Variant histology muscle invasive bladder cancer should not preclude neoadjuvant chemotherapy before cystectomy

To expand our current understanding of muscle-invasive urothelial carcinoma (UC) with evidence of variant histology (VH) or divergent differentiation (DD), this post-hoc analysis takes a second look at data published in the GETUG-AFU V05 VESPER Trial. The VESPER trial concluded that dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC) therapy was associated with increased progression-free survival (PFS) at three years compared to gemcitabine-cisplatin (GC) chemotherapy in the administration of neoadjuvant chemotherapy (NAC) prior to cystectomy for muscle invasive UC (1); however, the initial publication did not comment on the presence of or response to treatment when tumor samples contain VH/DD. When stratified for this variable, the results of this new study showed that when compared to pure UC the presence of VH/DD does not alter that proportion of pathologic downstaging or PFS with NAC prior to cystectomy (2). Alternatively, a proportion of the samples were found to contain >50% of squamous cell subtype, and these subjects were associated with decreased PFS at three years when compared to pure UC (2). The same association was reported for >50% micropapillary subtype, however, this association was not statistically significant (2).

The results of this analysis are clinically relevant to the management of muscle-invasive UC. Current guidelines recommend NAC prior to cystectomy for patients with pure muscle invasive UC as it has been shown to improve PFS as established by studies such as the VESPER trial (1,3). However, with growing evidence to support a significant incidence of VH/DD in UC samples, recommendations pointed towards management of UC with VH/DD are lacking. National Comprehensive Cancer Network (NCCN) guidelines currently state that UC with squamous, adenocarcinoma, micropapillary, nested, plasmacytoid, and sarcomatoid has the potential to progress more aggressively than pure muscle-invasive UC (3). However, recommendations for alternative treatment strategies for these subtypes do not exist in the NCCN guidelines, instead stating that these subtypes are usually treated in a similar manner to pure UC (3). Similarly, American Urological Association guidelines for the treatment of non-metastatic muscle-invasive bladder cancer includes only a small note on the presence of VH. The guidelines endorse that, based on expert opinion, clinicians should consider deviation from standard evaluation and management in such cases of VH (4). Current European guidelines follow the same format, acknowledging the increase in identification and reporting of VH in invasive UC, and stating that the presence of these variants is relevant to both staging and treatment without offering evidence-based mainstays of treatment for clinicians to follow (5). Prior studies have included samples of UC with VH/DD in treatment outcomes, such as the NIAGARA Trial which compared outcomes of muscle invasive bladder cancer treated with durvalumab plus GC prior to cystectomy versus GC only prior to cystectomy (6). While the NIAGARA trial reported no difference in outcomes for UC with squamous or glandular histological subtypes (6), the trial was not designed to evaluate the presence of VH/DD as an independent variable. Based on new data introduced in the study produced by Allory et al., guidelines may stand to be updated to recommend standard treatment for muscle-invasive UC with or without VH/DD.

The results of this study are consistent with prior evidence. A meta-analysis of approximately 10,000 samples showed an overall survival and cancer-specific survival benefit of NAC prior to cystectomy in all samples of UC with VH/DD (7). A retrospective cohort of more than 30,000 patients has surveyed the response of UC with VH/DD to NAC prior to cystectomy compared to pure UC (8). When using pathological downstaging as a measure of treatment response, the use of NAC was associated with pathological downstaging in all treatment groups (8). The study also measured overall survival as a treatment outcome and found that NAC was not associated with overall survival for subgroups of micropapillary UC, squamous cell UC, and adenocarcinoma UC (8). The findings related to squamous and micropapillary subtypes are consistent with those published in this study. Though they reported no difference in response to standard treatment between pure UC and those with VH/DD, subgroup analysis showed that for samples with >50% of squamous cellularity, there was decreased PFS compared to pure UC (P=0.045) (2). Similarly, samples with >50% micropapillary also had a decreased PFS compared with pure UC, although these results were not statistically significant (P=0.07) (2). However, controversy exists regarding NAC for UC with VH/DD based on conflicting data (9). A decreased likelihood of complete pathological response as well as decreased mean cancer-specific survival for samples of UC with VH/DD has been noted in prior work (9). The variation in treatment response reported across studies is likely the reason why current guidelines have yet to make official recommendations. Importantly, it should also be noted that a variety of alternative treatments are also being investigated for the management of UC with VH/DD, including antibody-drug conjugates (ADCs). Early prospective studies have shown efficacy of enfortumab vedotin (EV) in the treatment of advanced UC (10). This same ADC has shown similar treatment response in metastatic UC with the presence of VH/DD when histology includes squamous, plasmacytoid, and sarcomatoid, but samples with >50% VH/DD demonstrated a limited response (10). The new data provided by Allory et al. is supportive to recommend NAC prior to cystectomy for UC with VH/DD, but as in the case with early studies of ADCs, it is unclear whether UC with high proportions of squamous cell or micropapillary carcinomas should receive this same therapy. Inevitably, when deciding on the use of NAC for cases of VH/DD, the proportion and subtype of disease matter.

