Asian Pac J Cancer Prev. 2013;14(1):81-5.

Diagnostic role of survivin in urinary bladder cancer.

Anupam Kumar Srivastava1, Pankaj Kumar Singh1, Kirti Srivastava1, Dhramveer Singh2, Divakar Dalela2, Srikanta Kumar Rath3, Madhu Mati Goel4, Madan Lal Brahma Bhatt1*

1Department of Radiotherapy, 2Department of Urology, 4Department of Pathology, King George’s Medical University, 3Genotoxicity Laboratory, Division of Toxicology, Central Drug Research Institute, MG Marg, Lucknow, Uttar Pradesh, India *For correspondence: drmlbhatt@yahoo.com , sriannu57@gmail.com

 

ABSTRACT

BACKGROUND: Early diagnosis of carcinoma of bladder remains a challenge. Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is frequently activated in bladder carcinoma. The objective of this study was to investigate urinary survivin as a marker for diagnosis of urinary bladder.

MATERIALS AND METHODS: We examined urinary survivin concentration in 28 healthy individuals, 46 positive controls and 117 cases of histologically proven TCC prior to transurethral resection, using ELISA, and compared values with findings for urinary cytology.

RESULTS: Survivin was found to be significantly higher in the cancer group (P<0.05). A cut off value of 17.7 pg/ml was proposed, with an approximate sensitivity of 82.9% and specificity of 81.1% (P<0.0001), whereas urine cytology had a sensitivity of 66.7% and a specificity of 96.0%.

CONCLUSIONS: Urinary survivin can be used as a non-invasive diagnostic biomarker for TCC bladder, both for primary and recurrent disease.

DOI:http://dx.doi.org/10.7314/APJCP.2013.14.1.81

PMID: 23534808

 

SUPPLEMENT:

Numerous institutions routinely use screening cystoscopy, urinary cytology and random bladder biopsies in an attempt for initial diagnosis of transitional cell carcinoma (TCC). It is well known that, painless hematuria, the most prevalent symptom, is found in only 4-10% of cases of bladder cancer. These screening programs, however, have not met these universal tenets and, therefore, none of the protocol has been clinically useful for screening patients with the preclinical symptoms of bladder cancer. The application of biomarkers, as an adjunct or to supplant cystoscopy, as a screening test for diagnosis of bladder cancer in patients has not been extensively investigated and is the need of the hour. In the present study, we have evaluated the urinary survivin performed by ELISA (enzyme-linked immunosorbent assay) for TCC of urinary bladder and compared the results with the conventional urinary cytology. Taking the hypothesis that survivin could be used as a functional marker of early diagnosis in both new-onset and a recurrent bladder tumor, the current study was designed to assess the clinical utility of survivin as a diagnostic biomarker with the help of ELISA in detection of bladder cancer and it was compared with the cytology as the conventional marker in TCC. Approximately 50 cc. and naturally voided midstream urine sample was obtained prospectively from all subjects. ELISA was done with Quantikine® Human Survivin Immunoassay kits (RnD systems, MN, USA). the survivin concentration differed significantly between the three groups. In cancer patients (n=117) the survivin concentration was significantly different and higher (p<0.001) as compared to both healthy controls (n=28) and non malignant patients (n=46) while it did not differ (p=0.367) between healthy controls and non malignant patients. The survivin concentration showed direct and significant (p<0.001) correlation with stage, nodal status and cytology while it did not show any association (p=0.349) with grade. A significant association (p<0.001) was found in urinary survivin levels in patients with early stage disease (Ta-T2) versus advanced stage disease (T3-T4) and for all study sub-groups Vs control (p<0.001). The differences among the sub-groups were significant (p<0.05) except in treated superficial cases Vs primary superficial cases (p=1.0). Urinary survivin levels were analyzed with reference to nodal status patients with TCC. Out of 117 bladder cancer patients, 15 were node positive (N1) and rest of 102 node negative (N0) case. The difference between the two groups was statistically significant (p=0.001). Out of 15 node positive bladder cancer cases, 14 had higher urinary survivin levels, whereas 12 were urinary cytology positive. A significant difference was not found in survivin expression between primary (n=69) and recurrent (n=27) cases (p=0.573). The area under the ROC curve was 0.881 with an optimal cut-off value 17.74 pg/ml was proposed, corresponding to a sensitivity of 82.91% (95%CI: 74.84-89.23%) and specificity of 81.08% for TCC cases. Out of 117 cancer cases, 78 (66.7%) were found cytology positive and 96 (82.1%) were found survivin positive. Overall sensitivity of survivin was 82.91% and specificity was 81.08%, whereas urine cytology had sensitivity of 66.67% (95%CI: 57.36-75.11%) and specificity of 95.95%. The urinary survivin concentration showed more sensitivity than cytology (grade wise, stage wise and wise), but cytology was considerably more sensitive for high-grade tumors whereas in the patients of lower grade, the sensitivity of survivin was 79.31% in comparison to the 41.38% sensitivity by cytology. It is well known that urine cytology is not suitable for the diagnosis of lower grade carcinoma of urinary bladder. Also, the urine sample for cytology needs to be processed which is sometimes not possible.

Overall, our results indicate that survivin gives higher positive results in comparison to cytology, particularly in low grade, early stage disease. With the encouraging results of urinary survivin by ELISA system over conventional urinary cytology, the diagnosis of urinary bladder malignancy by examination of urinary survivin can become more reliable and least invasive. Based on the results of our study, we may recommend urinary survivin as a suitable diagnostic marker for the early diagnosis and monitoring the bladder cancer. Further evaluation of urinary survivin in a larger patient population is warranted before the use of urinary survivin for routine clinical use and early detection of urinary bladder cancer.

fig_1_convertedFig 1. Analysis of Survivin Concentration. Scatter plot shows ELISA absorbance values in healthy individuals, non cancer patients bladder cancer.



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