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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

  • Erik Veskimäe,
  • Estefania Linares Espinos,
  • Harman Maxim Bruins,
  • Yuhong Yuan,
  • Richard Sylvester,
  • Ashish M. Kamat,
  • Sharokh F. Shariat,
  • J. Alfred Witjes,
  • Eva M. Compérat

Publication: European Urology Oncology, Volume 2, Issue 6, Pages 625-642


Variant histology of muscle-invasive (MIBC) and metastatic (mBC) bladder cancer may define the cancer treatment modality and oncological outcomes.


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.


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.

Expert's summary

By Dr. Moschini

Urothelial carcinoma is the most frequent histology considering bladder cancer tumors, however, approximately 20-40% of patients are diagnosed with histological variants. Presence of variants histology represent an important element which might drive diagnostic and therapeutic decisions. Authors of this systematic review evaluated the prognostic effect and the impact of therapy on urothelial and non urothelial histological variants on oncological outcomes in patients affected by muscle invasive and metastatic bladder cancer. In their search they selected 41 articles involving a total of 27672 patients with histological variants. Most of the patients diagnosed with histological variants had similar oncological outcomes after radical cystectomy, although patients diagnosed with signet ring cell, spindle cell and neuroendocrine tumors showed inferior survival outcomes compared to pure urothelial carcinoma. Authors also highlighted that neoadjuvant chemotherapy might be beneficial in patients affected by micropapillary, plasmacytoid, sarcomatoid, mixed variants and especially for neuroendocrine tumors. Regarding metastatic bladder cancer, not enough evidence suggests treating it in a different fashion than a normal urothelial metastatic cancer. 

Expert's comment

This review highlights the poor quality of evidences at this time in the literature regarding this topic. In an era of personalized medicine, we need to evaluate all the available information regarding patients pathology in order to improve outcomes. Molecular analyses of the tumor might help to improve patients selection and to individuate best responders to chemotherapy and patients who might be treated with immunotherapy.