Urinary tract infections and risk of squamous cell carcinoma bladder cancer: A Danish nationwide case-control study

Schistosoma haematobium infection can lead to squamous cell carcinomas (SCC) of the bladder. Whether this also applies to more common urinary tract infections (UTIs) is unclear. We therefore aimed to investigate the association between UTIs, reflected by the use of specific antibiotics and risk of SCC of the bladder. We conducted a Danish nationwide case-control study and identified histologically verified bladder cancer cases (2000-2015; n = 12,271) and age- and sex-matched cancer-free controls. We computed odds ratios (ORs) with 95% confidence intervals (CI) associating the use of UTI-specific antibiotics with SCC bladder cancer, using conditional logistic regression. We applied a 2-year lag-time to minimize reverse causation. To aid interpretation, similar analyses were performed for other bladder cancer types and other antibiotics. We identified 333 SCC cases (2.7% of all bladder cancers). Compared to no use (0-1 prescription), high-use (≥10 prescriptions) of UTI-specific antibiotics was associated with SCC with an OR of 11.4 (CI 7.6-17.2) and a clear dose-response pattern (p_trend < 0.001). Use of phenoxymethylpenicillin, an antibiotic not used against UTIs, was not associated with SCC after adjustment for use of UTI-specific antibiotics (OR 0.5). Furthermore, UTI-specific antibiotic use was not associated with urothelial carcinomas (n = 11,029; OR 1.13; CI 0.97-1.32). Excluding patients with known urogenital disease did not influence the SCC estimates (overall OR 10.8; CI 6.2-18.9). Data on smoking were lacking, however, a quantitative bias analysis suggested this to be of limited importance. In conclusion, common UTIs are strong, dose-dependent and specifically associated with risk of SCC of the bladder.