EAU 2024: Initial Staging in Bladder Cancer: Histologic Subtype, Molecular Phenotype, and Biomarkers Are Enough

(UroToday.com) The 2024 European Association of Urology (EAU) annual congress held in Paris, France between April 5th and 8th was host to a plenary session addressing imaging-related controversies for the staging of genitourinary cancers. Professor Eva Comperat discussed why histological variants, molecular phenotype, and biomarkers are enough for the characterizing bladder tumors.


The current International Collaboration of Cancer Reporting (ICCR) currently recommends that the following histologic variables be reported for all bladder cancer tumors:

  • Resections: Sample size and percentage of tumor
  • Tumor size (cystectomies)
  • Tumor subtype
  • Presence/absence of non-invasive carcinoma
  • Tumor grade (low versus high)
  • Microscopic extension
  • Lymphovascular invasion
  • Surgical margins
  • Regional lymph node involvement (N+/-; capsule extension +/-; size)
  • Co-existent pathology (e.g., carcinoma in situ [CIS])
  • Ancillary studies
  • pTNM (year)

Why do histologic subtypes matter in bladder cancer? First, it is important to note that subtypes are more common with muscle-invasive disease, compared to non-muscle invasive bladder cancer. Subtypes matter for:

  • Diagnostic considerations
  • Prognostic and therapeutic implications
  • Consideration for upfront cystectomy for some subtypes

The histologic subtypes with the most aggressive clinical patterns are:

  • Micropapillary
  • Plasmacytoid
  • Giant cell
  • Sarcomatoid
  • Poorly differentiated

Numerous studies have consistently demonstrated that patients with variant histology urothelial carcinoma of the bladder have worse prognoses compared to patients with pure urothelial carcinoma of the bladder. As summarized in the Kaplan Meier curves below, patients with variant histology had worse recurrence-free and cancer-specific survivals following radical cystectomy (without neoadjuvant chemotherapy), compared to patients with pure urothelial carcinoma.1
A 2017 analysis of the National Cancer Database has similarly demonstrated that for patients with muscle-invasive bladder cancer undergoing a radical cystectomy between 2003 and 2011, the presence of squamous cell carcinoma (HR: 1.26; 95% CI: 1.07 – 1.49; p=0.006) and neuroendocrine (HR: 1.53; 95% CI: 1.21 – 1.95; p<0.001) types were associated with worse overall survival outcomes, compared to pure urothelial carcinoma.2
Professor Comperat argued that current histologic diagnostic reporting standards can be qualified as ‘precision’ medicine given that uro-pathologists already report all items which are needed for treating patients. Are there additional strategies that could be used to further risk stratify patients and guide treatment decision-making? 

In 2020, Kamoun et al. used 1,750 muscle invasive bladder cancer transcriptomic profiles from 16 published datasets and two additional cohorts to reach a consensus on molecular subtypes for muscle invasive bladder cancer. They identified a consensus set of six molecular classes:

  • Luminal papillary (24%)
  • Luminal non-specified (8%)
  • Luminal unstable (15%)
  • Stroma-rich (15%)
  • Basal/squamous (35%)
  • Neuroendocrine-like (3%).

