Chemo Day 63 - grim facts re micropapillary BC

One unusual aspect of my type of bladder cancer is that it has micropapillary features.  I was told in late December 2011 that this was a particularly aggressive form of urothelial carcinoma (bladder cancer), and that it increased the risk that it would spread outside the bladder.  (According to a 2007 article in Modern Pathology, “a micropapillary pattern is defined as papillary tufts without a fibrovascular core and is known to be a factor that indicates a poor prognosis in numerous cancers.”)  In my conversations with my doctors, they explained how transitional cell carcinoma (or TCC, which is the specific type of urothelial carcinoma that I have) with micropapillary features occurred in fewer that 5% of all bladder cancer patients.  They also said that fewer than 5% of patients diagnosed with bladder cancer were under age 50.  Dr. Bill Shipley of Mass General told me that he could not remember another case where another patient as young as I was had micropapillary bladder cancer and presented with 11 distinct tumors in the bladder, as I did.  These circumstances led him to call my case “most interesting.”  I have learned that one does not want to have an “interesting” case of cancer.  You want your case to be ordinary, boring, with an established treatment and proven success. 

Last week, the chairman of BCAN called me after reading my blog.  He read how my cancer had been diagnosed with micropapillary features, and wanted to share his experience with it, as his cancer also had micropapillary features (although his was not muscle-invasive).   He said that many pathologists were not trained to recognize TCC with micropapillary features.  I told him how GW’s pathologist didn’t recognize it, but the Hopkins pathologist did.  He also said that it was important to have my treatment plan established or confirmed by one of the top cancer centers.  I told him that Hopkins and Mass. General has consulted with GW for my treatment, and all had agreed that I should have neoadjuvant chemo, followed by RC surgery.  He encouraged me to stay on top of the doctors and be an aggressive advocate, noting that it took him a while before he was comfortable doing that. 

His call caused me to go back and do some more research re TCC with micropapillary features.  Now that I’m on vacation, I have some time to do this.  The data are not encouraging.  I’ve read several articles, and abstracts or summaries of three are below.   

Quick summary:  The fact that bladder cancer could have micropapillary features was not identified until 1994.  Bladder cancer with micropapillary features likely is underreported today, since many pathologists are not trained to recognize it. Generally, patients with micropapillary features in their bladder cancer face significantly greater risks that the cancer will spread, and lower odds that it will respond to chemotherapy.  The mortality rate for patients with mircropapillary bladder cancer are significantly lower than other bladder cancer patients.

This first article reports on a study by MD Anderson in Texas re micropappilary bladder cancers.  MD Anderson first identified micropapillary features in bladder cancer in 1994, and specializes in studying it.  This article reports on the largest retrospective review of patients with micropapillary bladder cancer:

Source:  Cancer. 2007 Jul 1;110(1):62-7.

Available at: http://onlinelibrary.wiley.com/doi/10.1002/cncr.22756/pdf

Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson Cancer Center experience with 100 consecutive patients.

Kamat AM, Dinney CP, Gee JR, Grossman HB, Siefker-Radtke AO, Tamboli P, Detry MA, Robinson TL, Pisters LL.  Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. akamat@mdanderson.org

Abstract
BACKGROUND:
Micropapillary bladder carcinoma is a rare variant of urothelial carcinoma. To improve understanding of this disease, the authors performed a retrospective review of their experience.

METHODS:
The authors reviewed the records of 100 consecutive patients with micropapillary bladder cancer who were evaluated at The University of Texas M. D. Anderson Cancer Center.

RESULTS:
The mean age of the patients was 64.7 years, with a male:female ratio of 10:1. The TNM stage of disease at the time of presentation was Ta in 5 patients, carcinoma in situ (CIS) in 4 patients, T1 in 35 patients, T2 in 26 patients, T3 in 7 patients, T4 in 6 patients; N+ in 9 patients, and M+ in 8 patients. Kaplan-Meier estimates of 5-year and 10-year overall survival (OS) rates were 51% and 24%, respectively. Bladder-sparing therapy with intravesical bacillus Calmette-Guerin therapy was attempted in 27 of 44 patients with nonmuscle-invasive disease; 67% (18 patients) developed disease progression (>or=cT2), including 22% who developed metastatic disease. Of 55 patients undergoing radical cystectomy for surgically resectable disease (<or=cT4a), 23 received neoadjuvant chemotherapy and 32 were treated with initial cystectomy, with no significant difference noted in stage distribution between the 2 groups. For the 23 patients treated with neoadjuvant chemotherapy, the median OS was 43.2 months with 32% of patients still alive at 5 years. For the 32 patients treated with initial cystectomy, the median survival had not been reached at the time of last follow-up, with 71% still alive at 5 years.

