What Is the Prognostic and Clinical Importance of Urothelial and Nonurothelial Histological Variants of Bladder Cancer in Predicting Oncological Outcomes in Patients with Muscle-invasive and Metastatic Bladder Cancer? A European Association of Urology Muscle Invasive and Metastatic Bladder Cancer Guidelines Panel Systematic Review

CONTEXT: Variant histology of muscle-invasive (MIBC) and metastatic (mBC) bladder cancer may define the cancer treatment modality and oncological outcomes. OBJECTIVE: To determine the prognostic effect and impact of therapy of urothelial and nonurothelial histological variants on the oncological outcomes of MIBC and mBC. EVIDENCE ACQUISITION: Medline, Embase, Cochrane controlled trial databases, and ClinicalTrials.gov were systematically searched. Patients with histological variants of MIBC or/and mBC from prospective and retrospective comparative studies and single-arm case series published after the year of 2000 were included. Treatment outcomes (overall, recurrence-free, and disease-specific survival) were extracted and reported. Risk of bias (RoB) assessment was performed using Quality in Prognosis Studies tool. EVIDENCE SYNTHESIS: The search yielded 2450 unique articles, of which 41 articles involving a total of 27 672 patients with histological variants were included. Twenty-eight studies had a comparative study design. Two different study settings were seen: large database studies without centralised pathological review and small series with re-review by uropathologists. Although most of the histological variants show similar oncological outcomes after radical cystectomy (RC), signet ring cell, spindle cell, and neuroendocrine tumours showed inferior survival compared with pure urothelial bladder cancer (PUC). Owing to potential misleading interpretations and reporting as well as large heterogeneity between studies, a narrative synthesis approach instead of subgroup analyses was used. Most studies had a moderate RoB. CONCLUSIONS: The data about prognosis and treatment of the variant histology are still immature and assessed mostly in cystectomy patients. Based on this systematic review, all patients with MIBC should be treated with RC. Neoadjuvant chemotherapy may be beneficial for patients with micropapillary, plasmacytoid, sarcomatoid, and mixed variants, and especially for patients with neuroendocrine tumours. Metastatic bladder cancer should be treated as PUC. PATIENT SUMMARY: In this report, we looked at the prognosis and treatment of different bladder cancer histologies. We found that outcomes varied with divergent histologies and appropriate treatment should be based on the histological finding.