These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including clinical outcomes. Patients with luminal papillary (median overall survival: 4 years) and stroma-rich muscle-invasive disease (3.8 years) have the best survival outcomes, whereas patients with basal/squamous (1.2 years) and neuroendocrine-like subtypes (1 year) have the worst prognoses.3  
In addition to being prognostic biomarkers, these molecular subtypes have been proposed as predictive biomarkers for response to neoadjuvant chemotherapy. It has been demonstrated that patients with genomically unstable and urothelial-like tumors have higher proportions of complete pathological response following neoadjuvant chemotherapy and radical cystectomy (52% and 31%), compared to 21% for the basal/squamous subtype.4  genomically unstable and urothelial-like tumors have higher proportions of complete pathological response following neoadjuvant chemotherapy and radical cystectomy (52% and 31%), compared to 21% for the basal/squamous subtypegenomically unstable and urothelial-like tumors have higher proportions of complete pathological response following neoadjuvant chemotherapy and radical cystectomy (52% and 31%), compared to 21% for the basal/squamous subtype 2
This molecular subtyping can be further used to guide specific treatment. It has been demonstrated that 16/17 (94%) patients with pure large nested variant of urothelial carcinoma are FGRG3 mutated. Conversely, only 1/7 patients with mixed tumors had FGFR3 mutations. This has important treatment implications as it suggests that patients with pure variants are more likely to benefit from treatment with erdafitinib, a pan-FGFR inhibitor.56/17 (94%) patients with pure large nested variant of urothelial carcinoma are FGRG3 mutated. Conversely, only 1/7 patients with mixed tumors had FGFR3 mutations. This has important treatment implications as it suggests that patients with pure variants are more likely to benefit from treatment with erdafitinib, a pan-FGFR inhibitor
Interestingly, it appears that molecular subtypes demonstrate tropism for different organs (i.e., different patterns of metastatic spread). In a 2024 analysis of 146 patients with de novo metastatic disease or recurrence following curative treatment, Sjodahl and colleagues observed the following:

  • Significant depletion of bone metastases in the Basal/squamous molecular subtype
  • Enrichment for bone metastases in the urothelial-like subtype
  • Genomically unstable subtype was depleted of lung metastases, but enriched for atypical sites, including six out of seven patients with brain metastases.
  • Stroma-rich primary tumor samples were associated with local recurrence, but not with distant sites.

The investigators concluded that molecular subtypes of urothelial bladder cancer are significantly associated with specific metastatic sites, suggesting that subtype-specific molecular determinants could exist at various steps in the metastatic cascade.6

What current biomarkers are available in clinical practice?

  • Urinary cytology
  • Commercially available urine tests
    • Example: Xpert® Bladder Cancer Monitor, Cxbladder
    • Cytokines, telomeres
    • Urinary molecular markers
  • Low serum albumin
  • Tissue-based biomarkers (example: PD-L1, HER2)
  • Genetic mutations (FGFR, HER2)
  • Liquid biopsies (results depend on age, prior treatment, etc.)

Professor Comperat’s take-home messages were as follows:

  • Histology reports using the current reporting standards are normally sufficient to guide current treatment decision-making
  • Urothelial carcinoma is defined by morphology and/or molecular class
    • Probably both   knowledge is increasing in this space
  • How should we deal with partial/multiple subtypes?
    • Treat the predominant subtype/variant or the most aggressive one? We do not currently know.
  • Not all problems have been resolved, but knowledge in this space is increasing.

Presented by: Professor Eva Comperat, MD, PhD, Chair of Uropathology at the Medical University of Vienna and Head of the Department of Pathology at the L'Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Sorbonne University, Paris, France

Written by: Rashid Sayyid, MD, MSc - Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 European Association of Urology (EAU) annual congress, Paris, France, April 5th - April 8th, 2024

References:
  1. Soave A, Schmidt S, Dahlem R, et al. Does the extent of variant histology affect oncological outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy? Urol Oncol. 2015;33(1): 21.e1-21.e9.
  2. Vetterlein MW, Seisen T, Leow JJ, et al. Effect of Nonurothelial Histologic Variants on the Outcomes of Radical Cystectomy for Nonmetastatic Muscle-invasive Urinary Bladder Cancer. Clin Genitourin Cancer. 2017;S1558-7673(17)30248-3.
  3. Kamoun A, de Reynies A, Allory Y, et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2020;77(4): 420-433.
  4. Sjodahl G, Abrahamsson J, Holmsten K, et al. Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes. Eur Urol. 2022;81(5): 523-532.
  5. Weyerer V, Eckstein M, Comperat E, et al. Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype. Cancers (Basel). 2020;12(3): 763.
  6. Sjodahl G, Eriksson P, Holmsten K, et al. Metastasis and recurrence patterns in the molecular subtypes of urothelial bladder cancer. Int J Cancer. 2024;154(1): 180-190.