Micropapillary Bladder Cancer: I Have It, Now What Does it Mean?

More than 75k people in the United States are diagnosed with bladder cancer on an annual basis and its estimated that >500k people in the US are living with the disease.[1,2]  Greater than 90% of bladder cancers are urothelial cancer (UC; of the lining of the bladder); and 75% of UC are non-muscle invasive or growing out of the lining of bladder.  There are rare variants of UC including nested, microcystic, inverted, squamous and glandular differentiation, sarcomatoid, clear cell and micropapillary variants.

Micropapillary is currently the most well-studied, independent histology.  Although rare relative to the large number of patients with undifferentiated, conventional UC, micropapillary cancer still affects a significant proportion of patients.  Here we will review the definitions and implications of micropapillary bladder cancer for those patients with a new diagnosis.

Epidemiology and Statistics [3]

• 0.7-2.2% of all UC are micropapillary
• Average age at diagnosis: 65
• Male-to-female ratio  10:1

Histology and Pathology [4-8]

• Micropapillary tumors grow in delicate filiform processes in infiltrating clusters lacking vascular stalks (see images from WebPathology.com)
• Vascular and lymphatic invasion is common.
• 80% cases found with conventional UC

• The amount of micropapillary cancer does not have bearing on outcomes; outcomes are consistent if 10% or greater of the tumor contains micropapillary cancer
• Less than 9% have non-muscle invasive disease; 70% will progress to invasive disease.
• At cystectomy for non-muscle invasive disease:
• >50% can be upstaged
• >25% had occult lymph node metastases
• 50% present as muscle-invasive, node-positive or metastatic disease

Treatment and Outcomes

Retrospective studies show an overall worse prognosis for micropapillary cancer when compared to conventional UC of the bladder.[9-10]  However, micropapillary cancer often presents at and advanced stage and two case-matched series did not show a survival difference between micropapillary and conventional UC when matched stage-for-stage.[11,12]  

It is clear that micropapillary urothelial cancer is an aggressive variant of bladder cancer; it is unclear if it is independently worse than conventional urothelial cancer.

In general, surgical removal of the bladder (radical cystectomy) is the most effective treatment for micropapillary cancer.  Rare cures are achieved with transurethral resection if non-invasive cancer and complete resection is achieved; although BCG treatments are ineffective if tumors are incompletely resected.[8,13]   

In a few studies, neoadjuvant chemotherapy (NAC; chemotherapy before cystectomy) does not appear to be effective for micropapillary cancer.[8,14]  In the initial report of micropapillary cancer from MD Anderson Cancer Center demonstrated a 5-year survival of 71% for those undergoing immediate cystectomy and 63% for those receiving NAC before surgery.[8]  However, the data regarding the use of NAC is sparse and other centers have reported beneficial outcomes with NAC.  For instance, Meeks et al demonstrated 45% downstaging from transurethral resection to cystectomy and a significant survival advantage to patients downstaged to pT0 (no residual cancer in the bladder) with NAC.[15]  Ghonheim and colleagues argue for the use of NAC citing an 86% rate of micrometastatic lymph node metastases.

Therefore, the use of neoadjuvant chemotherapy remains controversial - with some centers advocating its use and some centers believing that neoadjuvant chemotherapy may actually worsen survival by delaying therapy.   

Survival Statistics for Micropapillary Cancer of the Bladder

All Patients [11,12,16]

• Overall Recurrence-Free Survival: 58% at 5 years
• Local Recurrence-Free Survival: 62% at 10 years
• Distant Metastases-Free Survival: 44% at 10 years
• Cancer-Specific Survival: 31% at 10 years
• Overall Survival: 40-67% at 5 years, 21% at 10 years

Non-Muscle Invasive Micropapillary Bladder Cancer

BCG failure: 67% progressed, of which 22% developed metastases

Immediate Cystectomy: 72% alive at 5-years

Cystectomy after Intravesical Treatment: 60% alive at 5-years

Muscle-Invasive Micropapillary Bladder Cancer

Immediate Cystectomy: 70% alive at 5-years

If pT0 (no cancer at found at cystectomy) or carcinoma-in-situ (CIS): no deaths at 38 months

If Locally Advanced Cancer: 22% alive at 4 years

If Non-Organ Confined Disease: 38.1 months median survival

If Non-Resectable Disease: 17 month median survival

1. American Cancer Society, Facts & Figures 2014; Accessed March 21, 2014.  http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf
2. Surveillance, Epidemiology, and End Results (SEER) Stat Fact Sheets: Bladder Cancer; Accessed March, 21, 2014.  http://seer.cancer.gov/statfacts/html/urinb.html  
3. Amin MB, Ro JY, el-Sharkawy T,et al: Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol 1994; 18: 1224-1232.
4. Johansson SL, Borghede G, Holmang S,et al: Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol 1999; 161: 1798-1802.
5. Kamat AM, Dinney CP, Gee JR,et al: Micropapillary bladder cancer: a review of the University of Texas M.D. Anderson Cancer Center experience with 100 consecutive patients. Cancer 2007; 110: 62-67.
6. Lopez-Beltran A, Cheng L: Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol 2006; 37: 1371-1388.
7. Johansson SL, Borghede G, Holmang S,et al: Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol 1999; 161: 1798-1802.
8. Kamat AM, Dinney CP, Gee JR,et al: Micropapillary bladder cancer: a review of the University of Texas M.D. Anderson Cancer Center experience with 100 consecutive patients. Cancer 2007; 110: 62-67.
9. Comperat E, Roupret M, Yaxley J, et al. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases. Pathology 2010; 42:650–654. 
10. Samaratunga H, Khoo K. Micropapillary variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study. Histopathology 2004; 45:55–64. 

11. Wang JK, Boorjian SA, Cheville JC, et al. Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World J Urol 2012; 30:801–806.

12. Fairey AS, Daneshmand S, Wang L, et al. Impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy. Urol Oncol 2013.

13. Gaya JM, Palou J, Algaba F, et al. The case for conservative management in the treatment of patients with nonmuscle-invasive micropapillary bladder carcinoma without carcinoma in situ. Can J Urol 2010; 17:5370–5376.

14. Bristow RE, Gossett DR, Shook DR,et al: Micropapillary serous ovarian carcinoma: surgical management and clinical outcome. Gynecol Oncol 2002; 86: 163-170.

15. Meeks JJ, Taylor JM, Matsushita K, et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int 2013; 111:E325–E330.
16. Ghoneim IA, Miocinovic R, Stephenson AJ, et al. Neoadjuvant systemic therapy or early cystectomy? Single-center analysis of outcomes after therapy for patients with clinically localized micropapillary urothelial carcinoma of the bladder. Urology 2011; 77:867–870.