Urine survivin as a diagnostic biomarker for bladder cancer: a systematic review BJUIBJU INTERNATIONAL † ‡ Ja Hyeon Ku * , Guilherme Godoy * , Gilad E. Amiel * and Seth P. Lerner * * Scott Department of Urology, Baylor College of Medicine , and ‡ Michael E. Debakey Veterans Affairs Medical Center, Houston, TX, USA , and † Department of Urology, Seoul National University College of Medicine, Seoul, Korea Accepted for publication 9 November 2011 To determine the clinical utility of urine What ’ s known on the subject? and What does the study add? survivin as a bladder tumour marker we Although many tests for identifying patients with new or recurrent bladder cancer systematically reviewed the available have been used, a reliable method has yet to be established. Recently, increasing evidence. A comprehensive literature review attention has focused on the role of survivin in bladder cancer detection. was performed, from August 1997 to March 2011, using three search engines in Because urine survivin tests have better sensitivity than cytology, urine survivin could English including PubMed, Cochrane potentially replace routine cytology and might be used as an adjunct method for Library, and SCOPUS. Two reviewers cystoscopy. However, the clinical utility of urine survivin as a bladder tumour marker independently evaluated both trial identifi ed in the present study remains to be elucidated. eligibility and methodological quality and data extraction. We included studies that subsets of data. There were 2051 subjects, cytology, but did not match cytology for evaluated urine survivin, used cystoscopy including 1038 in the case group and 1013 specifi city. The clinical utility of urine and/or histopathology as the reference in the control group, and heterogeneity survivin as a bladder tumour marker standard, and allowed the construction of was present among diagnostic studies. The identifi ed in the present study remains to a 2 × 2 contingency table. Bivariate pooled sensitivity and specifi city for urine be elucidated. random effect meta-analyses were used to survivin tests were 0.772 (95% confi dence calculate the summary estimated of interval [ CI ] 0.745 – 0.797) and 0.918 (95% sensitivity and specifi city and to construct CI 0.899 – 0.934), respectively. The area KEYWORDS a summary receiver-operating under the curve of urine survivin tests characteristics curve of urine survivin tests. was 0.9392. When a subgroup analysis bladder neoplasm , survivin , urine , In all, 14 studies were included in the with six studies was performed, urine diagnostic test , systematic review , present review; two studies had two survivin tests had better sensitivity than meta-analysis INTRODUCTION compared with expensive and invasive tests [ 5 ] . Most of these tests have a better cystoscopy procedures. Although urine sensitivity for detecting bladder cancer than Bladder cancers are the second most cytology is highly sensitive in the urinary cytology, but the specifi city is lower. common urological malignancy in the recognition of high-grade urothelial It remains unclear whether or not these Western world, with an estimated 70 530 carcinomas, urine cytology has poor tests offer additional information that is new cases diagnosed each year in the USA sensitivity in low-grade bladder tumours useful for the detection and management of [ 1 ] . Most diagnosed patients (75 – 85%) [ 5 ] . In addition, urine cytology has poor non-muscle invasive bladder tumours [ 5 ] . present with non-muscle invasive disease, inter- and intra-observer reproducibility [ 6 ] . Therefore, a reliable diagnosis and which is characterised by a probability of Cystoscopy is the ‘ gold standard ’ method for surveillance method has yet to be recurrence and progression at 5 years of diagnosing bladder cancer and is also used established. 31 – 78% and 1 – 45%, respectively [ 2 ] . Early in the surveillance of patients with a history diagnosis and postoperative monitoring of of bladder cancer [ 3 ] . However, this method An ideal marker would be offi ce-based, rapid bladder cancer is benefi cial to improve is an invasive and costly procedure, may and inexpensive, and have high specifi city patient prognosis [ 3 ] because detecting miss small papillary tumours and carcinoma and sensitivity in the target population, bladder cancer earlier may decrease the rate in situ , and may be over used particularly in which might reduce the burden of frequent of progression [ 4 ] . patients with low-grade disease. cystoscopy and cost of care. Recently, increasing attention has focused on the role Screening, as well as follow-up of patients Many studies have searched for, developed, of survivin in bladder cancer detection. with bladder cancer, is usually performed and evaluated new tests for identifying Survivin is a structurally unique inhibitor of by urinary cytology as an adjunct to patients with new or recurrent bladder apoptosis protein (IAP) characterized by a cystoscopy. Urine cytology has advantages cancer that are more reliable than cytology highly conserved baculovirus IAP repeat 630 © 2012 BJU INTERNATIONAL | 