostic significance of tumoral lymphatic vessels in upper tract urothelial carcinoma (UTUC).
  
  
  METHODS
  The study included 65 patients who had a radical nephroureterectomy (RNU) for UTUC between 1997 and 2004. All pathological slides were re-evaluated by one reference pathologist and clinical data were reviewed. Lymphatic endothelial cells (LECs) were stained immunohistochemically using D2-40. The lymphatic vessel density (LVD) was described in representative intratumoral (ITLVD), peritumoral (PTLVD) and non-tumoral (NTLVD) areas. Random samples were selected for double-immunostaining with D2-40 and CD-34 (to distinguish blood and lymphatic vessels) and the proliferation marker Ki-67 to detect lymphangiogenesis. The primary outcome measures were disease-specific survival (DSS) and disease recurrence (urothelial and/or distant).
  
  
  RESULTS
  The median (interquartile range) PTLVD was 4.0 (3.0-6.3), and significantly higher than that for ITLVD, of 0.3 (0-1.7) (P < 0.001), and NTLVD, of 3 (2.0-3.7) (P < 0.001). Both a higher ITLVD and PTLVD, the presence of lymphovascular invasion (LVI) (each P < 0.001) and a high tumour grade (P = 0.004) were associated with reduced DSS on univariate analysis. A higher PTLVD (P = 0.028) and the presence of LVI (P = 0.020) independently predicted reduced DSS on multivariate analysis. IT and PT lymphatic vessels showed proliferating LECs in all analysed samples.
  
  
  CONCLUSIONS
  Lymphangiogenesis is present in UTUC, as shown by a significantly increased PTLVD and proliferating LECs. Our findings suggest functional relevance of PT lymphatic vessels during lymphatic tumour spread. PTLVD is a potential novel prognostic factor for DSS in UTUC, and further prospective studies will be needed to determine the effect of its routine evaluation on clinical outcomes of this malignancy.
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. christian.bolenz@uro.ma.uni-heidelberg.de
authors.forename: Christian
authors.initials: C
authors.lastname: Bolenz
authors.forename: Mario I
authors.initials: MI
authors.lastname: Fernández
authors.forename: Lutz
authors.initials: L
authors.lastname: Trojan
authors.forename: Katja
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Edwin
authors.initials: E
authors.lastname: Herrmann
authors.forename: Annette
authors.initials: A
authors.lastname: Steidler
authors.forename: Christel
authors.initials: C
authors.lastname: Weiss
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.forename: Peter
authors.initials: P
authors.lastname: Alken
authors.forename: Maurice Stephan
authors.initials: MS
authors.lastname: Michel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000473:pathology* / Q000601:surgery; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009392:Nephrectomy / Q000379:methods*; D011379:Prognosis; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000473:pathology* / Q000601:surgery; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; C117468:PDPN protein, human; D000098853:Podoplanin