A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma

Abstract

Background: One third of patients with stage T1 urothelial carcinoma (UC) progress to muscle-invasive disease requiring radical surgery. Thus, reliable tools are needed for risk stratification of stage T1 UC.

Objective: To investigate the extent to which stratification of stage T1 tumours into previously described molecular pathologic UC subtypes can provide improved information on tumour progression.

Design, setting, and participants: A population-based cohort of 167 primary stage T1 UCs was characterised by immunohistochemistry and classified into the molecular subtypes urobasal (Uro, 32%), genomically unstable (GU, 58%), and squamous-cell-carcinoma-like (SCCL, 10%).

Outcome measurements and statistical analysis: Progression-free survival using univariate and multivariate models.

Results and limitations: Subtype classification was validated using nine additional markers with known subtype-specific expression. Analysis of mRNA expression of progression biomarkers revealed a strong association with molecular subtype. Kaplan-Meier analyses showed that the risk of progression was low for Uro tumours and high for GU/SCCL tumours. High progression risk scores were found only for GU/SCCL tumours. Clinical risk factors such as multifocality, concomitant carcinoma in situ, invasion depth, lymphovascular invasion, and high CD3(+) lymphocyte infiltration were observed almost exclusively in GU/SCCL cases.

Conclusions: Molecular subtypes Uro, GU, and SCCL were identified in an independent population-based cohort of stage T1 UCs. Biomarkers and clinical risk factors for progression were associated with molecular subtype. Rapidly progressing T1 tumours were of subtype GU or SCCL and had either a high progression risk score or an elevated CD3(+) cell count.

Patient summary: We show that classification of stage T1 urothelial carcinoma into molecular subtypes can improve the identification of patients with progressing tumours.

Keywords: Bladder cancer; High risk; Molecular classification; Outcome; Prognosis; Stage T1.