110, 630–636 | doi:10.1111/j.1464-410X.2011.10884.x URINE SURVIVIN IN DIAGNOSIS OF BLADDER CANCER (BIR) domain. Survivin is a 12-amino acid search criteria. We then determined the fi nal version of the Quality Assessment of protein (16.5 kDa) encoded at chromosomal studies included in the meta-analysis after Diagnostic Accuracy Studies (QUADAS) tool region 17q25, and acts as an IAP by applying the same inclusion and exclusion [ 11 ] , which has 14 items. Every included inhibiting caspases 3, 7, and 9 [ 7 ] . Survivin criteria to the remaining content of the study was assessed by ‘ yes ’ , ‘ no ’ , and is almost exclusively expressed in malignant articles. To be enrolled in the present study, ‘ unclear ’ from the variations (items 1 and 2), epithelium and can be measured in urine at retrieved studies had to fulfi l the following the bias (items 3 – 7, 10 – 12, and 14) and the mRNA and protein level [ 8 ] . Survivin is inclusion criteria: provide a 2 × 2 the report quality (items 8, 9, and 13), expressed in human and rat embryogenesis contingency table; detect survivin in urine; respectively, and the causes of bias and tissues and most human tumours, but not in published in English; include a per patient variations were identifi ed. normal adult tissues (except the thymus analysis; and use cystoscopy and/or gland) [ 9 ] , which makes survivin especially histopathology as the reference standard. HOMOGENEITY TEST signifi cant compared with other IAP Exclusion criteria were as follows: non- members broadly distributed in normal adult human study; review articles; letters; Heterogeneity was explored using the tissues. Given the sharp differential editorial comments; case reports; articles chi-square test and likelihood ratio (LR) I2 . expression of survivin in cancerous vs that did not include raw data; and studies LR I2 measures the percentage of the total normal tissues, the detection of survivin on cancer not arising in the bladder. When variation across studies that are due to appears to be a suitable tool for cancer data or subsets of data were presented in heterogeneity rather than chance. LR I 2 is diagnosis. As a member of IAPs, survivin is more than one article, only the largest series evaluated as follows: I 2 = (Q – df)/Q × 100%, overexpressed in undifferentiated cells were included in the analysis. A cohort of where Q is Cochran ’ s heterogeneity statistic associated with a high potential of cell patients was not included more than once and df is the degrees of freedom. An I 2 proliferation [ 10 ] . in the same analysis. Included studies met > 50% may be considered to represent the quality criteria for studies of diagnosis substantial heterogeneity [ 12 ] . For the We performed a systematic review of the of the Oxford Centre for Evidence-Based LR chi-square test, we judged that diagnostic accuracy of trials of urine Medicine. Briefl y, the studies had clearly heterogeneity was signifi cant for P < 0.05. survivin tests for bladder cancer. The present identifi ed different groups of patients (with When there was evidence of heterogeneity, study sought to evaluate and compare the and without disease, and positive and data were analysed using a random effects detection validity (sensitivity and specifi city) negative tests). All included studies had a meta-analysis to obtain a summary estimate of urine survivin tests in the diagnosis of true-negative group that was free of the for the test sensitivity with 95% CIs. Studies bladder cancer and to construct a summary disease according to the defi nition used in in which positive results were confi rmed receiver-operating characteristic (ROC) the present study. were conducted using a pooled specifi city curve. with 95% CIs. EXTRACTION OF DATA THRESHOLD EFFECT ANALYSIS MATERIALS AND METHODS One reviewer (J.H.K) screened the titles and abstracts identifi ed by the search strategy A different threshold may be used in SEARCH STRATEGY and then two reviewers (J.H.K. and G.G.) included studies to defi ne positive test independently assessed the full tests for results due to lack of standardisation. A A comprehensive computer literature search inclusion. The database was designed to differential threshold effect may be the for abstracts was performed to identify ensure the most relevant data with respect reason for detectable sensitivities and articles about the diagnostic performance of to author, year of publication, demographics specifi cities of test accuracy studies. urine survivin for the detection of bladder of the patients, tumour characteristics, Summary ROC curves were constructed to cancer. We did a systematic review of geographic location, period of recruitment, see the variation between studies and original articles published between August study design, adoption of the ‘ blind ’ method, summarise the results quantitatively. A 1997 and March 2011 that analysed the and reference standard. The data extracted threshold effect was suspected with the diagnostic role of urine survivin in patients from articles comprised the number of ROC space graph if the points aligned in a with bladder cancer.