- Email: [email protected]
Hematogenous Tumor Cell Spread Following Standard Transurethral Resection of Bladder Carcinoma
EURURO-6762; No. of Pages 2 EUROPEAN UROLOGY XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Research Letter
Hematogenous Tumor Cell Spread Following Standard Transurethral Resection of Bladder Carcinoma Simon Blaschke a,y,*, Frank Koenig b,c,y, Martin Schostak a Cancer of the urothelium is the second most common urological malignancy. In almost 75% of all newly diagnosed tumors, bladder cancer is non–muscle-invasive (NMIBC) [1]. Prognosis varies considerably; 45% of all patients develop a muscle-invasive tumor over time and up to 78% experience local recurrence [2]. It has been shown that transurethral resection of the bladder (TURB) causes intravesical tumor cell spreading and seeding of identical tumor cell clones in the bladder [3]. Therefore, we hypothesized that TURB causes spreading of tumor cells not only intravesically but also hematogenously. To test this hypothesis, we initiated a small study measuring circulating tumor cells (CTCs) before and after resection to ascertain feasibility for future prospective trials. Eight patients with suspicion of urothelial bladder cancer according to ultrasound and/or cystoscopy were included in the trial. To establish the impact of standard TURB on CTC occurrence, a blood sample was taken immediately before and after TURB. All participants gave written informed consent for use of their blood samples in scientific studies. The CellSearch system has been approved by the US Food and Drug Administration as a diagnostic tool for detecting CTCs in metastatic prostate cancer. Targeting the epithelial cell adhesion molecule, the system is based on immunomagnetic enrichment and fluorescent labeling for semiautomated microscopic cell analysis [4]. The CellSearch system was used to enumerate CTCs in samples taken before and after TURB for each patient. In seven of eight patients, urothelial carcinoma was confirmed by histopathology. Three patients had a T2 tumor, two patients had a T1 tumor, and two patients had a Ta tumor. In two patients with high-grade tumors, CTCs were detected preoperatively, and in the patient with a high-grade T2 tumor, CTCs increased postoperatively. In two patients with muscle-invasive disease, CTCs were detectable after but not before TURB. One of these patients had massive tumor cell dissemination. All patients with
low-grade tumors and one patient with a pT1 high-grade tumor had no detectable CTCs (Table 1). Detection of CTCs after TURB in this randomized cohort may lead to the assumption that resection of an urothelial carcinoma might be the origin for systemic tumor cell spread. As these results are preliminary, further prospective studies are required to validate the data obtained. Correlation with further follow-up data will help in understanding the long-term effects of tumor cell dissemination after TURB. Detection of CTCs with proof of disseminated tumor cells could be a risk factor for present or future metastatic disease. Several studies of urothelial carcinoma of the bladder have shown that disseminated tumor cells can already be detected in nonmetastatic tumor disease [5]. CTC measurement could help in planning further adjuvant treatment strategies in NMIBC [6]. If CTCs are detected after resection of high-grade tumors, early cystectomy should be discussed with the patient and/or neoadjuvant chemotherapy should be offered. These preliminary findings demonstrate that the TURB technique might involve risks that should not be underestimated.
Table 1 – Circulating tumor cell (CTC) count in eight patients before and after transurethral resection of the bladder (TURB) Sex
Female Female Male Female Male Male Male Male
Age (yr)
94 66 64 85 76 84 88 66
Histopathology
No tumor Ta low grade T1 low grade Ta high grade T1 high grade T2 high grade T2 high grade T2 high grade
CTC count Before TURB
After TURB
0 0 0 1 0 0 4 0
0 0 0 0 0 1 5 12
http://dx.doi.org/10.1016/j.eururo.2016.03.051 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Blaschke S, et al. Hematogenous Tumor Cell Spread Following Standard Transurethral Resection of Bladder Carcinoma. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.051
EURURO-6762; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
[5] Gazzaniga P, Gradilone A, de Berardinis E, et al. Prognostic value of
Conflicts of interest: The authors have nothing to disclose.
circulating tumor cells in nonmuscle invasive bladder cancer: a CellSearch analysis. Ann Oncol 2012;23:2352–6.
Acknowledgments: This project was supported by an unlimited grant
[6] Gazzaniga P, de Berardinis E, Raimondi C, et al. Circulating tumor
from Bayer Pharma AG (grants4targets ID 2014-03-1100).
cells detection has independent prognostic impact in high-risk nonmuscle invasive bladder cancer. Int J Cancer 2014;135:1978–82.
References [1] Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors
a
Department of Urology, University Clinic Magdeburg, Magdeburg, Germany b
of urothelial bladder cancer. Eur Urol 2013;63:234–41.
c
[2] van den Bosch S, Witjes JA. Long-term Cancer-specific survival in patients with high-risk, non–muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol 2011;60:493–500.
y
CTC Laboratory, CellLab, Berlin, Germany
ATURO Urology Practice, Berlin, Germany
These authors contributed equally to this work.
[3] Hafner C, Knuechel R, Zanardo L, et al. Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial
*Corresponding author. Department of Urology, University Clinic
carcinomas of the upper and lower urinary tract. Oncogene
Magdeburg, Leipzigerstrasse 44, Magdeburg 39120, Germany.
2001;20:4910–5. [4] de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells
Tel. +49 39 16715036; Fax: +49 39 16715094. E-mail address: [email protected] (S. Blaschke).
predict survival benefit from treatment in metastatic castrationresistant prostate cancer. Clin Cancer Res 2008;14:6302–9.
