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BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis

Authors: Pavlos Msaouel, Michael Koutsilieris

Published in: BMC Cancer | Issue 1/2011

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Abstract

Background

The diagnostic value and prognostic significance of circulating tumor cell (CTC) detection in patients with bladder cancer is controversial. We performed a meta-analysis to consolidate current evidence regarding the use of CTC detection assays to diagnose bladder and other urothelial cancers and the association of CTC positivity with advanced, remote disease.

Methods

Studies that investigated the presence of CTCs in the peripheral blood of patients with bladder cancer and/or urothelial cancer were identified and reviewed. Sensitivities, specificities, and positive (LR+) and negative likelihood ratios (LR-) of CTC detection in individual studies were calculated and meta-analyzed by random effects model. Overall odds ratio of CTC positivity in patients with advanced disease versus those with organ-confined cancer was also calculated.

Results

Overall sensitivity of CTC detection assays was 35.1% (95%CI, 32.4-38%); specificity, LR+, and LR- was 89.4% (95%CI, 87.2-91.3%), 3.77 (95%CI, 1.95-7.30) and 0.72 (95%CI, 0.64-0.81). CTC-positive patients were significantly more likely to have advanced (stage III-IV) disease compared with CTC-negative patients (OR, 5.05; 95%CI, 2.49-10.26).

