Mitotic activity index and CD25+ lymphocytes predict risk of stage progression in non-muscle invasive bladder cancer

PLoS One. 2020 Jun 2;15(6):e0233676. doi: 10.1371/journal.pone.0233676. eCollection 2020.

Abstract

In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high‑risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (≤ 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Transitional Cell / genetics
  • Carcinoma, Transitional Cell / immunology
  • Carcinoma, Transitional Cell / pathology*
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Kaplan-Meier Estimate
  • Ki-67 Antigen / metabolism
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Male
  • Middle Aged
  • Mitotic Index*
  • Neoplasm Recurrence, Local / diagnosis*
  • Neoplasm Recurrence, Local / epidemiology
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / immunology
  • Neoplasm Staging
  • Prognosis
  • Reproducibility of Results
  • Urinary Bladder / pathology
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / immunology
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / pathology*

Substances

  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Ki-67 Antigen

Grants and funding

The author(s) received no specific funding for this work. Jan Baak AS did not provide support in the form of salaries for authors and did not have any additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.