JU INSIGHT Impact of Divergent Differentiation and Histological Subtype of Urothelial Carcinoma on Outcomes

By: Yves Allory, MD, PhD, Université Paris-Saclay, UVSQ, Institut Curie, Saint-Cloud, France, Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Paris, France; Stephane Culine, MD, PhD, Université de Paris Cité, AP-HP, Hôpital Saint-Louis, Paris, France; Clémentine Krucker, BSc, Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Paris, France; Jacqueline Fontugne, MD, PhD, Université Paris-Saclay, UVSQ, Institut Curie, Saint-Cloud, France, Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Paris, France; Valentin Harter, PhD, Centre François Baclesse, North-West Canceropole Data Center, Caen, France; Christian Pfister, MD, PhD, Université de Rouen Normandie, Inserm, CIC Inserm 1404, Onco-Urology, Hôpital Universitaire Charles Nicolle, Rouen, France | Posted on: 19 Apr 2024

Allory Y, Culine S, Krucker C, Fontugne J, Harter V, Pfister C. Impact of divergent differentiation and/or histological subtype of urothelial carcinoma on patient outcomes in the GETUG-AFU V05 VESPER trial. J Urol. 2024;211(4):564-574.

Study Need and Importance

Neoadjuvant cisplatin-containing combination chemotherapy (NAC) improves overall survival in patients with muscle-invasive bladder cancer. However, it remains unclear whether the presence of a variant histology (VH) or divergent differentiation (DD) impacts response and outcome after NAC, with a lack of large and prospective series with central pathological review to better estimate the clinical value of VH/DD.

What We Found

The multicenter randomized VESPER trial provided the opportunity to assess pathological response rate and progression-free survival (PFS) according to the presence of VH/DD on initial diagnostic transurethral resection of bladder tumor for 300 patients treated with NAC. VH/DD was identified in 177/300 patients (59%). When comparing presence of a VH/DD and pure urothelial carcinoma, no difference for complete pathological response, downstaging, and organ-confined disease rates, or for the PFS was evidenced. However, subgroup analyses showed an increased hazard of PFS for urothelial carcinoma with ≥ 50% squamous differentiation (HR adjusted: 2.11, 95% CI 1.01-4.38) or micropapillary subtype (HR adjusted: 2.03, 95% CI 0.98-4.22; Figure).

Figure. Progression-free survival according to presence or not of variant histology or divergent differentiation (VH/DD) with hazard ratios from Cox proportional hazard models adjusted from randomization arm (A) and Kaplan-Meier curves for pure urothelial carcinoma (UC) vs any VH/DD from 10% to 49% vs squamous divergence (sq. diff.) ≥ 50% vs micropapillary subtype (microp.) ≥ 50% (B).

Limitations

In our study, the frequency of VH/DD was significantly higher than reported in current practice, which can limit the generalizability of our conclusions. Additionally, pathological review of all cases was performed by 1 expert genitourinary pathologist, and interobserver variability may exist, including between experts. As the pathological review was based on a subset of representative slides selected by the primary pathologist, a selection bias cannot be ruled out.

Interpretation for Patient Care

In the neoadjuvant population of the VESPER trial, our post hoc analysis reported no evidence for association of the presence of VH/DD with pathological response rate or PFS. However, with a decreased PFS in patients with ≥ 50% squamous differentiation or ≥ 50% micropapillary subtype on diagnostic transurethral resection of bladder tumor, our results suggest considering for these patients more efficient systemic therapies than current cisplatin-based NAC.