title: Does presence of squamous and glandular differentiation in urothelial carcinoma of the bladder at cystectomy portend poor prognosis? An intensive case-control analysis.
abstract: OBJECTIVE
  The prognostic significance of squamous and glandular elements, the most common histologic variants of urothelial carcinoma of the bladder (UCB), is unclear. This study aimed to examine the sole influence of squamous or glandular or both differentiation on UCB outcome following cystectomy and to identify factors that explain the relatively poor prognosis observed in UCB patients with these differentiation elements.
  
  
  METHODS
  A total of 2,444 patients who underwent radical cystectomy with extended lymph node dissection at a single referral center between 1976 and 2008 were considered. We identified 141, 97, and 21 patients with squamous, glandular, and squamous + glandular differentiation elements, respectively ("cases"). Pure UCB patients without differentiation were matched 1:1 to these cases for demographic, tumor, and treatment characteristics ("controls"). Cases were also compared with an independent cohort of 1,244 pure UCB controls. Recurrence-free and overall survivals were compared between cohorts using univariable and multivariable Cox proportional hazards analyses.
  
  
  RESULTS
  Median follow-up for cases, controls, and independent control cohort was 15.2, 11.0, and 12.2 years, respectively. Cases were matched to controls for pathologic stage (chi-square P = 1.00) and administration of intravesical agents (P≥0.85), neoadjuvant (P≥0.31), and adjuvant (P≥0.96) chemotherapy. Cases were also balanced with controls for age, gender, and race (P≥0.30). Following this intensive matching, no differences in outcomes between cases and controls were observed (log-rank P≥0.12). Pathologic stage was predictive of outcome in cases with differentiation by multivariable analysis (P≤0.004). When compared to an independent control cohort, cases with differentiation were observed to present with higher pathologic stage at cystectomy (chi-square P≤0.005).
  
  
  CONCLUSIONS
  Outcomes of UCB patients with squamous or glandular or both differentiation are similar to those of patients with pure UCB, given comparable demographic, clinicopathologic, and management characteristics. However, UCB with differentiation present with higher pathologic stage, thus explaining the aggressive clinical course in these patients.
authors.affiliation: Department of Pathology and Center for Personalized Medicine, University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA.
authors.forename: Anirban P
authors.initials: AP
authors.lastname: Mitra
authors.affiliation: Department of Urology, Johann Wolfgang Goethe University Hospital and Faculty of Medicine, Frankfurt, Germany.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Bartsch
authors.affiliation: Department of Urology, Johann Wolfgang Goethe University Hospital and Faculty of Medicine, Frankfurt, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Bartsch
authors.affiliation: Institute of Urology, University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA.
authors.forename: Gus
authors.initials: G
authors.lastname: Miranda
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Eila C
authors.initials: EC
authors.lastname: Skinner
authors.affiliation: Institute of Urology, University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA. Electronic address: daneshma@usc.edu.
authors.forename: Siamak
authors.initials: S
authors.lastname: Daneshmand
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000473:pathology / Q000601:surgery*; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D015653:Cystectomy / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology*; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000601:surgery*
keywords: Case-control studies; Pathology; Prognosis; Transitional cell carcinoma; Urinary bladder neoplasms