Trends in the diagnosis of variant bladder cancer: a national retrospective cohort analysis

The diagnosis of variant bladder cancer (VBC) has significant clinical implications, yet remains a challenge for pathologists and clinicians. Our objective was to characterize the changes in VBC diagnosis over time using a national retrospective cohort.

The National Cancer Database was queried for all cases of pure urothelial and VBC using International Classification of Disease-O-3 morphologic codes from 2004 to 2021. The diagnosis of each type of VBC was trended from 2004 to 2021 to identify significant differences. This was performed in total and across varying facility types (community cancer program, academic program, comprehensive cancer program, and integrated network) with multivariable regression demonstrating significant associations with VBC diagnosis.

Between 2004 and 2021, 753,880 patients with pure urothelial carcinoma (UC) and 30,884 patients with VBC were identified. The diagnosis of VBC across all bladder cancer cases increased from 3.5% of cases in 2004-2009 (first tertile) to 4.3% of cases in 2016-2021 (third tertile) (p < 0.001), a relative 22.5% rise. This was concentrated in micropapillary subtype, sarcomatoid subtype, and neuroendocrine carcinoma (p < 0.001). Squamous differentiation did not demonstrate a significant change in diagnosis across time (p = 0.20). The increase in VBC diagnosis was noted across all facility types, including both community cancer facilities (3.0% of cases in 2004-2009 to 3.7% of cases in 2016-2021) and academic research facilities (4.4% of cases in 2004-2009 to 7.4% of cases in 2016-2021). Multivariable regression demonstrated a significant association between later year of diagnosis, black race, higher clinical stage, and facility type with diagnosis of VBC (p < 0.05).

Our findings suggest that the diagnosis of VBC is increasing nationally over time. The increase in diagnosis is among micropapillary, sarcomatoid, and neuroendocrine subtypes, and is occurring across comprehensive cancer and academic centers, reflecting the growing need for a centralized review.