Development and Validation of an Improved Pathological Nodal Staging System for Urothelial Carcinoma of the Bladder

Current pathological nodal staging for bladder cancer is based on lymph node (LN) location but not on the number of positive LNs.

We sought to improve prognostic classification by creating a novel staging system incorporating positive LN burden.

We sampled 12515 patients with muscle-invasive bladder cancer (MIBC) from the National Cancer Database (NCDB) and 5928 MIBC patients from the Surveillance, Epidemiology, and End Results (SEER) database for our development and validation cohorts, respectively.

Multivariable Cox proportional hazards analysis with restricted cubic splines was used to assess the association between the number of metastatic LNs and overall mortality (OM). A novel staging system was derived by recursive partitioning analysis (RPA) in NCDB and was validated in SEER by assessing discrimination (Harrel's c-index) and calibration (mean absolute prediction error).

Mortality risk increased continuously with more metastatic LNs; the effect was most pronounced up to four LNs (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.12-1.22) and attenuated beyond four nodes (HR 1.03, 95% CI 1.02-1.05). RPA generated a novel staging system predicting mortality by metastatic nodal number with cutpoints at zero (reference), one (HR 1.57, 95% CI 1.46-1.69), two to three (HR 2.03, 95% CI 1.88-2.19), four to seven (HR 2.46, 95% CI 2.25-2.70), and more than seven (HR 3.83, 95% CI 3.38-4.33) positive LNs. Location of LN involvement was not a significant predictor of OM. In external validation, the novel staging system showed good risk discrimination (optimism corrected c-index 0.677, 95% CI 0.672-0.682) and calibration (mean absolute prediction error 0.011 for 5-yr OM). Results are limited by development and validation using secondary data.

The number of metastatic LNs predicts mortality better than LN location and may improve pathological nodal staging in MIBC.

This retrospective study found that the number of metastatic lymph nodes more accurately predicts survival than the location of metastatic lymph nodes in patients with muscle-invasive bladder cancer. This finding argues for change to the current bladder cancer staging system.