EAU 2024: Rapid Fire Debate 3: Healthy Patient with T1HG Micropapillary NMIBC - What Is the Best Treatment Option? What If Mixed Histologic Subtypes in Addition to Micropapillary?

(UroToday.com) The 2024 European Association of Urology (EAU) annual congress held in Paris, France was host to a plenary session addressing imaging-related controversies for the staging of genitourinary cancers. Professors Paolo Gontero, Benjamin Pradere, and Ashish Kamat participated in a rapid-fire debate discussing the optimal management of a healthy patient with T1HG micropapillary non-muscle invasive bladder cancer (NMIBC).

Professor Gontero presented a case of a 57-year-old moderately obese male with an excellent performance status (ECOG 0) with known comorbidities including non-insulin-dependent diabetes and mild COPD, who presented with an episode of gross hematuria in January 2017. His cystoscopy demonstrated a solitary 3.5 cm papillary tumor, with CT demonstrating an absence of hydronephrosis, extravesical extension, or other locoregional disease otherwise. His TURBT was macroscopically complete. On pathology, there was evidence of a solitary high-grade T1 lesion with detrusor muscle present and not involved. Notably, he had mixed divergent differentiation with 10% micropapillary subtype.

At that time, the patient was recommended for radical cystectomy plus bilateral pelvic lymph node dissection; however, he refused radical intervention and the TUR specimen was sent for a re-review. This confirmed the presence of a micropapillary subtype in 10% of the specimen, but also additionally demonstrated a plasmacytoid subtype in 5% of the tissue. He underwent a repeat TURBT that was negative, including scar resection + mapping biopsies.

What is the optimal therapy in this situation? Professor Pradere proceeded to argue in favor of intravesical therapy as the best option in this setting, whereas Professor Kamat argued in favor of upfront radical cystectomy.

What is the evidence for upfront radical cystectomy versus bladder preserving strategies in these patients? The majority of the evidence originates from small, single center studies that, to date, have demonstrated contradicting results. A 2014 report from the Memorial Sloan Kettering Cancer Center of 36 patients with T1 micropapillary disease demonstrated that there was no difference in 5 year cancer-specific survival outcomes between the two modalities (81% versus 76%).¹ However, a report from the MD Anderson Cancer Center of 72 patients demonstrated that the outcomes appear to be significantly better for patients who underwent upfront radical cystectomy (5-year cancer-specific survival: 100%), compared to those who underwent a delayed cystectomy (5-year cancer-specific survival: 62%).²

This debate is further complicated by 2016 data from the National Cancer Database that demonstrates that among 166 patients with cT1 disease, patients who opt for bladder preserving strategies have superior outcomes to those undergoing a radical cystectomy. A follow-up report published in 2022 demonstrates non-significant differences in 5-year overall survival in favor of patients treated with bladder-preserving therapy (53% versus 44%, p=0.14).³

It is clear that patients with cT1 disease who harbor micropapillary disease have significantly worse pathologic outcomes compared to those who have pure urothelial histology, with a higher risk of under-staged disease at the time of TURBT. However, the 5-year overall survival outcomes of patients with cT1 micropapillary disease are similar to those with cT1 urothelial carcinoma of the bladder, with 5-year overall survival of 58–60%. This highlights the importance of re-staging TURBT, pre-operative MRI, expert pathology, and possibly the incorporation of FDG-PET for staging, where appropriate, to maximize survival outcomes for these patients.

In a multicenter, retrospective analysis of 119 patients with high grade T1 micropapillary disease, Lonati et al. demonstrated that cancer-specific and overall survivals did not significantly differ between patients treated with immediate radical cystectomy versus conservative management (p=0.5), despite conservatively-treated patients having higher rates of disease recurrence and progression.⁴

He concluded his presentation by noting the following:

• 10% of high-risk NMIBC patients have lethal disease and should be considered for upfront radical cystectomy. However, many are suitable for bladder preservation.
• The prognosis of variant micropapillary urothelial carcinoma is worse than that of pure urothelial carcinoma
  • In select patients with HG T1 disease, it is reasonable to propose a bladder sparing strategy
• Patients with micropapillary disease have high rates of disease progression, pathologic nodal involvement, and disease understaging
  • When bladder preservation is proposed, closer follow-up is recommended
  • The role of imaging, including MRI and FGD-PET, may be important at diagnosis and follow-up
  • Pathologist assessment remains critical
• In the future, we need histomorphology recognition of micropapillary urothelial carcinoma using artificial intelligence tools and an analysis of HER2 status and the luminal molecular subtype for potential targeted therapeutic strategies
• Prioritize bladder preservation, when possible, without compromising oncologic outcomes
  • Use risk stratification to propose the best strategy

