Abstract
OBJECTIVE: To assess whether the distribution of concomitant carcinoma in situ (CIS; unifocal or multifocal) with papillary non-muscle-invasive bladder cancer (NMIBC) impacts the risk of progression, as concomitant CIS is an established risk factor for progression in papillary NMIBC and commonly used calculators do not make this distinction. PATIENTS AND METHODS: In this multi-institutional retrospective cohort study from both academic and community hospitals, clinicopathological data were collected from patients with pTa/pT1 NMIBC treated from 2005 to 2022. Unifocal concomitant CIS was defined as CIS present in only one specimen (i.e., papillary disease with CIS at the tumour base or isolated CIS in one specimen). Multifocal concomitant CIS was characterised by CIS in multiple specimens. Progression was defined as the development of muscle-invasive or metastatic disease. Fine-Gray regression was performed to identify progression-associated factors, using all-cause mortality as a competing risk. RESULTS: Among 2923 patients, 383 (13%) progressed over a median (interquartile range) follow-up of 5.1 (3.0-8.5) years. Concomitant CIS was found in 327 patients (11%), with 233 and 94 harbouring unifocal and multifocal CIS, respectively. Recurrent tumours, T1 stage, high-grade disease, multifocal CIS, and multiple tumours were independently associated with increased progression risk (all P < 0.05). Among patients with concomitant CIS, multifocal CIS remained a significant prognosticator (sub-distribution hazard ratio 1.90, 95% confidence interval 1.18-3.05; P = 0.008) adjusting for age, sex, tumour history, stage, grade, number of tumours, tumour diameter, and Bacillus Calmette-Guérin treatment. CONCLUSIONS: Papillary NMIBC progression risk varies with concomitant CIS distribution. Only multifocal concomitant CIS is a risk factor for progression in patients with T1 NMIBC. If validated in further studies, risk calculators should consider including this CIS distinction. Submitting separate specimens at the time of transurethral resection, as recommended by guidelines, should be encouraged.