CONCLUSIONS:
Micropapillary bladder cancer is associated with a poor prognosis. Intravesical therapy appears to be ineffective in this disease and patients with surgically resectable disease should be offered early radical cystectomy.

KWB comments:  MD Anderson is an aggressive advocate for early cystectomy in patients with micropapillary bladder cancer.  Some data they cite suggests neoadjuvant chemo is ineffective, but other data suggests that it may have a positive effect.  5 and 10 year survival for micropapillary bladder cancer patients undergoing RC is 71% and 53%, respectively. However, those who went through the treatment that I’m going through is grim: “For the 23 patients treated with neoadjuvant chemotherapy, the median OS was 43.2 months with 32% of patients still alive at 5 years.”  Overall, however, this article reinforces the fact that I’ve got the worst type of TCC bladder cancer, and the one with the lowest survival rate.  

Next is a 2009 article reporting on experiences from France with micropapillary bladder cancer.  It is a review of patient records between 1994 and 2007 from a French cancer center; 11 of 911 bladder cancer patients had micropapillary features; 10 of the 11 were dead in less than 3 years.  Maybe they should have gone to MD Anderson. 

Micropapillary bladder cancer: a review of Léon Bérard Cancer Center experience

Pierre Heudel^*, Fadi El Karak, Nabil Ismaili, Jean-Pierre Droz and Aude Flechon

Source:  http://www.biomedcentral.com/1471-2490/9/5

Abstract

Background

Micropapillary bladder cancer is a rare and aggressive variant of urothelial carcinoma. A retrospective review of our experience in management of patients with muscle-invasive or metastatic micropapillary bladder cancer was performed to better define the behavior of this disease.

Methods

We reviewed the records of the 11 patients with micropapillary bladder cancer who were evaluated and treated at Léon Bérard Cancer Center between 1994 and 2007, accounting for 1,2% of all urothelial tumors treated in this institution.

Results

Mean patients age was 60 years. The majority of patients (72%) were diagnosed after 2004. After a median follow-up of 31.7 months, median overall survival was 19 months. Two patients presented with stage II, one with stage III and eight with stage IV disease All 5 patients who had node positive metastases and treated with radical surgery and adjuvant chemotherapy relapsed and had a disease free survival of 9.6 months.

Conclusion

Micropapillary bladder cancer is probably an underreported variant of urothelial carcinoma associated with poor prognosis. Adjuvant chemotherapy might have a questionable efficacy and the optimal treatment strategy is yet to be defined.

KWB comments:  The one patient who survived was pT2N0M0, like me.  But this paragraph in the study gives me pause:

"The presence of MPC in urothelial carcinoma was found to be associated with an advanced stage of disease at the time of presentation and an aggressive clinical course [8,9,11,12]. In 2004, Samaratunga et al. [8] reported 20 cases of micropapillary bladder cancer and correlated the pathological stage and prognosis with the extent and extension of the micropapillary component on the pathology specimen. In patients with superficial bladder cancer, intravesical BCG was shown to be ineffective and the authors concluded that the optimal treatment strategy for non-invasive bladder cancer with micropapillary components should be a radical cystectomy [13]. The same authors stated in another study that in muscle invasive surgically resectable disease, radical cystectomy should be performed precociously. In this paper, the incidence of pathologic upstaging was 52.7% and the incidence of occult lymph node disease detected at the time of cystectomy was 27.3%. Moreover patients undergoing neoadjuvant chemotherapy were found to have a non-organ-confined disease (≥ T3) in 68% of cases compared to patients treated with upfront surgery (34%) (p = 0,0157). There was no survival benefit from the addition of neoadjuvant chemotherapy and the authors recommended no such approach especially in the absence of lymphovascular invasion [10]. Moreover, in this study, of the 15 patients with lymph node positive disease, 11 received adjuvant chemotherapy after radical cystectomy, and only 5 were alive at the time of last follow-up (follow-up time ranging from 29 to 42 months). This tends to show the chemoresistant characters of micropapillary bladder cancer. In fact, in other organ sites, micropapillary carcinoma appears to be less responsive to chemotherapy. For example, a retrospective study evaluated the pattern of chemoresistance in invasive micropapillary/low grade serous ovarian carcinoma and high grade serous ovarian carcinoma. Authors concluded that patients with recurrent invasive micropapillary/low grade serous ovarian carcinoma were more likely to manifest drug resistance to standard chemotherapy agents (platinum and paclitaxel) [14]."

