Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy

Urol Oncol. 2020 Apr;38(4):262-268. doi: 10.1016/j.urolonc.2019.11.004. Epub 2019 Dec 4.


Purpose: Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort.

Materials and methods: A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like.

Results: We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery.

Conclusions: The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.

Keywords: Bladder cancer; Gene expression analysis; Molecular subtypes; Neuroendocrine; Urothelial carcinoma.

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoadjuvant Therapy / methods*
  • Reproducibility of Results
  • Treatment Outcome
  • Urinary Bladder Neoplasms / drug therapy*


  • Antineoplastic Agents
  • Cisplatin