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Scoring the percentage of Ki67 positive nuclei is superior to mitotic count and the mitosis marker phosphohistone H3 (PHH3) in terms of differentiating flat lesions of the bladder mucosa
  1. Sven Gunia1,
  2. Christoph Kakies2,
  3. Andreas Erbersdobler2,
  4. Stefan Koch1,
  5. Matthias May3
  1. 1Department of Pathology, HELIOS Clinic Bad Saarow, Bad Saarow, Germany
  2. 2Department of Pathology, University of Rostock, Rostock, Germany
  3. 3Department of Urology, St. Elisabeth Clinic Straubing, Straubing, Germany
  1. Correspondence to Sven Gunia, Institute of Pathology, HELIOS Clinic Bad Saarow, Charité-University Medicine Academic Teaching Hospital, Pieskower Street 33, Bad Saarow 15526, Germany; sven.gunia{at}


Aims To systematically compare different approaches for evaluating mucosal proliferative activity regarding their diagnostic role for delineating flat lesions of the bladder mucosa.

Methods 32 carcinoma in situ (CIS) and 31 flat non-CIS conditions (low-grade dysplasia and reactive atypia) of the bladder mucosa were assessed by two independent pathologists in two rounds in terms of their proliferative activity assessed by the mitotic counts on H&E-stained sections (mitoses per mm2) and immunohistochemically using the MIB-1 antibody and the mitosis marker phosphohistone H3 (PHH3). Two different approaches for immunoscoring (percentage of stained nuclei vs dichotomised height of mucosal staining considering lower half vs full-thickness marker expression) were applied. κ statistics were used to evaluate interobserver and intraobserver reproducibility.

Results Scoring the percentage of Ki67 expressing cell nuclei seems to be superior to dichotomisation of the height of mucosal staining as well as to PHH3 immunostaining and conventional mitotic counts in terms of delineating CIS from flat non-CIS conditions. This approach shows substantial (κ=0.62–0.65; p<0.001) interobserver and substantial to almost perfect (κ=0.67–0.83; p<0.001) intraobserver reproducibility.

Conclusions The MIB-1 antibody is a useful adjunct in the differential diagnosis of conventionally challenging flat lesions of the bladder mucosa. In particular, 16% or more Ki67 positive cell nuclei favours CIS over flat non-CIS conditions, whereas 15% or less Ki67 positive cell nuclei is supportive of non-CIS conditions. However, due to some important limitations of MIB-1 staining, the MIB-1 antibody should be used as a component of a panel.

  • Flat lesions of the bladder mucosa
  • mucosal proliferative activity
  • immunohistochemistry
  • MIB-1 antibody
  • mitosis marker phosphohistone H3
  • conventional mitotic counts
  • bladder
  • cancer
  • histopathology

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  • Competing interests None.

  • Patient consent Archivated paraffin-embedded tissues were assessed and the patient identification was kept anonymous.

  • Ethics approval The ethics approval was provided by IRB approval for the present study and was obtained from the Medical Ethics Committee of the federal state Brandenburg (LÄKB) and has been assigned the reference number 28981/2011.

  • Provenance and peer review Not commissioned; externally peer reviewed.