Introduction:

Variant histology in bladder urothelial carcinoma is found in ~30% of cases, and is associated with higher incidence of locally advanced disease and occult regional lymph node metastasis.  Neoadjuvant chemotherapy (NAC) is the gold-standard treatment of resectable cT2-4 disease and has been shown to achieve pathologic complete response in select patients at the time of radical cystectomy (RC). Post-hoc analysis of a landmark randomized trial has demonstrated preserved chemosensitivity and even pT0 status in the setting of variant histology. While there is much interest in the role of bladder preservation for such patients, the observation of pT0N+ pathology in patients who undergo subsequent RC has prompted concerns about this approach. How variant histology impacts pathologic downstaging after NAC has not yet been widely explored.

Methods:

A retrospective cohort analysis of 5,335 cT2-4N0M0 patients who underwent NAC and RC between 2004 and 2016 was performed using the National Cancer Database (NCDB). These patients were stratified by histological type into pure urothelial cell carcinoma (UCC) and variant groups (i.e. squamous, glandular, micropapillary, etc) using the WHO ICD-O classification. The rate of pathologic downstaging to ≤pT1 was analyzed, along with concomitant persistent pN+ status. In addition, overall survival was analyzed using Kaplan-Meier estimation and multivariable Cox-proportional hazards regression, stratified by histology type. Multivariable models were adjusted for confounding demographic and clinicopathologic variables.

Results:

We found that 7.9% of cases contained variant histology while 92.1% were pure UCC.  Pure UCC was associated with significantly better unadjusted survival with a 5-year survival rate of 48.8% compared to 38.5% in the variant (p<0.001). After adjusting, UCC was associated with significantly decreased mortality hazard relative to variant histology (aHR=0.75; p<0.001). UCC had lower adjusted odds of being pN+ (aOR=0.60, p<0.001), specifically pN2 (aOR=0.57) and pN3 (aOR=0.40). Furthermore, node-positive variant histology patients demonstrated higher node positive count compared to pure UCC (median 3 vs 2 nodes, p<0.001).  

Regarding pathologic downstaging rates between pure UCC and variant histology there was no detected significant difference in pT0, partial downstaging to pTis, pTa, or pT1, or any pT downstaging after NAC. Of those that were downstaged to pT0 but upstaged to pN+, the incidence was twice as common in the variant group, but did not reach statistical significance (p=0.190; Table). 

Conclusion:

Our study showed that the propensity for distant spread undoubtedly contributed to significantly worse survival outcomes in the variant histology group. Patients with variant histology were more likely to harbor occult regional lymph node metastasis in the setting of intravesical pathologic complete response (pT0). Therefore, RC with thorough pelvic lymph node dissection remains the gold-standard for surgical consolidation after NAC especially in cases of variant histology.

Funding: N/A