A great challenge in the management of high-grade nonmuscle-invasive bladder cancer (NMIBC) is the detection of disease recurrence and progression following induction bacillus Calmette-Guerin (BCG) therapy. Moreover, predicting disease responsiveness to BCG has remained elusive. Current gold standard follow-up involves regular cystoscopic evaluation with visual inspection for disease recurrence. Although cystoscopy is associated with minimal morbidity, it remains invasive, and detection of recurrence is surgeon dependent.
Given the limitations of cystoscopy, a multitude of complementary tests (urine cytology, fluorescence in situ hybridization, cytokine and genetic profiling) have been investigated as potential biomarkers to predict NMIBC responsiveness, recurrence, and progression. Unfortunately, a sensitive and specific biomarker for NMIBC has not been discovered.
Our understanding of NMIBC biomarkers and BCG therapy has relied on the historical dogma that urine is sterile. However, recent advances in microbial detection have greatly expanded our knowledge of bacterial communities within the human body. Using enhanced culture techniques and DNA sequencing technology, live bacteria and bacterial DNA have been identified in urine samples deemed “culture negative” using standard clinical microbiology techniques (J Clin Microbiol 2012; 50:1376-83). Initial investigations in female patients supported the hypothesis that certain bacterial communities provide protection and that disruption of these communities may cause lower urinary tract symptoms (MBio 2014; 5:e01283–14). Subsequent investigation led to similar findings in men, with increased bacterial detection in more symptomatic patients (Eur Urol Focus Aug 21, 2018 [Epub ahead of print]).
Links between microbiome, disease
These relationships between microbes and symptoms have led to considerable excitement about the potential for previously uncharacterized relationships between the urinary microbiome and other urologic diseases, including bladder cancer.
The role of microorganisms as carcinogens is widely understood in the gastrointestinal tract. Infection and chronic gastric inflammation associated with Helicobactor pylori is a strong risk factor for gastric malignancy and esophageal adenocarcinoma. Moreover, dysbiosis of the colonic microbiome has been implicated in development of colorectal cancers.
In the genitourinary system, schistosomiasis and recurrent urinary tract infection are known factors in the development of squamous cell carcinoma of the bladder. However, interactions between microbes and the development of urothelial cell carcinoma (UCC) have not been characterized. It is feasible that urinary tract dysbiosis may influence the development of malignancy, and recent urinary microbiome investigations have paved the way for an exciting new area of bladder cancer research (Urology 2019; 126:10-5).
While investigation into the association of the urinary microbiome and NMIBC is in its infancy, initial studies have associated patients at high risk for UCC pathogenesis and progression with enrichment of certain bacterial communities (Front Cell Infect Microbiol 2018; 8:167). Unfortunately, the studies to date on this topic have been limited by their design, with all being case control studies with heterogeneous patient populations and small sample sizes.
Despite the limitations of these studies, their findings have exciting implications. There is a significant need for noninvasive biomarkers to predict the clinical course of UCC, and the possibility of using the urinary microbiome for risk stratification is highly intriguing. Further investigation of the relationship between the urinary microbiome and UCC may also shed light on pathophysiologic mechanisms and assessing response to therapy (figure).