title: Prognostic comparison of proliferation markers and World Health Organization 1973/2004 grades in urothelial carcinomas of the urinary bladder.
abstract: European treatment guidelines of non-muscle-invasive urothelial carcinoma of the urinary bladder are strongly dependent on grade, but grading reproducibility is wanting. Protocolized proliferation features such as Mitotic Activity Index (MAI), Ki-67, and phosphohistone H3 are prognostic and reproducible. The objective of this population-based study was to compare proliferation biomarkers with each other and with World Health Organization (WHO) 1973/2004 grades with regard to prediction of stage progression. A total of 193 primary non-muscle-invasive urothelial carcinomas were analyzed using WHO73/04 grades and measurement of the proliferation markers mentioned above. Sensitivities, specificities, and positive and negative predictive values with confidence intervals (CIs) were estimated with regard to progression prediction. Kaplan-Meier survival curves were made, and the hazard ratio and Harrell's C-index with 95% CIs, P values, and adjusted C-index for stage progression or not of WHO73, WHO04, and the proliferation markers were calculated. The median follow-up time was 75 months (range, 1-127). A total of 111 patients (52%) experienced recurrence within 5 years, and 14 patients (7%) progressed. High values of MAI predicted stage progression with a positive predictive value of 0.22 (95% CI, 0.12-0.37). The positive predictive value of Ki-67 and phosphohistone H3 were 0.15 (both 95% CIs, 0.07-0.29) and comparable to that of the WHO04. The prognostic value of MAI was strongest, exceeding that of the other proliferation markers and the WHO grading systems. In conclusion, in non-muscle-invasive urinary bladder urothelial carcinomas, proliferation biomarkers have prognostic value, possibly exceeding that of the WHO classifications.
authors.affiliation: Department of Pathology, Stavanger University Hospital, 4068 Stavanger, Norway; Clinical Institute-1, Medical Odontology Faculty, University in Bergen, 5020 Bergen, Norway. Electronic address: okmangrud@hotmail.com.
authors.forename: Ok Målfrid
authors.initials: OM
authors.lastname: Mangrud
authors.affiliation: Department of Pathology, Stavanger University Hospital, 4068 Stavanger, Norway.
authors.forename: Einar
authors.initials: E
authors.lastname: Gudlaugsson
authors.affiliation: Department of Pathology, Stavanger University Hospital, 4068 Stavanger, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Skaland
authors.affiliation: Department of Urology, Stavanger University Hospital, 4068 Stavanger, Norway.
authors.forename: Ilker
authors.initials: I
authors.lastname: Tasdemir
authors.affiliation: Department of Research, Stavanger University Hospital, 4068 Stavanger, Norway.
authors.forename: Ingvild
authors.initials: I
authors.lastname: Dalen
authors.affiliation: Department of Pathology, Stavanger University Hospital, 4068 Stavanger, Norway.
authors.forename: Bianca
authors.initials: B
authors.lastname: van Diermen
authors.affiliation: Department of Pathology, Stavanger University Hospital, 4068 Stavanger, Norway; Clinical Institute-1, Medical Odontology Faculty, University in Bergen, 5020 Bergen, Norway.
authors.forename: Jan P A
authors.initials: JP
authors.lastname: Baak
authors.affiliation: Department of Pathology, Stavanger University Hospital, 4068 Stavanger, Norway.
authors.forename: Emiel A M
authors.initials: EA
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002295:Carcinoma, Transitional Cell / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D019459:Urothelium / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor
keywords: Grading; Prognostic value; Reproducibility; Urinary bladder; Urothelial carcinoma