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Radiologic Imaging of Patients With Bladder Cancer
Radiologic Imaging of Patients With Bladder Cancer Andrei S. Purysko,a Hilton M. Leão Filho,b and Brian R. Hertsa Imaging has an ancillary but important role in the detection, staging, and follow-up of bladder cancer. Computed tomography urography (CTU) has widely replaced intravenous urography (IVU) and is currently the imaging modality most commonly used for the initial evaluation of patients with or suspected of having bladder tumors, as CTU allows a fast and comprehensive evaluation of the urinary tract in a single exam. Magnetic resonance imaging (MRI) affords better soft tissue contrast, which allows for more accurate staging than can be achieved with other imaging modalities; the role of MRI in bladder cancer is expected to grow. Despite myriad technical advances, imaging of the bladder has several limitations and technical challenges. The performance of the common and some promising newer imaging modalities in the evaluation of bladder cancer are discussed. Semin Oncol 39:543-558 © 2012 Elsevier Inc. All rights reserved.
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ladder cancer is the most common malignancy of the urinary tract, and according to the most recent analysis of cancer cases in the United States, it is the fifth most common malignancy overall, with a stable incidence in men and a declining incidence in women.1 Approximately 90% to 95% of bladder cancers are primary and epithelial in origin (ie, transitional cell carcinomas).2 The most common risk factor for bladder cancer is cigarette smoking.3 The gold standard for the diagnosis of bladder cancer is cystoscopy; however, imaging also plays an important role in the evaluation and management of patients with bladder cancer. For years, intravenous urography (IVU) was the mainstay for imaging the upper urinary tract and bladder; more recently, computed tomography (CT) and, to a lesser extent, magnetic resonance imaging (MRI) now play a greater role. Despite myriad technical advances in these imaging techniques, there are still several limitations and technical challenges when imaging the urinary bladder. In the following sections, we discuss the performance of aDepartment
of Radiology, Section of Abdominal Imaging, and Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. bRadiology Department, HCor—Hospital do Coração, São Paulo, SP, Brazil. Financial disclosures or conflicts of interest: Dr Herts receives research funding from Siemens Medical for the investigation of CT dose and dose reduction techniques. Address correspondence to Brian R. Herts, MD, Imaging Institute, Desk Hb6, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected] 0270-9295/ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2012.08.010
Seminars in Oncology, Vol 39, No 5, October 2012, pp 543-558
various imaging modalities in the detection, staging, and post-treatment follow-up of bladder cancer.
BLADDER CANCER DETECTION The search for bladder cancer most often occurs in the context of hematuria, as approximately 85% of patients with bladder cancer present with painless macroscopic hematuria; however, only 15% of cases of macroscopic hematuria originate in the bladder.4,5 In general, the recommended evaluation of patients with hematuria includes urine cytology, cystoscopy, and at least one imaging study to evaluate both the upper and lower urinary tracts. There are few data to support any one bladder imaging modality as superior to the others for the detection of bladder neoplasms.6 The final diagnosis of bladder cancer ultimately depends on histologic evaluation of a biopsy specimen obtained during cystoscopy.7 However, cystoscopy is invasive, time-consuming, expensive, and often requires sedation or anesthesia. Cystoscopy also may lead to iatrogenic injuries. Additionally, cystoscopy examination may not be suitable in patients with severe urethral strictures or in those with active bleeding, and evaluation of lesions located in the base and neck of the bladder or within a bladder diverticulum is difficult because of the limited field of view.8
Intravenous Urography Historically, IVU has been the initial imaging study used to evaluate patients with hematuria (Figure 1). IVU is widely available and cost-effective.9 For patients diagnosed with bladder cancer, IVU is used to assess for the presence of synchronous urothelial tumors in 543
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Figure 1. Transitional cell carcinoma of the bladder on intravenous urography (IVU). Coned-down view of the bladder from IVU shows a mass-like filling defect along the left lateral bladder (arrowheads).
the upper urinary tract, although these tumors occur in less than 5% of patients with bladder cancer.10 Up to 60% of known bladder tumors are visualized by IVU, whereas 66.6% of the upper urinary tract lesions are detected.11–14 However, with the advent of modern multidetector row CT scanners, IVU has been almost entirely replaced by CT urography (CTU) for the evaluation of patients with hematuria.