The results of this post-hoc analysis provides valuable data supporting the argument for NAC prior to cystectomy in samples of VH/DD that have any proportion of the tumor composed of UC. Significant values support that patients with UC with VH/DD should undergo treatment according to guidelines outlined for pure UC, as response and PFS seem to be unaffected by the presence of VH/DD (2). In addition to the investigation of treatment measures for UC with >50% squamous or micropapillary subtype, the matter of pathologic classification was addressed in this study. Using a 10% threshold to identify the presence of VH/DD in tumor samples, it was found that 59% of samples contained evidence of VH/DD (2). Of these, only 25% had been previously reported before the study began. The need for central review of pathology in trials of UC with VH/DD is critical to the proper distribution of treatment arms and evaluation of outcomes. The discrepancy seen here highlights the inherent subjectivity of quantification of VH/DD. The use of genitourinary pathologists in the identification of VH/DD may be more effective than by non-expert pathologists and could thus increase the reproducibility of the data (11). The proposed use of artificial intelligence (AI) in this arena should not be overlooked, specifically the emergence of computational pathology (CPATH) for bladder cancer. Early outcomes claim to observe greater than 80% accuracy when CPATH was used to inform disease survivability based on tumor grade, stage, and tissue type (12). Further studies proving the usefulness of CPATH compared to expert pathologist review of VH/DD in UC is necessary to inform next steps.

While additional data to support these claims will be beneficial for the implementation of new guidelines, the data here is an invaluable addition to what was previously known about UC with VH/DD.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-80/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-80/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Pfister C, Gravis G, Fléchon A, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40:2013-22. [Crossref] [PubMed]
2. Allory Y, Culine S, Krucker C, et al. Impact of Divergent Differentiation and/or Histological Subtype of Urothelial Carcinoma on Patient Outcomes in the GETUG-AFU V05 VESPER Trial. J Urol 2024;211:564-74. [Crossref] [PubMed]
3. National Comprehensive Cancer Network. Treatment by cancer type. 2024 Jun [cited 2025 Jan 30]. Available online: https://www.nccn.org/guidelines/category_1
4. Holzbeierlein J, Bixler BR, Buckley DI, et al. Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/SUO Guideline (2017; Amended 2020, 2024). J Urol 2024;212:3-10. [Crossref] [PubMed]
5. Witjes JA, Bruins HM, Cathomas R, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol 2021;79:82-104. [Crossref] [PubMed]
6. Powles T, Catto JWF, Galsky MD, et al. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. N Engl J Med 2024;391:1773-86. [Crossref] [PubMed]
7. Zhu Z, Xiao Y, Hu S, et al. Neoadjuvant and Adjuvant Chemotherapy for Variant Histology Bladder Cancers: A Systematic Review and Meta-Analysis. Front Oncol 2022;12:907454. [Crossref] [PubMed]
8. Chakiryan NH, Jiang DD, Gillis KA, et al. Pathological Downstaging and Survival Outcomes Associated with Neoadjuvant Chemotherapy for Variant Histology Muscle Invasive Bladder Cancer. J Urol 2021;206:924-32. [Crossref] [PubMed]
9. Catarino R, Alves L, Pereira D, et al. Neoadjuvant chemotherapy for muscle-invasive bladder cancer: does variant histology matter? Int Urol Nephrol 2022;54:3163-9. [Crossref] [PubMed]
10. Zarrabi KK, Saxena A, Mouw KW, et al. Unmet Potential of Antibody-Drug Conjugates: An Evaluation of the Past, Present, and Future of Antibody-Drug Conjugate Development in Advanced Urothelial Carcinoma. Am Soc Clin Oncol Educ Book 2025;45:e471924. [Crossref] [PubMed]
11. Shah RB, Montgomery JS, Montie JE, et al. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital. Urol Oncol 2013;31:1650-5. [Crossref] [PubMed]
12. Khoraminia F, Fuster S, Kanwal N, et al. Artificial Intelligence in Digital Pathology for Bladder Cancer: Hype or Hope? A Systematic Review. Cancers (Basel) 2023;15:4518. [Crossref] [PubMed]