This last article is a  technical description of micropapillary bladder cancer:

Source:  http://uncommon-cancer.blogspot.com/2011/05/micropapillary-bladder-cancer.html

The histomorphologic spectrum of many epithelial cancers is now recognized to include a subset of cells characterized by groups of nesting high in lacunar spaces that have a "micropapillary" architecture. This pattern was first reported in 1982 by The Henderickson et al. described an aggressive variant of endometrial adenocarcinoma. In this context, an infiltrating pattern, biologically aggressive expansion behavior remarkably reminiscent of ovarian serous papillary carcinoma was evident. Subsequently, a micropapillary variant has been recognized in cancers arising from breast, bladder, thyroid, lung and pancreas, and has therefore come to be seen as a general feature of epithelial cancer. It seems likely that this phenotype arises from a fundamental aspect of epithelial carcinogenesis, and the finding of a "genetic signature" recognizable that cuts across these different sites would not be surprising. Researchers at the MD Anderson Cancer Center were the first to report a subset of bladder cancers showing a micropapillary histomorphology, the publication of the first series of 18 patients in 1994.

As discussed in the context of sarcomatoid and small cell morphology is typical of a micropapillary component seen in a context that includes more typical of CBT. From this first series of patients, micropapillary variant was observed to have a more aggressive clinical course and a particular tendency for prominent lymphovascular invasion. Subsequently published a series of cases in Sweden, Harvard, Australia, Wayne State University, and the City of Mexico, along with many individual case reports. These reports established that micropapillary bladder cancer has a characteristic morphology that can be identified reliably. Moreover, the trend first reported to the clinical subclassification, aggressive behavior, and the relatively poor response to standard systemic chemotherapy has been fully confirmed. Ultrastructural studies in the context of micropapillary breast cancer suggested secretory granules along the basement membrane, ie, loss of normal cell polarity which is the secretory activity in the basal surface, not only on the surface apical.

This concept of "inside out" morphology has been reinforced by the demonstration that the gene product mucinous glycoprotein MUC1 is abnormally located at the basal surface micropapillary cancers, including bladder origin. Although not yet formally established, it seems likely that a mechanical connection is made between this type of abnormal phenotype, early submucosal infiltration and early access to the lymphatic vessels that characterize the clinical course of these cancers. In our experience, the unusual finding of a bladder cancer is the stage pT1N1 almost always associated with micropapillary histology. micropapillary bladder cancer has been reported to occur infrequently. In the series of cases of Sweden, on the basis of a population-based registry, the incidence of bladder cancer was 0.7%. That report-biased Mexico City put the incidence of 38/630 (6%). In a similar registry biased at the MD Anderson Cancer Center, we found 162 cases for an incidence of 4.2%. Of course, these reports come from genetic and environmental contexts very different, and it is very possible that the incidence of different geographic region. The clinical management of micropapillary bladder cancer should take into account the very real possibility that clinically understaged and can grow quickly. Therefore, we call for "early" cystectomy for any tumor that invades the lamina propria, and certainly calls for any patient with disease cT1 or higher after a trial of intravesical therapy will be guided to cystectomy without delay. For patients with locally advanced disease, the prognosis is worse than for patients with TCC conventional systems. In the MD Anderson Cancer Center experience, patients with cT4a cT3b or treated with a combination of systemic chemotherapy and surgery (in any order), had a lower overall cure rate compared with patients with conventional systems TCC. In the metastatic setting, both the response rate and overall survival of patients with micropapillary cancer are below our historical expectations. Despite the aggressive implementation of combination chemotherapy, patients with micropapillary cancer still have a relatively poor outcome. This has been methotrexate / vinblastine / doxorubicin / cisplatin (MVAC), with ifosfamide-based combinations, and gemcitabine / cisplatin. It is important to recognize, however, that although the overall results are lower than those obtained for patients with conventional TCC, many patients do well, and therefore continue to offer conventional therapy for patients in this subgroup