title: Nuclear E-cadherin expression is associated with the loss of membranous E-cadherin, plasmacytoid differentiation and reduced overall survival in urothelial carcinoma of the bladder.
abstract: BACKGROUND
  Loss of E-cadherin represents a hallmark of plasmacytoid differentiation. We analyzed the effect of membranous E-cadherin loss and its nuclear accumulation in patients with locally advanced conventional urothelial carcinoma (UC) who were treated with radical cystectomy and adjuvant chemotherapy.
  
  
  METHODS
  A total of 247 formalin-fixed, paraffin-embedded tumor samples were reviewed to detect histological variants of UC. Immunohistochemical staining of E-cadherin was performed and analyzed for membranous and nuclear expression. The correlation between E-cadherin expression and histology was assessed, and overall survival (OS) was analyzed with univariate and multivariate Cox regression and Kaplan-Meier analyses. Correlation of nuclear E-cadherin to tumor stage (pT), lymph node metastasis (pN), histologic subtype, and chemotherapy was performed by Fisher's exact test.
  
  
  RESULTS
  Membranous and nuclear E-cadherin expression was strongly correlated to plasmacytoid urothelial carcinoma (PUC) (p < 0.001). Complete loss of membranous E-cadherin expression was observed in 76.2 % of PUCs, 11.1 % of conventional UCs, and 0 % of micropapillary urothelial carcinoma (MPCs). Nuclear accumulation was found in 47.6 % of PUCs, 10 % of MPCs, and 1.8 % of UCs. Sixty-two percent of all tumors with negative membranous E-cadherin expression and nuclear accumulation were PUCs (p = 0.035). In a Kaplan-Meier analysis, mean survival with nuclear E-cadherin expression was 31.9 months [95 % confidence interval (CI) 16.1-47.6] of patients without nuclear staining 61 months (95 % CI 53.5-67.7; p = 0.045). A univariate Cox regression analysis showed that nuclear E-cadherin accumulation was associated with a 2-fold increase in risk of death (95 % CI 1.03-4.06; p = 0.04). In multivariate Cox regression analysis adjusted to type of chemotherapy, tumor stage, and tumor grade, the hazard ratio for patients with nuclear E-cadherin was 2.03 (95 % CI 1.00-4.121; p = 0.050).
  
  
  CONCLUSIONS
  Nuclear E-cadherin is associated with PUCs and is suggested to be an independent prognostic factor in advanced UC.
authors.affiliation: Department of Urology, University Hospital Erlangen, Erlangen, Germany. bastian.keck@uk-erlangen.de
authors.forename: Bastian
authors.initials: B
authors.lastname: Keck
authors.forename: Sven
authors.initials: S
authors.lastname: Wach
authors.forename: Frank
authors.initials: F
authors.lastname: Kunath
authors.forename: Simone
authors.initials: S
authors.lastname: Bertz
authors.forename: Helge
authors.initials: H
authors.lastname: Taubert
authors.forename: Jan
authors.initials: J
authors.lastname: Lehmann
authors.forename: Michael
authors.initials: M
authors.lastname: Stöckle
authors.forename: Bernd
authors.initials: B
authors.lastname: Wullich
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D000328:Adult; D000368:Aged; D015820:Cadherins / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D015653:Cystectomy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D019459:Urothelium
chemical_list: D015820:Cadherins