Ultrasound Transabdominal ultrasound (US) is a safe, noninvasive, relatively low-cost imaging method that can be used to examine the kidneys and the urinary bladder when the latter is distended. US is the study of choice for the initial investigation of hematuria in some centers. Advocates of US for the evaluation of hematuria report that there are few differences between US and IVU for the detection of various renal and bladder pathologies, and US can be performed without the risks associated with intravenous iodinated contrast material or exposure to ionizing radiation.15–17 However, most centers reserve US for radiation-sensitive populations, specifically for children and pregnant women.18 Additionally, the ability of US to depict upper tract urothelial tumors is poor and US has a low sensitivity when detecting bladder cancers. Reported sensitivity of transabdominal US for bladder tumors has been found to vary from 26% to 91.4%.8,15,19 Diagnosing bladder cancer with US entails detection of either focal bladder wall thickening or the presence of a fixed bladder wall mass protruding into the bladder lumen (Figure 2). The accuracy of US in detecting bladder lesions depends on several factors, most notably the morphology, size, and location of the lesion. Sessile lesions, lesions less than 0.5 cm in diameter
A.S. Purysko, H.M. Leão Filho, and B.R. Herts
regardless of location, and lesions of any size located in the bladder neck or dome are difficult to detect.20 Ozden et al reported that up to 42% of cancers in the anterior lower bladder wall were missed by US.21 The accuracy of US is also limited by equipment quality, body habitus, bladder distension, and examiner experience.17,19,22 Three-dimensional (3D) virtual sonography and contrast-enhanced US (CEUS) are well-established refinements in US imaging that have more recently been tested in the evaluation of bladder cancer. Favorable results have been reported with both techniques, but the available data are currently limited. Kocakoc et al evaluated 31 patients with known or suspected bladder cancer using two-dimensional (2D) gray-scale sonography combined with multiplanar reconstructions and 3D virtual sonography.23 For tumor detection, combined 2D and 3D sonography had a sensitivity of 96.4%, a specificity of 88.8%, a positive predictive value (PPV) of 97.6%, and a negative predictive value (NPV) of 84.2%. Although these results correlated well with conventional cystoscopy findings, the study was unable to demonstrate a statistically significant improvement with these techniques versus with 2D gray-scale imaging. Other research has shown that CEUS has a reported sensitivity of 88.5%, specificity of 88.9%, PPV of 95.8%, and NPV of 72.7%.17
Computed Tomography/ Computed Tomographic Urography With widespread availability and dedicated protocols, CT has supplanted the use of IVU in many insti-
Figure 2. Papillary transitional cell carcinoma of the bladder on ultrasound. Transabdominal ultrasound shows a polypoid intraluminal bladder tumor (arrow) at the bladder trigone. P, prostate; SV, seminal vesicle.
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Figure 3. Transitional cell carcinoma of the bladder on CT urography (CTU). Coronal volume-rendered reformatted image from CTU demonstrates a large mass within the urinary bladders; reformatted images are created to simulate the more familiar intravenous urogram image. Coronal coned-down image of the bladder shows a predominantly intravesical mass (asterisk on B) arising from the right lateral wall with bladder wall thickening. Cystoscopic view of the bladder mass (C, arrows).
tutions for evaluation of the urinary tract. The most recent revision of the American College of Radiology appropriate criteria ranks CTU as the best initial imaging examination for the evaluation of patients with hematuria.18 Multidetector CT (MDCT) datasets composed of isotropic voxels allow images of equal spatial resolution to be obtained in any plane, and 3D reformation of the excretory-phase images can produce images that mimic the appearance of IVU (Figure 3).24,25 Protocols for CTU vary, but in general they include unenhanced, nephrographic, and excretory-phase imaging or unenhanced imaging with a combination of the latter two phases (split-bolus technique). Two studies comparing CTU with cystoscopy are noteworthy. Turney et al conducted a study in a fasttrack hematuria clinic in which 200 consecutive patients were prospectively evaluated with CTU and flexible cystoscopy on the same day.26 The prevalence of bladder cancer in these patients was 24%. The sensitivity, specificity, and NPV of CTU for the detection of
bladder cancer in this study were 93%, 99%, and 98%, respectively. In a different study, Sadow et al found in a retrospective study of 838 CTUs from patients who also had been evaluated by cystoscopy within a 6-month period, that the overall sensitivity, specificity, PPV, and NPV for CTU in detecting bladder cancer were 79%, 94%, 75%, and 95%, respectively. Higher specificity and NPV (96% and 98%, respectively) was noted in the subgroup of patients with hematuria.27 The sensitivity of CTU in this latter study was greater in patients with gross hematuria than in those with microscopic hematuria (83.3% v 42.9%).27 As with other imaging modalities, CT has limited ability to detect small bladder lesions. In one study evaluating the ability of dynamic contrast-enhanced MDCT to detect bladder cancer, the overall sensitivity achieved with thin-section images combined with multiplanar reconstructions was 90%; sensitivity decreased to 79% for lesions 1 cm or smaller and to 58% for lesions 5 mm or smaller.28 Some bladder cancers in initial stages may present as faint color changes in the
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mucosa and can only be detected on direct visualization. CT also has limited ability to distinguish tumors from changes related to biopsy or transurethral resection of the bladder (TURB) performed during cystoscopy. One study found that the frequency of concordance between findings at CT and findings from histologic examination was greater in patients with a time interval of 7 or more days between those procedures than in those with a time interval of fewer than 7 days.29 The use of CT to detect bladder cancer also is limited in patients with severely impaired renal function, patients with metallic prostheses in the pelvis that cause imaging artifacts, and patients with bladder lesions adjacent to the prostate, as these may be mistaken for a normal prostate or for a prostatic lesion.26,30 Positron emission tomography (PET)/CT is limited in its ability to provide evidence for a primary diagnosis of urothelial tumors because of tracer excretion into the urinary tract; however, PET/CT is often used for staging bladder cancer (as discussed later).
