S-phase – an independent prognostic marker in upper tract urothelial carcinoma

Abstract

Objectives

To evaluate S-phase fraction as a predictor of invasiveness and cancer-specific survival in upper tract urothelial carcinoma (UTUC).

Patients and methods

One hundred and fifteen patients having undergone radical nephroureterectomy were analysed with histology in radical nephroureterectomy specimens as reference test and S-phase fraction as index test. Ploidy and S-phase were determined using flow cytometry. Differences in S-phase fraction were calculated between stages, grades (WHO 1999 and 2004 classifications), ploidy and patients that died of UTUC and those who did not. Five- and 10-year-cancer-specific survivals were calculated. Areas under the ROC curve (AUCs) of S-phase fraction in relation to tumour stage and to death from UTUC were measured. Multiple Cox regression was performed.

Results

Independent prognostic markers of death from UTUC were S-phase fraction and stage. Correlation between S-phase fraction and risk of dying from UTUC was strong, with a 17% greater risk of death from UTUC with every 1% increase in S-phase fraction, hazard ratio = 1.17, 95% CI = 1.10–1.25, p < 0.001, Spearman’s rho ρ = 0.65. AUCs for S-phase fraction as predictors of stage and death from UTUC were 0.8 (95% CI = 0.705–0.894) and 0.77 (95% CI = 0.67–0.87), respectively. Cancer-specific survival was statistically significantly different between stages, ploidy and WHO 1999 grades, but not between WHO 2004 grades. This was also reflected in S-phase fraction, which differed in LG-G1 compared with LG-G2 and in HG-G2 compared with HG-G3.

Conclusion

S-phase fraction was a good test for predicting both invasiveness and cancer-specific survival. Using both WHO 1999 and 2004 classifications, rather than one system alone, had a higher predictive value of cancer-specific survival.

Keywords:

• Urothelial carcinoma
• upper urinary tract
• cancer-specific survival
• cell proliferation
• diagnostic test
• S-phase fraction

Geolocation information

The authors and the patient cohorts are located in Stockholm, Sweden.

Author contributions

C. Malm: project development, data collection and management, data analysis, manuscript writing. G. Jaremko: data collection, histopathology analysis, manuscript editing. M. Brehmer: project development, data collection and manuscript editing.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Regional Board of Ethics and was conducted in line with the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all individuals participating in the study.

Additional information

Funding

This study was supported by the Foundation in Memory of Johanna Hagstrand and Sigfrid Linnér (Stiftelsen Johanna Hagstrand och Sigfrid Linnérs Minne) (MB) and statistical analyses were performeddone in close cooperation with statistician Fredrik Johansson