Conclusions

CTC evaluation can confirm tumor diagnosis and identify patients with advanced bladder cancer. However, due to the low overall sensitivity, CTC detection assays should not be used as initial screening tests.
Appendix
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Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin. 2010, 60: 277-300. 10.3322/caac.20073.CrossRefPubMed
3.
Dahm P, Gschwend JE: Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol. 2003, 44: 672-681. 10.1016/S0302-2838(03)00416-0.CrossRefPubMed
4.
Mazeman E: Tumors of the upper excretory urinary tract, calices, renal pelvis and ureter. J Urol Nephrol (Paris). 1972, 78 (Suppl 9): 1-219.
5.
Catto JW, Yates DR, Rehman I, Azzouzi AR, Patterson J, Sibony M, Cussenot O, Hamdy FC: Behavior of urothelial carcinoma with respect to anatomical location. J Urol. 2007, 177: 1715-1720. 10.1016/j.juro.2007.01.030.CrossRefPubMed
6.
Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG: Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998, 52: 594-601. 10.1016/S0090-4295(98)00295-7.CrossRefPubMed
7.
Edge SB, American Joint Committee on Cancer, American Cancer Society: AJCC cancer staging handbook: from the AJCC cancer staging manual. 2010, New York: Springer, 7
8.
Shariat SF, Palapattu GS, Karakiewicz PI, Rogers CG, Vazina A, Bastian PJ, Schoenberg MP, Lerner SP, Sagalowsky AI, Lotan Y: Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol. 2007, 51: 137-149. 10.1016/j.eururo.2006.05.021. discussion 149-151CrossRefPubMed
9.
Raj GV, Bochner BH: Radical cystectomy and lymphadenectomy for invasive bladder cancer: towards the evolution of an optimal surgical standard. Semin Oncol. 2007, 34: 110-121. 10.1053/j.seminoncol.2006.12.011.CrossRefPubMed
10.
Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, et al: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001, 19: 666-675.PubMed
11.
Mocellin S, Keilholz U, Rossi CR, Nitti D: Circulating tumor cells: the 'leukemic phase' of solid cancers. Trends Mol Med. 2006, 12: 130-139. 10.1016/j.molmed.2006.01.006.CrossRefPubMed
12.
Msaouel P, Pissimissis N, Halapas A, Koutsilieris M: Mechanisms of bone metastasis in prostate cancer: clinical implications. Best Pract Res Clin Endocrinol Metab. 2008, 22: 341-355. 10.1016/j.beem.2008.01.011.CrossRefPubMed
13.
Nezos A, Pissimisis N, Lembessis P, Sourla A, Dimopoulos P, Dimopoulos T, Tzelepis K, Koutsilieris M: Detection of circulating tumor cells in bladder cancer patients. Cancer Treat Rev. 2009, 35: 272-279. 10.1016/j.ctrv.2008.11.003.CrossRefPubMed
14.
Nezos A, Msaouel P, Pissimissis N, Lembessis P, Sourla A, Armakolas A, Gogas H, Stratigos AJ, Katsambas AD, Koutsilieris M: Methods of detection of circulating melanoma cells: A comparative overview. Cancer Treat Rev. 2011, 37: 284-290. 10.1016/j.ctrv.2010.10.002.CrossRefPubMed
15.
Cristofanilli M: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. Semin Oncol. 2006, 33: S9-14.CrossRefPubMed
16.
Gudemann CJ, Weitz J, Kienle P, Lacroix J, Wiesel MJ, Soder M, Benner A, Staehler G, Doeberitz MV: Detection of hematogenous micrometastasis in patients with transitional cell carcinoma. J Urol. 2000, 164: 532-536. 10.1016/S0022-5347(05)67418-6.CrossRefPubMed
17.
Karl A, Tritschler S, Hofmann S, Stief CG, Schindlbeck C: Perioperative search for circulating tumor cells in patients undergoing radical cystectomy for bladder cancer. Eur J Med Res. 2009, 14: 487-490.CrossRefPubMedPubMedCentral
18.
Naoe M, Ogawa Y, Morita J, Omori K, Takeshita K, Shichijyo T, Okumura T, Igarashi A, Yanaihara A, Iwamoto S, et al: Detection of circulating urothelial cancer cells in the blood using the CellSearch System. Cancer. 2007, 109: 1439-1445. 10.1002/cncr.22543.CrossRefPubMed
19.
Kinjo M, Okegawa T, Horie S, Nutahara K, Higashihara E: Detection of circulating MUC7-positive cells by reverse transcription-polymerase chain reaction in bladder cancer patients. Int J Urol. 2004, 11: 38-43. 10.1111/j.1442-2042.2004.00739.x.CrossRefPubMed
20.
Lu JJ, Kakehi Y, Takahashi T, Wu XX, Yuasa T, Yoshiki T, Okada Y, Terachi T, Ogawa O: Detection of circulating cancer cells by reverse transcription-polymerase chain reaction for uroplakin II in peripheral blood of patients with urothelial cancer. Clin Cancer Res. 2000, 6: 3166-3171.PubMed
21.
Fujii Y, Kageyama Y, Kawakami S, Kihara K, Oshima H: Detection of disseminated urothelial cancer cells in peripheral venous blood by a cytokeratin 20-specific nested reverse transcriptase-polymerase chain reaction. Jpn J Cancer Res. 1999, 90: 753-757.CrossRefPubMed
22.
Okegawa T, Hayashi K, Hara H, Nutahara K, Higashihara E: Immunomagnetic quantification of circulating tumor cells in patients with urothelial cancer. Int J Urol. 2010, 17: 254-258. 10.1111/j.1442-2042.2010.02454.x.CrossRefPubMed
23.
Ribal MJ, Mengual L, Marin M, Algaba F, Ars E, Fernandez PL, Oliva R, Villavicencio H, Alcaraz A: Molecular staging of bladder cancer with RT-PCR assay for CK20 in peripheral blood, bone marrow and lymph nodes: comparison with standard histological staging. Anticancer Res. 2006, 26: 411-419.PubMed
24.
Retz M, Lehmann J, Roder C, Weichert-Jacobsen K, Loch T, Romahn E, Luhl C, Kalthoff H, Stockle M: Cytokeratin-20 reverse-transcriptase polymerase chain reaction as a new tool for the detection of circulating tumor cells in peripheral blood and bone marrow of bladder cancer patients. Eur Urol. 2001, 39: 507-515. 10.1159/000052496. discussion 516-507CrossRefPubMed
25.
Soria JC, Morat L, Durdux C, Housset M, Cortez A, Blaise R, Sabatier L: The molecular detection of circulating tumor cells in bladder cancer using telomerase activity. J Urol. 2002, 167: 352-356. 10.1016/S0022-5347(05)65467-5.CrossRefPubMed
26.
Guzzo TJ, McNeil BK, Bivalacqua TJ, Elliott DJ, Sokoll LJ, Schoenberg MP: The presence of circulating tumor cells does not predict extravesical disease in bladder cancer patients prior to radical cystectomy. Urol Oncol. 2009
27.
Rink M, Chun FK, Minner S, Friedrich M, Mauermann O, Heinzer H, Huland H, Fisch M, Pantel K, Riethdorf S: Detection of circulating tumour cells in peripheral blood of patients with advanced non-metastatic bladder cancer. BJU Int. 2011, 107: 1668-1675. 10.1111/j.1464-410X.2010.09562.x.CrossRefPubMed
28.
Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A: Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol. 2006, 6: 31-10.1186/1471-2288-6-31.CrossRefPubMedPubMedCentral
29.
30.
DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials. 1986, 7: 177-188. 10.1016/0197-2456(86)90046-2.CrossRefPubMed
31.
Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG: Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol. 2006, 6: 50-10.1186/1471-2288-6-50.CrossRefPubMedPubMedCentral
32.
Sterne JA, Egger M, Smith GD: Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. BMJ. 2001, 323: 101-105. 10.1136/bmj.323.7304.101.CrossRefPubMedPubMedCentral
33.
34.
Zhao S, Liu Y, Zhang Q, Li H, Zhang M, Ma W, Zhao W, Wang J, Yang M: The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a meta-analysis of published literature. Breast Cancer Res Treat. 2011
35.
36.
Nakanishi Y, Toyoizumi S, Nakajima A, Hamada C: Subgroup Analysis in Meta-Analysis: a comparison of different methods. Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku. 2007, 12: 13-24. 10.3820/jjpe.12.13.CrossRef
37.
Gazzaniga P, Nofroni I, Gandini O, Silvestri I, Frati L, Agliano AM, Gradilone A: Tenascin C and epidermal growth factor receptor as markers of circulating tumoral cells in bladder and colon cancer. Oncol Rep. 2005, 14: 1199-1202.PubMed
38.
Champelovier P, Mongelard F, Seigneurin D: CK20 gene expression: technical limits for the detection of circulating tumor cells. Anticancer Res. 1999, 19: 2073-2078.PubMed
39.
Okegawa T, Kinjo M, Nutahara K, Higashihara E: Value of reverse transcription polymerase chain assay in peripheral blood of patients with urothelial cancer. J Urol. 2004, 171: 1461-1466. 10.1097/01.ju.0000118648.29024.b7.CrossRefPubMed
40.
Li SM, Zhang ZT, Chan S, McLenan O, Dixon C, Taneja S, Lepor H, Sun TT, Wu XR: Detection of circulating uroplakin-positive cells in patients with transitional cell carcinoma of the bladder. J Urol. 1999, 162: 931-935. 10.1097/00005392-199909010-00093.CrossRefPubMed
41.
Desgrandchamps F, Teren M, Dal Cortivo L, Marolleau JP, Bertheau P, Villette JM, Cortesse A, Teillac P, Le Duc A, Hamdy FC: The effects of transurethral resection and cystoprostatectomy on dissemination of epithelial cells in the circulation of patients with bladder cancer. Br J Cancer. 1999, 81: 832-834. 10.1038/sj.bjc.6690771.CrossRefPubMedPubMedCentral
42.
Naoe M, Ogawa Y, Takeshita K, Iwamoto S, Miyazaki A: Use of the CellSearch Circulating Tumor Cell Test for monitoring urothelial cancer: two case reports of metastatic urothelial cancer. South Med J. 2008, 101: 439-441. 10.1097/SMJ.0b013e3181684fe1.CrossRefPubMed
43.
Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004, 10: 6897-6904. 10.1158/1078-0432.CCR-04-0378.CrossRefPubMed
44.
Gallagher DJ, Milowsky MI, Ishill N, Trout A, Boyle MG, Riches J, Fleisher M, Bajorin DF: Detection of circulating tumor cells in patients with urothelial cancer. Ann Oncol. 2009, 20: 305-308.CrossRefPubMed
45.
Osman I, Kang M, Lee A, Deng FM, Polsky D, Mikhail M, Chang C, David DA, Mitra N, Wu XR, et al: Detection of circulating cancer cells expressing uroplakins and epidermal growth factor receptor in bladder cancer patients. Int J Cancer. 2004, 111: 934-939. 10.1002/ijc.20366.CrossRefPubMed
46.
Yuasa T, Yoshiki T, Isono T, Tanaka T, Hayashida H, Okada Y: Expression of transitional cell-specific genes, uroplakin Ia and II, in bladder cancer: detection of circulating cancer cells in the peripheral blood of metastatic patients. Int J Urol. 1999, 6: 286-292. 10.1046/j.1442-2042.1999.00064.x.CrossRefPubMed
47.
Yuasa T, Yoshiki T, Tanaka T, Kim CJ, Isono T, Okada Y: Expression of uroplakin Ib and uroplakin III genes in tissues and peripheral blood of patients with transitional cell carcinoma. Jpn J Cancer Res. 1998, 89: 879-882.CrossRefPubMed
48.
Gradilone A, Petracca A, Nicolazzo C, Gianni W, Cortesi E, Naso G, Vincenzi B, Cristini C, De Berardinis E, Di Silverio F, et al: Prognostic significance of survivin-expressing circulating tumour cells in T1G3 bladder cancer. BJU Int. 2010, 106: 710-715. 10.1111/j.1464-410X.2009.09130.x.CrossRefPubMed
49.
Meye A, Bilkenroth U, Schmidt U, Fussel S, Robel K, Melchior AM, Blumke K, Pinkert D, Bartel F, Linne C, et al: Isolation and enrichment of urologic tumor cells in blood samples by a semi-automated CD45 depletion autoMACS protocol. Int J Oncol. 2002, 21: 521-530.PubMed
50.
Gazzaniga P, Gandini O, Giuliani L, Magnanti M, Gradilone A, Silvestri I, Gianni W, Gallucci M, Frati L, Agliano AM: Detection of epidermal growth factor receptor mRNA in peripheral blood: a new marker of circulating neoplastic cells in bladder cancer patients. Clin Cancer Res. 2001, 7: 577-583.PubMed
51.
Gazzaniga P, Gradilone A, Frati L, Agliano AM: Epidermal growth factor receptor mRNA expression in peripheral blood of bladder cancer patients: a potential marker to detect treatment failure. Clin Cancer Res. 2001, 7: 4288-4289.PubMed
52.
Kaneda T, Hoshi S, Mao H, Takahashi T, Suzuki K, Sato M, Orikasa S: Detection of urogenital malignant cells in the peripheral blood by nested RT-PCR using keratin 19 mRNA. Nippon Hinyokika Gakkai Zasshi. 1998, 89: 33-42.PubMed
53.
Angulo JC, Ferruelo A, Rodriguez-Barbero JM, Nunez C, de Fata FR, Gonzalez J: Detection and molecular staging of bladder cancer using real-time RT-PCR for gelatinases (MMP-2, MMP-9) and TIMP-2 in peripheral blood. Actas Urol Esp. 2011, 35: 127-136.CrossRefPubMed
54.
Loberg RD, Fridman Y, Pienta BA, Keller ET, McCauley LK, Taichman RS, Pienta KJ: Detection and isolation of circulating tumor cells in urologic cancers: a review. Neoplasia. 2004, 6: 302-309. 10.1593/neo.03484.CrossRefPubMedPubMedCentral
55.
Koutsilieris M, Lembessis P, Luu-The V, Sourla A: Repetitive and site-specific molecular staging of prostate cancer using nested reverse transcriptase polymerase chain reaction for prostate specific antigen and prostate specific membrane antigen. Clin Exp Metastasis. 1999, 17: 823-830. 10.1023/A:1006783330996.CrossRefPubMed
56.
Sawabata N, Okumura M, Utsumi T, Inoue M, Shiono H, Minami M, Nishida T, Sawa Y: Circulating tumor cells in peripheral blood caused by surgical manipulation of non-small-cell lung cancer: pilot study using an immunocytology method. Gen Thorac Cardiovasc Surg. 2007, 55: 189-192. 10.1007/s11748-007-0101-2.CrossRefPubMed
57.
Lembessis P, Msaouel P, Halapas A, Sourla A, Panteleakou Z, Pissimissis N, Milathianakis C, Bogdanos J, Papaioannou A, Maragoudakis E, et al: Combined androgen blockade therapy can convert RT-PCR detection of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts from positive to negative in the peripheral blood of patients with clinically localized prostate cancer and increase biochemical failure-free survival after curative therapy. Clin Chem Lab Med. 2007, 45: 1488-1494. 10.1515/CCLM.2007.301.CrossRefPubMed
58.
Nezos A, Lembessis P, Sourla A, Pissimissis N, Gogas H, Koutsilieris M: Molecular markers detecting circulating melanoma cells by reverse transcription polymerase chain reaction: methodological pitfalls and clinical relevance. Clin Chem Lab Med. 2009, 47: 1-11. 10.1515/CCLM.2009.009.CrossRefPubMed
59.
Cheng L, Zhang S, MacLennan GT, Williamson SR, Lopez-Beltran A, Montironi R: Bladder cancer: translating molecular genetic insights into clinical practice. Hum Pathol. 2011, 42: 455-481. 10.1016/j.humpath.2010.07.007.CrossRefPubMed
Metadata
Title
Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis
Authors
Pavlos Msaouel
Michael Koutsilieris
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-336

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