Magnetic Resonance Imaging In recent years, MRI of the abdomen and pelvis has greatly improved with the development of faster imaging acquisition techniques that help overcome both respiratory and bowel motion artifacts. With MRI, multiplanar imaging acquisition and multiplanar imaging reconstruction with 3D sequences can be performed. MRI does not involve the risks of ionizing radiation; however, MRI is not as widely available as CT and is more expensive. Although studies have shown good sensitivity in the detection of bladder cancer, the role of MRI in the detection of urothelial lesions remains under investigation.18 In a prospective study of 36 patients with a history of bladder cancer comparing CT and MRI, the sensitivity and PPVs for tumor detection were 93% and 96%, respectively, for CT; 94% and 94%, respectively, for MRI on T2-weighted imaging; and 100% and 93%, respectively, for dynamic gadolinium-enhanced MRI.31 Another prospective study of 79 patients with 83 bladder tumors demonstrated that the detection of small (⬍1.0 cm) lesions significantly improved on MRI after the administration of intravenous contrast media, compared with detection on precontrast MRI images and CT.32 Although gadolinium-based contrast agents used on MRI are not nephrotoxic when administered at recommended doses, in patients with chronic kidney disease, these agents are associated with the development of nephrogenic systemic fibrosis (NSF), a severely debilitating and potentially fatal systemic fibrosis. It is accepted that patients with stage IV or V chronic kidney disease (estimated glomerular filtration rate [eGFR] ⬍30 mL/min) are at increased
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risk of developing NSF, and so the use of gadolinium agents should be avoided in these patients.7,33
New MRI Technique: Diffusion-Weighted Imaging Diffusion-weighted imaging (DWI) is a promising MRI technique for detecting and characterizing lesions in several organs of the abdomen and pelvis. Recent refinements allow this imaging to occur under free breathing, which enables longer scan times, thinner slices, and signal averaging; these factors in turn improve image quality.34,35 In DWI, image signal is based on the natural thermally induced Brownian motion of water molecules: the signal intensity is high if water molecules are restricted in their motion, which can be caused by cell membranes or, in the case of free fluid, by high viscosity.36 This diffusion of water molecules can be calculated and displayed on apparent diffusion coefficient (ADC) maps. The high cell density in tumors can produce restricted diffusion (Figure 4), although restricted diffusion does not occur exclusively in malignant tissues. In one study of 130 patients presenting with gross hematuria, the sensitivity, specificity, PPV, NPV, and accuracy of DWI were 98.1%, 92.3%, 100%, 92.3%, and 97%, respectively.36 Two false negatives on T2-weighted MRI were correctly diagnosed with DWI. The agreement between DWI and cystoscopic findings for identifying bladder neoplasm was excellent (K⫽ 0.94). In another prospective study evaluating the performance of DWI, 121 of 123 tumors noted on cystoscopy were detected on DWI, including 14 of 16 lesions smaller than 10 mm.37 DWI also may be beneficial in differentiating malignant from benign urinary bladder lesions based on the lower ADC values demonstrated by the malignant lesions.38
Virtual Cystoscopy Virtual endoscopic imaging also has been used for the detection of bladder cancer. Volumetric data obtained with either helical CT or MRI are computer rendered to generate 3D images, and with commercially available software, endoluminal visualization of any hollow viscus is then possible.39 Virtual cystoscopy (VC) is most commonly CT based, but regardless of the imaging modality used, adequate distension of the bladder with gas or contrast media is vital (Figure 5). This distension can be achieved by directly inserting the gas or contrast media through a catheter or by using the urine as a natural contrast or by using intravenous contrast that is then excreted into the urinary tract. Although this technique does not produce any new information apart from what is available on the axial CT slices, it does allow for rapid evaluation of the often complex morphology of hollow organs in a more intuitive fashion.40
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to the tumor size.39,41– 43 When compared to transabdominal US, VC has demonstrated favorable results: for tumors <1 cm, VC’s sensitivity was found to be 93.5% versus US’s sensitivity of 50%.8 Additionally, US frequently missed lesions in the anterior and posterior wall, whereas these lesions were identified by VC. There is no evidence to support the use of VC on a routine basis in patients with hematuria. VC requires extra time, both in the scanner and on post processing, and is associated with a higher cost and increased radiation exposure.42 Additionally, unless VC uses contrast excreted by the urinary system, it is an invasive study.
