The tumor microenvironment (TME) in non–muscle-invasive bladder cancer (NMIBC) plays an important role in the anticancer response. We aimed to identify the prognostic biomarkers in the TME of patients with NMIBC for progression to ≥T2. From our institutional database, 40 patients with T1 high-risk NMIBC who progressed were pair matched for Club Urologico Español de Tratamiento Oncologico (CUETO) progression variables with 80 patients who never progressed despite longer follow-up. Progression was defined as ≥T2 or extravesical disease. Patients were treated at least with bacillus Calmette-Guérin (BCG) induction (five or more of six doses). Immunohistochemical (IHC) markers for the TME were used on tissue at first T1 diagnosis: CD8-PanCK, GZMB-CD8-FOXP3, CD163, PD-L1 SP142/SP263, fibroblast activation protein-α (FAP), and CK5-GATA3. Full tissue slides were annotated digitally. Relative marker area (IHC-positive area/total area) or density (IHC-positive cells per area; n/mm²) was calculated, differentiating between regions of interest (ROIs; T1, Ta, and carcinoma in situ) and between compartments (stromal, epithelial, and combined). Differences in IHC variables were assessed using the t test, for continuous variables using analysis of variance and comparisons of more than two groups using Tukey’s test. Conditional logistic regression for progression at 5-yr follow-up was performed with clusters based on pair matching. Only FAP expression (increase per 50%) in T1 (odds ratio [OR]: 1.33; 95% confidence interval [CI]: 1.04–1.70) and all ROIs combined (OR: 1.62; 95% CI: 1.14–2.29) correlated significantly with progression. None of the other clinicopathological/IHC variables correlated with progression. FAP is a potential prognostic biomarker for progression in high-risk NMIBC. FAP is a marker for cancer-associated fibroblasts and is linked to immunosuppression and neoangiogenesis, which makes future investigation clinically relevant. We found that progression of high-risk non–muscle-invasive bladder cancer to muscle-invasive disease is less in patients with lower fibroblast activation protein-α (FAP) expression, which is a marker for cancer-associated fibroblasts.

Background: Survival in patients with urothelial cancer (UC) recurrence after initial treatment with curative intent is limited and treatment options are sparse. Metastasectomy could be considered a treatment option in selected cases. Identifying prognostic factors for survival can be used to counsel patients and aid multidisciplinary teams in making treatment decisions. Methods: We collected a retrospective case series of patients undergoing metastasectomy for oligometastatic UC between 1999 and 2018 at University Hospitals Leuven. Oligometastatic UC was defined as recurrence of UC in a single organ with ≤3 metastases. Survival outcomes of interest were: overall survival (OS), cancer-specific survival (CSS), and secondary recurrence-free survival (RFS2). Complications were reported using the Clavien-Dindo classification (CDC). Survival analysis are descriptive and were performed using Kaplan-Meier plots to visualize survival data and log-rank was used to compare survival between groups. Results: From 1999 to 2018, a total of 22 patients underwent metastasectomy of oligometastatic UC. Metastasectomy sites were: pulmonary (59.1%), loco-regional (13.6%), hepatic (9.1%), adrenal (4.5%), testicular (4.5%), nodal above aortic bifurcation (4.5%), and renal transplant (4.5%). The 5-year OS, CSS and RFS2 after metastasectomy were 51.4%, 57.0%, and 49.9%, respectively. Patients with primary upper tract urothelial cancer (UTUC) involvement and patients treated with hepatic metastasectomy had a significantly worse OS, CSS, and RFS2. Patients with a lesion size >8 mm and patients with >1 pulmonary lesion had a significantly worse CSS. Two CDC grade 3B occurred during follow-up and were both non-procedure related. Conclusions: Metastasectomy of oligometastatic UC is feasible and can achieve durable cancer control in a highly selected subgroup of patients. Our results suggest that patients with hepatic metastases or primary UTUC involvement could be considered poor candidates for metastasectomy, while patients with a small (<8 mm) or solitary pulmonary lesion might benefit most. These findings should be validated in multi-institutional collaborations or prospective clinical studies.