Wednesday, August 13, 2014

Non-Urothelial Bladder Cancer: A Primer in 2 Parts (Part 2: Urothelial Variants)

Part 2 Urothelial Variant Histologies


Background Highlights: Historically sarcomatoid carcinoma and carcinosarcoma were thought to be two distinct phenotypes; however this aggressive histology is now considered to be under the same umbrella with mesenchymal origins.
Management Notes: Due to the aggressive nature of this subtype, there is no role for intravesical therapy at any stage. Many patients go directly to cystectomy, though it's not currently known whether neoadjuvant chemotherapy is appropriate in this population. This is a group where intraoperative radiation therapy (IORT) may provide benefit, extrapolating from current principles in sarcoma surgery. [7]

Squamous Differentiation

Background Highlights: This is perhaps the most common histological variant, affecting at least 16-20% of bladder cancer patients. New research has connected squamous differentiation to a distinct "basal" bladder cancer subtype that is more aggressive [8]. These patients have p63 upregulation at presentation.
Management Notes: While much is still being discovered with regards to the squamous "basal" subtype, currently most clinicians would treat this histological variant similar to urothelial cancer with intravesical BCG for non-muscle invasive disease and pre-operative chemotherapy in muscle invasive disease.


Background Highlights: Micropapillary urothelial carcinoma is another aggressive histologic variant, closely resembling serous carcinoma of the ovary. It is likely underdiagnosed, and portains a worse prognosis.
Management Notes: There is good data to support early cystectomy, and forgo intravesical treatments in early stage micropapillary bladder cancer [9]. Recently, new research has identified a link between the micropapillary histologic variant and the ERBB2 (HER2) genetic mutation. [10] This is significant because the HER2 mutation is associated with worse prognosis [11]; however, there are current drugs available that target the HER2 receptor, and therefore there is newfound hope that patients with HER2 mutations may benefit from early identification and treatment.

Click here to read our previous blog entry on Micropapillary Urothelial Cancer for more details.

Unanswered Questions:
If the current research momentum continues, this blog entry will be dated within a few years. Histologic variants will ultimately give way to molecular and genetic variants for which targeted therapies will be developed and delilvered. At Johns Hopkins and at other similar minded institutions this is the ultimate objective in treating each bladder cancer singularly and comprehensively.

Click here to read Part 1: Non-Urothelial Bladder Cancer

This blog was written by Max Kates, MD, a URO-2 resident at the Brady Urological Institute at Johns Hopkins.

[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Scosyrev E, Yao J, Messing E: Urothelial carcinoma versus squamous cell carcinoma of bladder: is survival different with stage adjustment?. Urology 2009; 73: 822.
[3] Zaghloul MS, Awwad HK, Akoush HH et al: Postoperative radiotherapy of carcinoma in bilharzial bladder: improved disease free survival through improving local control. Int J Radiat Oncol Biol Phys 1992; 23: 511
[4] Cheng L, Jones TD, McCarthy RP et al: Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma. Am J Pathol 2005; 166: 1533.
[5] Siefker-Radtke AO, Dinney CP, Abrahams NA et al: Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M. D. Anderson cancer experience. J Urol 2004; 172: 481.
[6] Siefker-Radtke AO, Kamat AM, Grossman HB et al: Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin in small-cell urothelial cancer. J Clin Oncol 2009; 27: 2592.
[7] Moningi S, Armour EP, Terezakis SA et al: High-dose-rate intraoperative radiation therapy: the nuts and bolts of starting a program. J Contemp Brachytherapy 2014; 6: 99.
[8] Choi W, Porten S, Kim S et al: Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014; 25: 152.
[9] Kamat AM, Gee JR, Dinney CP et al: The case for early cystectomy in the treatment of nonmuscle invasive micropapillary bladder carcinoma. J Urol 2006; 175: 881.
[10] Ross JS, Wang K, Gay LM et al: A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res 2014; 20: 68.
[11] Schneider SA, Sukov WR, Frank I et al: Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome. Mod Pathol 2014; 27: 758.


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