TYPES OF BLADDER NEOPLASMS
Figure 4. Transitional cell carcinoma of the urinary bladder on magnetic resonance imaging. Papillary tumor at the right ureterovesical junction with intermediate signal intensity on axial T2-weighted image (A, arrow). On corresponding diffusion-weighted image (B), the lesion (arrow) demonstrates high signal intensity, a characteristic of restricted diffusion.
Even when a urethral catheter is used, VC is less invasive than conventional cystoscopy and has a very low complication rate. This procedure also can depict extravesical anatomy, which is important for staging.8,36,39 VC images can be complementary to transverse images: some small lesions are better depicted or visible only on the virtual images, while areas of wall thickening are more readily apparent on transverse images.39 The reported sensitivity of VC for the detection of bladder cancer ranges from 60% to 100% and is related
The overwhelming majority (⬎90%) of bladder cancers are transitional cell carcinomas (TCC). These lesions can be papillary (Figures 6 and 7) or infiltrating (Figures 8 and 9) and can occur anywhere in the bladder. TCC of the bladder is rarely calcified; conversely, squamous cell tumors of the bladder, more common with chronic inflammation or associated with schistosomiasis and common in endemic areas, do demonstrate calcifications and are often mass-like, aggressive tumors (Figure 10). Adenocarcinomas are also masslike, aggressive tumors that arise in patients with bladder exstrophy or in those with an urachal remnant. In the latter case, tumors are located at the anterior and superior aspect of the bladder along the urachal ligament (Figure 11). When tumors arise in a bladder diverticulum, they more frequently invade perivesical fat because of the lack of muscularis mucosa in the wall of the diverticulum (Figure 12).4 Other than history and these basic imaging features, there is little to differentiate among the different primary bladder neoplasms, and so biopsy is usually needed.44 Other bladder tumors such as pheochromocytoma, lymphoma, and bladder leiomyosarcomas (Figures 13 and 14) are managed differently from TCC and are beyond the scope of this review.
STAGING The tumor-node-metastasis (TNM) system is the most common method for staging bladder cancer.10,12 CT and MRI allow for ready assessment of extravesical extension, lymph node enlargement, and distant metastases, all of which are used to determine the clinical stage, which allows clinicians to select the appropriate treatment and provide a prognosis.32
Tumor Staging In patients with bladder cancer, T stage refers to the depth of bladder wall invasion by the tumor. Clinical management of urinary bladder cancer is determined primarily on the basis of distinguishing superficial tu-
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A.S. Purysko, H.M. Leão Filho, and B.R. Herts
Figure 5. Papillary transitional cell carcinoma of the bladder on virtual cystoscopy. The lesion is not seen on a precontrast image (A) but becomes evident after the bladder is filled by the excreted contrast (black arrow, B). (C) Three-dimensional perspective volume-rendered image (virtual cystoscopy) simulating the conventional cystoscopy view of the tumor (black arrow), which is located near the left ureteral meatus (white arrow).
