HA-HAase URINE TEST: A Sensitive and Specific Method for Detecting Bladder Cancer and Evaluating Its Grade

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Heterogeneity in the ability to invade and metastasize is a fundamental characteristic of transitional cell carcinoma (TCC) of the bladder.8 TCC accounts for most (approximately 90%) bladder tumors. Low-grade TCC (G1) is generally confined to the mucosa (stage Ta) and rarely metastasizes (<2%). Intermediate-grade tumors range from noninvasive (Ta) lesions to tumors invading the lamina propria and beyond (stages ≥T1). Most high-grade TCC (G3), except for carcinoma in situ (CIS), is detected at or beyond stage T1.8, 21 Bladder cancer is usually detected when patients present with hematuria. Although for low-grade bladder tumors this mode of detection may be adequate, for high-grade tumors, hematuria may be a sign of poor prognosis. At clinical presentation patients with high-grade bladder cancer often have muscle invasive disease (stage ≥T2). Despite radical therapy, clinical metastasis develops in these patients within 2 years, and more than two thirds of patients die within 5 years of initial diagnosis.8, 21 The diagnosis of bladder cancer prior to muscle invasion would improve prognosis.

The multifocal nature of bladder tumors is responsible for their frequent recurrence.4, 23 Most recurring tumors are new occurrences and are of similar grade as the original tumor. In a period of 3 years, 50% of G1 tumors and 80% of G3 tumors typically recur. Close follow-up every 3 to 6 months is mandatory for most patients with bladder cancer.

The gold standard for bladder cancer detection and post-treatment surveillance protocols is cystoscopy, frequently supplemented with urine cytology, and biopsy of a suspicious area. Although flexible cystoscopy may diminish discomfort for patients, this modality is still expensive and invasive. Urine cytology is easy to perform, but its sensitivity for detecting G1 and G2 bladder tumors is low, and the evaluation may have a subjective bias.

Significant improvement in bladder cancer diagnosis and management could be achieved if a simple, noninvasive, highly sensitive and specific diagnostic test was designed. Such a test would complement existing standard detection methods or could be used as an independent method of diagnosis and follow-up. An ideal test could be designed if molecules associated with bladder tumor growth, metastasis, and angiogenesis could be identified. Soluble molecules would be secreted in urine and could serve as urinary markers for bladder cancer detection and follow-up. In searching for such molecules, the authors have focused on extracellular matrix components, in particular glycosaminoglycans, because these substances and proteoglycans coat the transitional epithelium of the bladder and function in normal bladder physiology.10 Research performed in the authors' laboratory demonstrates that two molecules, hyaluronic acid (HA) and hyaluronidase (HAase), are sensitive urinary markers for detecting bladder cancer and evaluating its grade.

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Address reprint request to Vinata B. Lokeshwar, PhD, Department of Urology (M-800), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101, e-mail: [email protected]

This work was supported by National Cancer Institute grant R29 CA 72821 (VBL) and L. Austin Weeks Endowment funds (NLB and VBL).