ASCO GU 2022: Local Therapies for Variant Histology in Bladder Cancer

(UroToday.com) The 2022 GU ASCO Annual meeting included a session on the management of rare variants in genitourinary cancers and a presentation by Dr. Eila Skinner discussing the role of local therapy for the management of variant histology in bladder cancer. Dr. Skinner notes that the 2016 WHO guidelines list several potential histologic variants:

With regards to the current data of urothelial variant histologies, there are several problems:

• Pathology is in flux – many variants have only been recognized in the past decade or two
• Most data is from cystectomy series, few include pathology re-review, especially in the control group
• Poor correlation between TURBT and subsequent cystectomy – as low as 10-30% for micropapillary
• Population series (NCDB, SEER) are affected by pathology inaccuracy and a lack of detail

 There are also problems with pathology, including high inter-observer variability among pathologist. On retrospective review of 1,211 cystectomies, 33% diagnosed with conventional urothelial carcinoma had variant histology [1]. Dr. Skinner notes that there is general agreement regarding several aspects of management of bladder variant histologies:

1. Urothelial with squamous or glandular differentiation should be treated with the same as regular urothelial carcinoma, as there is mixed evidence whether outcomes are different
2. Most variants have higher stage at cystectomy and more node positive disease
3. Pure squamous and pure adenocarcinoma are generally treated with surgery alone, which may be amenable to partial cystectomy depending on the tumor location
4. Neuroendocrine tumors should be treated with chemotherapy first

In the Indiana University cystectomy series from 2008-2013 (n = 624), 26% of specimens were variant histology, which was associated with worse pathologic characteristics [2]:

Additionally, variant histology with micropapillary and plasmacytoid was significantly associated with worse survival on multivariable analysis. In a multi-institutional assessment of micropapillary disease at the time of cystectomy (n=151, 1980-2011), when compared to 1,346 pure urothelial carcinoma cases, there was less organ confined disease for micropapillary disease (27% vs 60%) and more node positive disease (50% vs 22%). However, micropapillary histology was not a significant predictor of outcome on multivariable analysis [3].

Is it possible to safely treat NMIBC with variant histology with BCG? Data from MD Anderson Cancer Center assessed 72 patients with <=T1 micropapillary variant histology, over which 40 received initial BCG. Overall 75% recurred, 45% progressed to clinical T2 disease, 6 developed cN+/M1 disease before chemotherapy, with a disease specific survival of 60%. In the Memorial Sloan Kettering Cancer Center experience of 36 patients with <=T1 micropapillary variant histology, 21 received initial BCG of which 38% recurred and 10% progressed to T2 disease. In a multi-institutional analysis of 119 patients with high-grade T1 disease with micropapillary histology, 32 patients underwent immediate cystectomy and 87 patients received initial BCG [4]. Of these patients, 30 had a repeat TURBT prior to BCG and 34 (40%) had delayed cystectomy. Predictors of progression included pure micropapillary disease versus mixed histology, as well as lymphovascular invasion. Importantly, there was no difference in cancer specific mortality when stratified by immediate cystectomy vs conservative treatment:

With regards to NMIBC with variant histology, the AUA guidelines recommend considering initial cystectomy. Furthermore, repeat TURBT is critical:

• For pure squamous/adenocarcinoma - if negative, consider observation or partial cystectomy if possible
• For the others, if re-TUR is negative or only Ta/CIS, consider BCG
• For neuroendocrine – usually these patients should be considered for systemic therapy + radiation/cystectomy even when non-muscle invasive

 Should we give neoadjuvant therapy before cystectomy for >=cT2 with variant histology? Dr. Skinner notes that the pros of neoadjuvant therapy are that these tumors are very likely to be upstaged and outcomes are poor with cystectomy alone. The cons of this approach are that we do not have proof of a survival benefit. The only survival benefit has been seen in neuroendocrine tumors, with a similar rate of downstaging similar to urothelial carcinoma, except for pure squamous cell carcinoma.

Trimodal therapy in the setting of variant histology has been assessed versus urothelial carcinoma in the Massachusetts General Hospital experience [5]. This included 66 variant histologies (excluding pure squamous cell carcinoma and adenocarcinoma) compared to 237 pure urothelial carcinoma patients. Importantly, there was no difference in RFS or OS compared to urothelial carcinoma. As follows is the Kaplan Meier curve for disease-specific survival:

Dr. Skinner concluded her presentation of local therapy for the management of variant histology bladder cancer with the following concluding statements:

• Upstaging at cystectomy is common
• Consider neoadjuvant chemotherapy except for pure squamous and adenocarcinoma
• The role of chemoradiation is still uncertain

Presented By: Eila C. Skinner, MD, Stanford University School of Medicine, Palo Alto, CA

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022

References:

1. Linder BJ, Boorjian SA, Cheville JC, et al. The impact of histological reclassification during pathology re-review—evidence of a Will Rogers effect in bladder cancer? J Urol 2013, Nov;190(5):1692-1696.
2. Monn MF, Kaimakliotis HZ, Pedrosa JA, et al. Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol 2015;33(1):18.e15-18.e20
3. Mitra AP, Fairey AS, Skinner EC, et al. Implications of micropapillary urothelial carcinoma variant on prognosis following radical cystectomy: A multi-institutional investigation. Urol Oncol. 2019 Jan;37(1):48-56.
4. Lonati C, Baumeister P, Afferi L, et al. Survival outcomes after immediate radical cystectomy versus conservative management with Bacillus Calmette-Guerin among T1 high-grade micropapillary bladder cancer patients: Results from a Multicentre Collaboration. Eur Urol Focus 2021 Aug 18;S2405-4569(21)00195-4.
5. Krasnow RE, Drumm M, Roberts HJ, et al. Clinical outcomes of patients with histologic variants of urothelial cancer treated with trimodality bladder-sparing therapy. Eur Urol. 2017 Jul;72(1):54-60.