Next, Professor Kamat argued in favor of upfront radical cystectomy for patients with micropapillary HG T1 disease. He began by noting that the question on hand here is: do histologic variants matter in non-muscle invasive bladder cancer? Professor Kamat’s case for early cystectomy for the management of such patients dates back to 2006 when he published the MD Anderson Cancer Center experience on the treatment of patients with non-muscle invasive micropapillary disease. In this cohort of 27 patients managed with intravesical BCG, 89% of patients recurred and, notably, 67% progressed at a median of 8 months. Notably, 22% of patients developed metastatic disease, and only five were alive with an intact bladder at final analysis.⁴

The updated report published in 2015, previously referenced by Professor Pradere,² demonstrated that upfront cystectomy (n=36) was associated with superior survival outcomes compared to primary BCG.

Worrisomely, patients who underwent deferred cystectomy following disease progression to muscle invasiveness had a 5-year disease-specific survival of only 24%.²

What is the risk of metastases with primary BCG for patients with micropapillary bladder cancer? In the 2015 MD Anderson Cancer Center series, the risk was 27%. Conversely, this risk was demonstrated to be 34% and 85% in the MSKCC and the Cleveland Clinic Foundation series, respectively. Given that the odds in Russian Roulette are 1 in 6 (16%), Professor Kamat argued that managing such patients with primary BCG puts our patients at a significantly high risk.

Another important aspect of the case presentation is that this patient was found to have 5% plasmacytoid variant on the pathology re-review. It has long been established that these patients have adverse outcomes, irrespective of the primary therapy offered.

These patients also progress and recur in an unusual pattern, including peritoneal carcinomatosis (45%), bowel lesions (26%), and bone (26%).⁵ Accordingly, he argued that such patients are probably best served by a targeted neoadjuvant approach, as opposed to upfront radical cystectomy or intravesical therapy.

He concluded by noting that current guidelines support his stance and recommend consideration of early cystectomy in patients with evidence of sarcomatoid, plasmacytoid, or micropapillary NMIBC.

• Paolo Gontero, MD, Chairman Department of Urology, Molinette Hospital, University School of Medicine, Torino, Italy
• Benjamin Pradere, MD, MSc, Attending Urologist, Clinique La Croix du Sud, Quint Fonsegrives, France
• Ashish M. Kamat, MD, MBBS, Endowed Professor of Urologic Oncology (Surgery) and Cancer Research, Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX

1. Spaliviero M, Dalbagni G, Bochner BH, et al. Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol. 2014;192(3): 702-7.
2. Willis DL, Fernandez MI, Dickstein RJ, et al. Clinical outcomes of cT1 micropapillary bladder cancer. J Urol. 2015;193(4): 1129-34.
3. Dursun F, Elshabrawy A, Wang H, et al. Histological variants of non–muscle invasive bladder cancer: Survival outcomes of radical cystectomy vs. bladder preservation therapy. Urol Oncol. 2022;40(6): 275.e1-275.e10.
4. Lonati C, Baumeister P, Afferi L, et al. Survival Outcomes After Immediate Radical Cystectomy Versus Conservative Management with Bacillus Calmette-Guérin Among T1 High-grade Micropapillary Bladder Cancer Patients: Results from a Multicentre Collaboration. Eur Urol Focus. 2022;8(5): 1270-1277.
5. Kamat AM, Gee JR, Dinney CPN, et al. The case for early cystectomy in the treatment of nonmuscle invasive micropapillary bladder carcinoma. J Urol. 2006;175(3 Pt 1): 881-5.
6. Sood A, Rudzinski JK, Labbate CV, et al. Long-Term Oncological Outcomes in Patients Diagnosed With Nonmetastatic Plasmacytoid Variant of Bladder Cancer: A 20-Year University of Texas MD Anderson Cancer Center Experience. J Urol. 2024;211(2): 241-255.