March 31, 2016
Please cite this article in press as: Blaschke S, et al. Hematogenous Tumor Cell Spread Following Standard Transurethral Resection of Bladder Carcinoma. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.051
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Research Letter
Hematogenous Tumor Cell Spread Following Standard Transurethral Resection of Bladder Carcinoma Simon Blaschke a,y,*, Frank Koenig b,c,y, Martin Schostak a Cancer of the urothelium is the second most common urological malignancy. In almost 75% of all newly diagnosed tumors, bladder cancer is non–muscle-invasive (NMIBC) [1]. Prognosis varies considerably; 45% of all patients develop a muscle-invasive tumor over time and up to 78% experience local recurrence [2]. It has been shown that transurethral resection of the bladder (TURB) causes intravesical tumor cell spreading and seeding of identical tumor cell clones in the bladder [3]. Therefore, we hypothesized that TURB causes spreading of tumor cells not only intravesically but also hematogenously. To test this hypothesis, we initiated a small study measuring circulating tumor cells (CTCs) before and after resection to ascertain feasibility for future prospective trials. Eight patients with suspicion of urothelial bladder cancer according to ultrasound and/or cystoscopy were included in the trial. To establish the impact of standard TURB on CTC occurrence, a blood sample was taken immediately before and after TURB. All participants gave written informed consent for use of their blood samples in scientific studies. The CellSearch system has been approved by the US Food and Drug Administration as a diagnostic tool for detecting CTCs in metastatic prostate cancer. Targeting the epithelial cell adhesion molecule, the system is based on immunomagnetic enrichment and fluorescent labeling for semiautomated microscopic cell analysis [4]. The CellSearch system was used to enumerate CTCs in samples taken before and after TURB for each patient. In seven of eight patients, urothelial carcinoma was confirmed by histopathology. Three patients had a T2 tumor, two patients had a T1 tumor, and two patients had a Ta tumor. In two patients with high-grade tumors, CTCs were detected preoperatively, and in the patient with a high-grade T2 tumor, CTCs increased postoperatively. In two patients with muscle-invasive disease, CTCs were detectable after but not before TURB. One of these patients had massive tumor cell dissemination. All patients with
low-grade tumors and one patient with a pT1 high-grade tumor had no detectable CTCs (Table 1). Detection of CTCs after TURB in this randomized cohort may lead to the assumption that resection of an urothelial carcinoma might be the origin for systemic tumor cell spread. As these results are preliminary, further prospective studies are required to validate the data obtained. Correlation with further follow-up data will help in understanding the long-term effects of tumor cell dissemination after TURB. Detection of CTCs with proof of disseminated tumor cells could be a risk factor for present or future metastatic disease. Several studies of urothelial carcinoma of the bladder have shown that disseminated tumor cells can already be detected in nonmetastatic tumor disease [5]. CTC measurement could help in planning further adjuvant treatment strategies in NMIBC [6]. If CTCs are detected after resection of high-grade tumors, early cystectomy should be discussed with the patient and/or neoadjuvant chemotherapy should be offered. These preliminary findings demonstrate that the TURB technique might involve risks that should not be underestimated.
Table 1 – Circulating tumor cell (CTC) count in eight patients before and after transurethral resection of the bladder (TURB) Sex
Female Female Male Female Male Male Male Male
Age (yr)
94 66 64 85 76 84 88 66
Histopathology
No tumor Ta low grade T1 low grade Ta high grade T1 high grade T2 high grade T2 high grade T2 high grade
CTC count Before TURB
After TURB
0 0 0 1 0 0 4 0
0 0 0 0 0 1 5 12
http://dx.doi.org/10.1016/j.eururo.2016.03.051 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Blaschke S, et al. Hematogenous Tumor Cell Spread Following Standard Transurethral Resection of Bladder Carcinoma. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.051
EURURO-6762; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
[5] Gazzaniga P, Gradilone A, de Berardinis E, et al. Prognostic value of
Conflicts of interest: The authors have nothing to disclose.
circulating tumor cells in nonmuscle invasive bladder cancer: a CellSearch analysis. Ann Oncol 2012;23:2352–6.
Acknowledgments: This project was supported by an unlimited grant
[6] Gazzaniga P, de Berardinis E, Raimondi C, et al. Circulating tumor
from Bayer Pharma AG (grants4targets ID 2014-03-1100).
cells detection has independent prognostic impact in high-risk nonmuscle invasive bladder cancer. Int J Cancer 2014;135:1978–82.
References [1] Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors
a
Department of Urology, University Clinic Magdeburg, Magdeburg, Germany b
of urothelial bladder cancer. Eur Urol 2013;63:234–41.
c
[2] van den Bosch S, Witjes JA. Long-term Cancer-specific survival in patients with high-risk, non–muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol 2011;60:493–500.
y
CTC Laboratory, CellLab, Berlin, Germany
ATURO Urology Practice, Berlin, Germany
These authors contributed equally to this work.
[3] Hafner C, Knuechel R, Zanardo L, et al. Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial
*Corresponding author. Department of Urology, University Clinic
carcinomas of the upper and lower urinary tract. Oncogene
Magdeburg, Leipzigerstrasse 44, Magdeburg 39120, Germany.
2001;20:4910–5. [4] de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells
Tel. +49 39 16715036; Fax: +49 39 16715094. E-mail address: [email protected] (S. Blaschke).
predict survival benefit from treatment in metastatic castrationresistant prostate cancer. Clin Cancer Res 2008;14:6302–9.
March 31, 2016
Please cite this article in press as: Blaschke S, et al. Hematogenous Tumor Cell Spread Following Standard Transurethral Resection of Bladder Carcinoma. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.051