Background: Preclinical studies suggest that signal transducer and activator of transcription 3 (STAT3)-mediated recruitment of neutrophils to premetastatic tissue occurs prior to metastatic progression.
Objective: We sought to determine if neutrophilic infiltration in benign nodal tissue is associated with poor clinical outcome in patients with muscle-invasive bladder cancer.
Design, setting, and participants: Formalin-fixed, paraffin-embedded tissue was secured from 55 patients with muscle-invasive bladder cancer who had undergone cystectomy at our institution. Sections of benign lymph nodes were obtained and stained with primary antibodies against 3-fucosyl-N-acetyl-lactosamine, phosphorylated STAT3, and interleukin-17, the latter being a key mediator of neutrophil infiltration and STAT3 activation.
Outcome measurements and statistical analysis: The Kaplan-Meier method was used to interrogate differences in overall survival (OS) in patients with high versus low biomarker expression. Cohorts stratified by receipt and nonreceipt of neoadjuvant chemotherapy were separately explored.
Results and limitations: Of the 55 patients examined, 19 patients (35%) had no prior neoadjuvant chemotherapy. Amongst these patients, median OS was improved in patients with low 3-fucosyl-N-acetyl-lactosamine+ cell counts (196 mo vs 37 mo; p=0.0062) and low phosphorylated STAT3+ cell counts (278 mo vs 106 mo; p=0.025). In the same cohort, a trend towards improved OS in patients with low interleukin-17+ cell count was observed (not reached vs 117 mo; p=0.18). No differences in OS were noted in biomarker-based subgroups amongst patients that had received prior neoadjuvant chemotherapy.
Conclusions: The results herein support the hypothesis that bladder cancer metastasis may be driven by STAT3-mediated neutrophilic infiltration in premetastatic sites. Validation of these findings using tissues derived from a phase 3 surgical trial (Southwest Oncology Group 1011) is currently underway.
Patient summary: Lymph node metastases occur in up to 25% of patients with muscle-invasive cancer and it represents one of the most frequent sites of bladder cancer metastasis. This report provides preliminary evidence that neutrophil levels in benign lymph nodes may predict clinical outcome.
Keywords: Bladder cancer; Immune; Muscle invasive; Neutrophil; Premetastatic niche.
Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.