title: Expression and predictive value of lymph-specific markers in urothelial carcinoma of the bladder.
abstract: OBJECTIVE
  To evaluate the expression of multiple lymph-specific markers and to test its association with histopathological characteristics and clinical outcomes in patients with urothelial carcinoma of the bladder (UCB) treated by radical cystectomy (RC).
  
  
  METHODS
  Vascular endothelial growth factor-C and -D (VEGF-C/-D), its receptor VEGF receptor-3 (VEGFR-3), and chemokine receptor type 7 (CCR7) expressions were assessed by immunohistochemistry in RC specimens of 119 patients. Semiquantitative analyses of marker expressions were correlated with clinical and pathological characteristics. Univariable and multivariable analyses were performed to identify predictors of disease-specific survival (DSS) and recurrence free survival (RFS).
  
  
  RESULTS
  VEGF-C, VEGF-D, VEGFR-3, and CCR7 were overexpressed in 37.8%, 26.2%, 50.4%, and 23.5% of UCB samples, respectively. VEGF-D overexpression was significantly associated with a positive lymph node status (pN+). On univariable analysis, a higher pT stage, pN+, the presence of lymphovascular invasion (LVI) and vascular invasion (VI) (all P<0.001), and overexpressions of VEGF-D (P = 0.049) and VEGFR-3 (P = 0.032) were significantly associated with reduced DSS. On multivariable analysis, pT stage (P = 0.002) and pN+status (P = 0.009) were identified as independent predictors of reduced DSS. In a subgroup of patients without lymph node metastasis (pN0; n = 75), pT stage (P = 0.043) and VEGFR-3 overexpression (P = 0.008) were independent predictors of reduced DSS.
  
  
  CONCLUSIONS
  Lymph-specific markers are frequently overexpressed in UCB. VEGF-D overexpression is associated with the presence of lymphatic metastasis. In patients without lymph node metastasis at the time of RC, an assessment of VEGFR-3 expression may improve the identification of high-risk patients. These findings require prospective validation to determine the potential benefit of more aggressive adjuvant treatment.
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Jost
authors.initials: J
authors.lastname: von Hardenberg
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Martini
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Knauer
authors.affiliation: Institute of Pathology, University Hospital, Göttingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Becker
authors.affiliation: Department of Urology, University Hospital, Münster, Germany.
authors.forename: Edwin
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schubert
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Steidler
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany. Electronic address: christian.bolenz@umm.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Bolenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D015653:Cystectomy / Q000379:methods; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D011379:Prognosis; D054400:Receptors, CCR7 / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; C515370:CCR7 protein, human; D054400:Receptors, CCR7; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Bladder cancer; Immunohistochemistry; Lymphangiogenesis; Lymphatic vessels; Prognosis; Vascular endothelial growth factors