Virtual Histology of the Bladder Wall for Bladder Cancer Staging

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Bladder cancer (BCa) is one the five most common malignancies worldwide, which is staged by the penetration of bladder tumor in different layers of bladder wall for optimal treatment. Currently, a costly regimen of routine cystoscopy, transurethral resection of the tumor (TURBT) and imaging surveillance is recommended to counter the high BCa recurrence rate of 80%. Although radical cystectomy is the gold standard for staging accuracy, it is not practical for directing treatment. Since TURBT and available imaging modalities suffer from a ~50% failure rate in detecting muscle invasion, there is an unmet need for safe, radiologic measures to distinguish indolent from aggressive BCa for surveillance, to select patients for appropriate regimens of bladder sparing neoadjuvant therapy and to minimize the delay in curative cystectomy of aggressive BCa. Although dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after intravenous injection of gadolinium- based contrast agent (GBCA) was dramatically superior to computed tomography for tumor staging of BCa, MRI is relatively poorly developed and major barriers still exist in the adaption of MRI for BCa diagnosis and prognosis. Besides, injected GBCA carries the risk of allergic reaction, health risk and increased healthcare cost. The scientific premise of this exploratory study is based on our recent report of high-resolution MRI of rodent and human bladder wall following direct bladder instillation (via urethral catheter) of a novel contrast mixture (NCM) composed of Gadobutrol (GBCA) and Ferumoxytol in sterile water for positive contrast in bladder wall via diffusion of GBCA and simultaneous negative contrast in bladder lumen via retention of Ferumoxytol (molecular size 10 fold of GBCA). Thus, NCM enhanced T1 weighted MRI can leverage the differential GBCA permeability of cancerous and normal cells in bladder wall to accomplish three-dimensional (3D) bladder wall imaging for improved tumor detection and non-surgical BCa staging. Following specific aims are designed to establish the technical and scientific merit of NCM-MRI for BCa staging, before pursuing a future randomized clinical trial towards the goal of making high resolution 3D MRI, a clinical standard in BCa diagnosis and treatment. Aim 1 will evaluate the intermodality agreement between histopathologic staging of TURBT specimens and the pre-operative clinical staging of BCa by abbreviated NCM-MRI in 21 patients with at least one cystoscopically confirmed papillary bladder tumor. Aim 2 will evaluate the intermodality agreement between preoperative NCM-MRI for BCa staging with the gold standard of whole-mount pathologic review of cystectomy specimen in 21 histologically proven muscle invasive BCa patients. The strength of intermodality agreement between NCM-MRI and the histopathology will be assessed by Kappa (κ) statistics and the relative differences of two techniques by paired t test. MRI based active surveillance has transformed the care of prostate cancer and this exploratory study seeks to accomplish the goal of virtual histology through pixel-wise T1 mapping to demonstrate the potential of NCM enhanced MRI as minimally invasive tool for BCa staging.