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EAU 2018

EAU 2018: Does Variant Histology Change Management of Non-Invasive Bladder Cancer?

Copenhagen, Denmark (UroToday.com) This is one of a series of case-based debates. Each is set up as follows: 2 min case-presentation, 5-min discussant presentation (two sides of the debate, discussion), summary 2 minutes. This was a series arranged by Dr. Kamat, Dr. Grossman, and Dr. Stenzl.

Summary | Case Presentation: 56 year old male patient, 20 pack-year history (not active smoker), recurrent gross hematuria. Cystoscopy: 1 papillary tumor 4-5 cm in size.
Ultrasound: No evidence of upper tract disease
TURBT: 1 tumor photodynamic diagnosis (PDD)-positive, no flat lesions
Pathology: 1 pT1 tumor. Suspected variant, so sent out for 2nd opinion. Found to have macropapillary differentiation (no comment on percentage)

What now? Does the variant histology change your management?

Discussant 1: Ashish M. Kamat

In brief, Yes, it should!

Histologic variants matter:

  • Multitude of retrospective series have demonstrated worse outcomes
  • They have a higher propensity for locally advanced disease, greater proportion of LN metastases
  • Higher upstaging at RC than pure UC: HR 2.77
  • Demonstrated different response to different therapies: BCG, chemotherapy, radiotherapy
Kamat J. Urol 2006 – The Case of Early Cystectomy in Treatment of NMIBC

  • Patients treated with intravesical BCG: 
  • 89% recurred
  • 67% progressed (at a median of 8 months!) – very early
  • 22% to metastatic disease, Only 5 (of 27) were alive with bladder intact
  • Clearly these patients do poorly while treating with BCG
  • These patients have very poor survival after progression – 5 year DSS was 24%!
Kamat BJUI 2016 – They may be able to be risk stratified however.

  • 3 risk groups: Low risk: cT1, High risk: >= cT2, Highest risk: any T-stage with tumor-associated hydronephrosis
  • 5-year DSS was 92%, 51%, and 17%, respectively
He briefly addressed small cell carcinoma as well (neuroendocrine). While not the patient at hand, this variant has also been demonstrated to have worse outcomes. 

  • Has early, unique metastases to bone and brain
  • In MD Anderson experience (172 patients, only 6 were NMIBC) – upstaging to cT3+ or N+ on RC occurred in 50%
  • Patient receiving neoadjuvant chemotherapy did much better than those receiving adjuvant chemotherapy
He briefly alluded to the genomic classification that is being developed, with its implications on therapy. Specifically, many of these variants fall into specific molecular subtypes – and small cell actually is its own subtype (“Neuronal”). However, this is not ready for clinical practice!

Kamat et al, Curr Opin Urol, 2014 – reviewed current paradigm for dealing with variants.

  • For conventional UC, squamous differentiation or other variant – restaging TURBT. If no residual disease, BCG. If residual T1 or Tis, early cystectomy.
  • For micropapillary, sarcomatoid, plasmacytoid – early cystectomy
  • For small cell - neoadjuvant chemotherapy and early cystectomy
  • For pure squamous adenocarcinoma – early cystectomy
Discussant 2: D. McKonkey

He actually did not disagree with Dr. Kamat. But, his main point was that, while variants need to be treated differently, current pathologic grading schemes are insufficient to accurately identify all variants! Better selection needed, and that will be in the form of molecular grading.

Bladder cancer has both biologic and clinical heterogeneity, making management difficult.

Precision medicine requires precise measurements, but unfortunately, our current tools are not precise.

  • Calling variant histology is somewhat subjective, even amongst recognized GU pathologists
  • “Conventional” urothelial carcinomas also harbor variant biologic factors that are not recognized by conventional pathology
Variants have been associated with some of the established bladder cancer molecular subtypes:

  • Squamous, sarcomatoid, small cell  Basal subtype
  • Micropapillary, plasmacytoid  Luminal subtype
However, he demonstrated in a few studies that conventional UC specimens, without phenotypic evidence of variant histology, have demonstrated genetic changes similar to the variant histologies – which would suggest similar biologic behavior.

At this time, his conclusions are:

1) Continue to risk stratify based on clinical factors and pathology – treat variant histology different than pure UC patients
2) But, also perform WES and transcriptomic evaluation to see the heterogeneity more clearly
3) Objective measurements should trump subjective evaluation
4) Clinical trials will be key!

However, at this time, treatment options are primarily intravesical chemotherapy or radical cystectomy, favoring radical cystectomy. 


Presented by: M. Burger, Regensburg (DE)
Discussants: Ashish M. Kamat, MD Houston, TX and D. McConkey, Houston, TX


Written by: Thenappan Chandrasekar, MD Clinical Fellow, University of Toronto, twitter: @tchandra_uromd at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark