title: Loss of SPINK1 expression is associated with unfavorable outcomes in urothelial carcinoma of the bladder after radical cystectomy.
abstract: BACKGROUND
  We assessed the association of serine protease inhibitor Kazal type I (SPINK1) expression with clinicopathologic outcomes in urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC).
  
  
  METHODS
  Tissue microarrays comprising 438 consecutive UCB patients treated with RC between 1988 and 2003 and 62 cases of normal urothelium controls were evaluated for SPINK1 protein expression by immunohistochemistry (IHC). Semiquantitative evaluation was performed by 2 pathologists blinded to clinical outcomes (loss of expression: <50% cells or intensity 0-2).
  
  
  RESULTS
  In normal urothelium, SPINK1 expression was noted in umbrella cells of 32 of 62 controls (52%); 254 RC patients (57.9%) exhibited loss of SPINK1 expression. Loss of SPINK1 expression was significantly associated with higher pathologic stages (P = 0.002) and presence of lymph node metastasis (P = 0.04). At a median follow-up of 130 months (IQR: 98.4), loss of SPINK1 expression was associated with an increased risk of disease recurrence (P = 0.02) and cancer-specific mortality (P = 0.03). On multivariable analysis that adjusted for the effects of standard clinicopathologic parameters, SPINK1 was not an independent predictor of disease recurrence (P = 0.09) or cancer-specific mortality (P = 0.12).
  
  
  CONCLUSIONS
  Over half of UCB patients treated with RC exhibit loss of SPINK1 expression. Loss of SPINK1 correlates with features of biologically aggressive UCB. Although SPINK1 expression did not have independent prognostic value in RC patients, it may serve as a biomarker for tumor staging and may be useful as an adjunct in clinical decision-making.
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York, NY10065, USA; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rink
authors.forename: Kyung
authors.initials: K
authors.lastname: Park
authors.forename: Björn G
authors.initials: BG
authors.lastname: Volkmer
authors.forename: Evanguelos
authors.initials: E
authors.lastname: Xylinas
authors.forename: Jens
authors.initials: J
authors.lastname: Hansen
authors.forename: Eugene K
authors.initials: EK
authors.lastname: Cha
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.forename: Richard
authors.initials: R
authors.lastname: Hautmann
authors.forename: Rainer
authors.initials: R
authors.lastname: Küfer
authors.forename: Oliver
authors.initials: O
authors.lastname: Engel
authors.forename: Felix K
authors.initials: FK
authors.lastname: Chun
authors.forename: Roland
authors.initials: R
authors.lastname: Dahlem
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Mosquera
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000473:pathology / Q000601:surgery*; D002352:Carrier Proteins / Q000096:biosynthesis*; D015653:Cystectomy / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D012307:Risk Factors; D046888:Tissue Array Analysis / Q000706:statistics & numerical data; D016896:Treatment Outcome; D014359:Trypsin Inhibitor, Kazal Pancreatic; D001749:Urinary Bladder Neoplasms / Q000473:pathology / Q000601:surgery*
chemical_list: D002352:Carrier Proteins; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic