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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2012  |  Volume : 23  |  Issue : 5  |  Page : 1068-1073
Urinary tumor marker in bladder carcinoma in Upper Egypt, correlations with different clinicopathological features

1 Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
2 Department of Urology, Faculty of Medicine, Assiut University, Assiut, Egypt

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Date of Web Publication13-Sep-2012

How to cite this article:
Salama RH, Selem TH, Elhagagy AeA, El-Gammal M, Bakar SM. Urinary tumor marker in bladder carcinoma in Upper Egypt, correlations with different clinicopathological features. Saudi J Kidney Dis Transpl 2012;23:1068-73

How to cite this URL:
Salama RH, Selem TH, Elhagagy AeA, El-Gammal M, Bakar SM. Urinary tumor marker in bladder carcinoma in Upper Egypt, correlations with different clinicopathological features. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2022 Jan 17];23:1068-73. Available from: https://www.sjkdt.org/text.asp?2012/23/5/1068/100957
To the Editor,

Carcinoma of the bladder is the most preva­lent cancer in Egypt and in most African countries. [1] The two major types of bladder cancer in Egypt are bilharzial and non-bilharzial. The non-bilharzial type is similar to the western types, but the bilharzial type is commonly squamous. The continuous need for develo­ping a non-invasive method for early diagnosis and monitoring of bladder cancer resulted in various assays that determine soluble markers in the voided urine specimen. [2] The nuclear matrix (NM) contains proteins that contribute to the preservation of nuclear shape and orga­nization, and it harbors numerous enzymes and transcription factors. [3] The United States Food and Drug Administration had been approved nuclear matrix protein NMP (NMP22) for the detection or rapidly recurring bladder tumor. [4] Cadherin had an important process in mole­cular pathogenesis of bladder cancer, and may be responsible for development of muscle invasiveness and metastasis. Promoter hypermethylation had been identified as an important epigenetic event associated with the loss of E-cadherin gene expression during cancer progression. [5] Thus, cadherin cell adhesion mole­cules represent biological and molecular tar­gets for preventing disease progression. [6] Immunohistochemical studies have indicated that cathepsin D, independently of its proteolytic activity, stimulates not only cancer cell proli­feration but also tumor angiogenesis. [7] Tumors arising from growth alterations of cells in the epithelium lining the bladder are expected to externalize proteins and desquamate fragments of membrane to the bladder cavity, where they mix with the urine. The proteinuria in bladder cancer patients could be caused by a decreased tubular reabsorption of proteins. [8] In addition, the urine of bladder cancer patient may also contain degradation products of the extracel­lular matrix (ECM) derived from the proteolytic activity of invasive tumors. [9] We evaluated the urinary levels of NMP 22, soluble E-cadherin, cathepsin D and total pro­tein in primary bladder cancer, and we assessed their relation to the clinico-pathological fea­tures of the cancer. We retrospectively studied 90 patients in the period from May 2006 to May 2009 in our center. The study comprised 65 patients who had primary bladder cancer (clinically and radiologically) admitted for pa­thological and surgical evaluation, 14 patients with non-cancerous urological conditions (be­nign prostate hyperplasia, urinary tract infection and urolithiasis) and 11 healthy subjects. NMP22 was determined in urine samples by the Matritech NMP22 test kit, USA, based on enzyme immunoassay (EIA). The quantitative sandwich enzyme immunoassay technique was used for determination of sE-cadherin in urine by Quantikine, R&D Systems Inc., Minnea­polis, MN, USA. Cathepsin D activity was de­termined by a chemical method. [10] The patients were stratified into subgroups bilharzial or non-bilharzial cancer, pathological type (squamous, transitional and adenocarcinoma), tumor stage, tumor grade, tumor size and state of node metastasis. Forty patients were followed for disease progression after cystectomy and transurethral resection for three years or until local recurrence or distant metastasis had occurred. NMP22, E-cadherin, cathepsin D and total protein levels were higher in the cancer group, followed by benign group, and then the healthy control group [Table 1]. No significant diffe­rence was found among all the studied markers as regard the pathological types, T stages, and grades. Kaplan-Meier test was used to deter­mine bladder cancer recurrence after treatment in relation to the studied urinary markers. Ele­vated pre-treatment urinary NMP22, E-cadherin and total protein were associated significantly with bladder cancer recurrence (P = 0.02, 0.001, 0.005, respectively) [Figure 1], [Figure 2] and [Figure 3]. However, elevated pre-treatment urinary cathepsin D was not associated with bladder cancer recurrence (P = 0.3). Positive correlations between diffe­rent tumor variables and urinary markers were detected. Tumor size correlated with urinary NMP22 (r = 0.3, P = 0.02). Moreover, E-cadherin, cathepsin D and total protein corre­lated with tumor size (r = 0.3, 0.28, 0.2; P = 0.01, 0.01, 0.04, respectively) and lymph node metastasis (r = 0.32, 0.34, 0.2; P = 0.003, 0.005, 0.04, respectively), [Table 2]. In this study, a significant increase in NMP22 levels was found in the malignant group than in either the benign group or the healthy con­trols. These findings are in agreement with other authors. [10],[11] However, urinary tract infec­tion, inflammation and malignancy associated with other genitourinary organs were the pri­mary cause for false positive tests in the NMP22 evaluation. [12],[13] A negative result of NMP22 test in 49% of the 130 patients with biopsy confirmed bladder cancer was reported. Therefore, the false negative rate was high and thus NMP22 test could not replace cystoscopy for diagnosis of bladder cancer. [14] In our study, sensitivity and specificity of NMP22 were 84.4% and 59.3% in 65 patients with biopsy-confirmed bladder cancer. Multivariate analy­sis revealed that tumor size affected the urinary NMP22 values and the positive rate by tumor size was 42.3%, 59.1% and 85.0% for tumors of <10 mm, 10-30 mm and >30 m, respectively. [15] This is in agreement with our study. Similar to our findings, several studies did not find the quantitative value of NMP22 to be useful in differentiating the low from the high grade and stage, [16] while others reported a significant association. [17] These differences in results could be attributed to the different thresholds used in these studies, lack of control groups and no correction of the markers levels to urinary creatinine levels. sE-cadherin levels strongly correlated with tumor grade, but showed no significant correlation with the stage, size and number of the tumors as found by others. [18] However, it was significantly higher in the recurrent group than in the primary group, similar to others. [19] Moreover, in our study, E-cadherin, cathepsin D and total protein could be significantly helpful to recognize lymph node metastasis and correlated with tumor size; however, cathepsin D did not detect recurrence. This was consistent with others findings. [20] We conclude that NMP22 is a useful marker for detection of both squamous and transitional cell carcinoma of the bladder cancer, while sE-cadherin is the best in detecting adenocarcinoma. sE-cadherin, cathepsin D and total pro­tein will be significantly helpful to recognize lymph node metastasis and, also, correlated with tumor size as NMP22. In addition, NMP22, sE-cadherin and total protein were valid in testing recurrence. Combined use of NMP22, sE-cadherin and total protein improve the diagnosis of all types of bladder cancer with a significant sensitivity and specificity.
Figure 1: Kaplan-Meier survival curve testing recurrence interval in relation to NMP22 levels.

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Figure 2: Kaplan-Meier survival curve testing recurrence interval in relation to E-cadherin levels.

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Figure 3: Kaplan-Meier survival curve testing recurrence interval in relation to cathepsin D levels.

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Table 1: Demographic data of the studied subjects.

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Table 2: Urinary NMP22, E-cadherin, cathepsin D and total protein (units/mg creatinine) in all studied groups.

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   References Top

1.El-Mawla NG, el-Bolkainy MN, Khaled HM. Bladder cancer in Africa: Update. Semin Oncol 2001;28:174-8.  Back to cited text no. 1
2.Shariat SF, Casella R, Monoski MA, Sulser T, Gasser TC, Lerner SP. The addition of urinary urokinase-type plasminogen activator to uri­nary nuclear matrix protein 22 and cytology improves the detection of bladder cancer. J Urol 2003;170:2244-7.  Back to cited text no. 2
3.Sjakste N, Sjakste T, Vikmanis U. Role of the nuclear matrix proteins in malignant transfor­mation and cancer diagnosis. Exp Oncol 2004;26:170-8.  Back to cited text no. 3
4.Bredel M, Pollack IF, Hamilton RL, Birner P, Hainfellner JA, Zentner J. DNA topoisomerase IIalpha predicts progression-free and overall survival in pediatric malignant non-brainstem gliomas. Int J Cancer 2002;99:817-20.  Back to cited text no. 4
5.Chang HW, Chow V, Lam KY, Wei WI, Yuen A. Loss of E-cadherin expression resulting from promoter hypermethylation in oral tongue carcinoma and its prognostic significance. Cancer 2002;94:386-92.  Back to cited text no. 5
6.Bryan RT, Tselepis C. Cadherin switching and bladder cancer. J Urol 2010;184:423-31.  Back to cited text no. 6
7.Berchem G, Glondu M, Gleizes M, et al. Cathepsin-D affects multiple tumor progres­sion steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene 2002;21:5951-5.  Back to cited text no. 7
8.Hardwicke J. Proteinuria. Sci Basis Med Annu Rev 1970;211-29.  Back to cited text no. 8
9.Zhau HY, Babaian RJ, Hong SJ. A new 180 kDa. urine protein marker associated with bladder cancer. J Urol 1990;144:47-52.  Back to cited text no. 9
10.Eissa S, Swellam M, Sadek M, Mourad MS, El Ahmady O, Khalifa A. Comparative evaluation of the nuclear matrix protein, fibronectin, urinary bladder cancer antigen and voided urine cytology in the detection of bladder tumors. J Urol 2002;168:465-9.  Back to cited text no. 10
11.Godekmerdan A, Yahºi S, Semerciöz A, Ilhan F, Akpolat N, Yekeler H. Determination of Nuclear Matrix Protein 22 Levels in Cystitis, Urothelial Dysplasia and Urothelial Carcinoma. Turkish J Med Sci 2006;36:93-6.  Back to cited text no. 11
12.Sanchez-Carbayo M, Urrutia M, Silva JM, Romani R, De Buitrago JM, Navajo JA. Com­parative predictive values of urinary cytology, urinary bladder cancer antigen, CYFRA 21-1 and NMP22 for evaluating symptomatic pa­tients at risk for bladder cancer. J Urol 2001; 165:1462-7.  Back to cited text no. 12
13.Sawczuk IS, Bagiella E, Sawczuk AT, Yun EJ. Clinical application of NMP22 in the manage­ment of transitional cell carcinoma of the bladder. Cancer Detect Prev 2000;24:364-8.  Back to cited text no. 13
14.Casella R, Huber P, Blochlinger A, et al. Urinary level of nuclear matrix protein 22 in the diagnosis of bladder cancer: Experience with 130 patients with biopsy confirmed tumor. J Urol 2000;164:1926-8.  Back to cited text no. 14
15.Akaza H, Miyanaga N, Tsukamoto T, et al. Evaluation of urinary NMP22 (nuclear matrix protein 22) as a diagnostic marker for urothelial cancer-NMP22 as a urinary marker for surveillance of bladder cancer. NMP22 Study Group. Gan To Kagaku Ryoho 1997;24:829-36.  Back to cited text no. 15
16.Sumi S, Arai K, Kitahara S, Yoshida KI. Pre­liminary report of the clinical performance of a new urinary bladder cancer antigen test: Comparison to voided urine cytology in the detection of transitional cell carcinoma of the bladder. Clin Chim Acta 2000;296:111-20.  Back to cited text no. 16
17.Sanchez-Carbayo M, Herrero E, Megias J, Mira A, Soria F. Evaluation of nuclear matrix protein 22 as a tumour marker in the detection of transitional cell carcinoma of the bladder. BJU Int 1999;84:706-13  Back to cited text no. 17
18.Matsumoto K, Shariat SF, Casella R, Wheeler TM, Slawin KM, Lerner SP. Preoperative plasma soluble E-cadherin predicts metastases to lymph nodes and prognosis in patients undergoing radical cystectomy. J Urol 2003; 170:2248-52  Back to cited text no. 18
19.Shi B, Laudon V, Yu S, Dong D, Zhu Y, Xu Z. E-cadherin tissue expression and urinary soluble forms of E-cadherin in patients with bladder transitional cell carcinoma. Urol In 2008;81:320-4.   Back to cited text no. 19
20.Staack A, Tolic D, Kristiansen G, Schnorr D, Loening SA, Jung K. Expression of cathepsins B, H, and L and their inhibitors as markers of transitional cell carcinoma of the bladder. Urology 2004;63:1089-94.  Back to cited text no. 20

Correspondence Address:
Ragaa H.M. Salama
Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut
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DOI: 10.4103/1319-2442.100957

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  [Table 1], [Table 2]


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