mors (stage T1 or lower) from invasive ones (stage T2 or higher). Infiltration beyond the lamina propria requires more aggressive treatment than transurethral resection. Approximately 70% to 75% of bladder cancers present as non–muscle-invasive tumors, and of these tumors, the majority (70% to 75%) are confined to the bladder mucosa (stage Ta).10 IVU and transabdominal US are not recommended for staging because of their lower sensitivity in detecting bladder tumors and their inability to accurately evaluate extravesical extension. Endoluminal or intravesical US (ELUS or IVUS), introduced by a rigid cystoscope for intravesical evaluation, provides greater bladder wall detail and is sensitive and specific in detecting muscle invasion in bladder cancer; however, this technique is still not widely available and is invasive.12,45,46
CT is the modality most commonly used for staging bladder cancer, as the same study performed for tumor detection (CTU) can also be used for staging. The reported accuracy of CT for bladder tumor staging ranges from 40% to 92%.37,47 However, CT does not depict individual layers of the bladder wall and therefore cannot be used to reliably estimate the depth of tumor infiltration (Figure 15).48 Additionally, CT is unable to accurately detect microscopic or small-volume extravesical tumor extension.12 The limitations of CT are most significant when CT is performed shortly after TURB49; for this reason, CT should precede cystoscopy when possible. Inflammatory changes after TURB, namely, bladder wall thickening and perivesical fat stranding, may limit accurate cancer detection and diagnosis of perivesical invasion.29,50
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Figure 6. Papillary transitional cell carcinoma of the urinary bladder. (A) Routine enhanced and (B) excretoryphase computed tomography (CT) images from a CT urogram show a papillary mass projecting into the bladder lumen arising near the left ureterovesical junction. Note the higher visibility of the lesion when the bladder is distended with contrast-opacified urine during the excretory phase (B).
Perivesical invasion is diagnosed on CT when the interface between the bladder cancer and perivesical fat is irregular or when the bladder cancer shows overt growth beyond the outer margin of the bladder wall. Using these criteria, Kim et al found CT to have a sensitivity and specificity for diagnosing perivesical invasion of 89% and 95%, respectively, with a time interval of less than 7 days between TURB and the CT study.29 These values increased to 92% and 98%, respectively, when the time interval was 7 or more days. Although CTU offers the potential for a “one-stopshopping” examination to assess local disease, lymph
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nodes, distant metastases, and the upper urinary tract, MRI may offer advantages over CT for local staging. The inherent soft tissue contrast on MRI helps to identify the bladder wall layers and the delineation between the bright perivesical fat and the intermediate signal-intensity bladder, which improves estimation of depth of invasion and extravesical extension, respectively (Figures 16 and 17).12,46,47 In a review of the literature, Barentsz et al found the accuracy of MRI ranging from 76% to 96% for T-staging in bladder cancer.47 A study by Tachibana et al demonstrated superior detection of small tumors (⬍10 mm) and better staging for superficial tumors with MRI than with US and CT.51 The MRI accuracy values reported in the literature are generally 10% to 33% higher than those obtained with CT.37 However, these values should be interpreted with caution, as the studies are not directly comparable because of varying patient populations, particularly regarding pre- and post-TURBT status. For differentiating between superficial (ⱕT1) and muscle-invasive (ⱖT2) bladder tumors, the accuracy of dynamic contrastenhanced MRI has ranged from 75% to 92%, with overall accuracy for diagnosing tumor stage ranging from 52% to 93%.31,32,52–56 Diffusion-weighted MRI shows promise for staging bladder cancer (Figure 18). In a study conducted by El-Assmy et al, bladder cancer was correctly staged in 83 of 106 patients (78.3%) by DWI, which was significantly better (P ⬍.001) than the results obtained with T2-weighted images (39.6%).37 Overstaging was the most common error seen in organ-confined tumors. The accuracy of DWI was 63.6% in differentiating superficial from invasive tumors and 69.6% in differentiating organ-confined from non– organ-confined tumors. On a stage-by-stage basis, DWI accuracy was 63.6%, 75.7%, 93.7%, and 87.5% for stages T1, T2, T3, and T4, respectively. The value of DWI in staging was also demonstrated by Takeuchi et al.55 The accuracy of DWI for diagnosing the tumor stage of bladder cancer was significantly improved when DW images and contrast-enhanced images were viewed in addition to T2weighted images (92% v 67%, P ⬍.01). Importantly, the investigators found that the specificity of DWI for the diagnosis of muscle invasion was 97%. Furthermore, the ADC value, a quantitative measurement of diffusion, was significantly lower in high-grade disease than in low-grade disease, thus providing further information about tumor staging.55,57 However, ADC values depend on multiple factors related to both the MRI hardware (such as the field strengths and coils used for imaging) and the patient, and so specific ADC values determined by these studies cannot be generalized to other sites.
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Figure 7. Multiple papillary transitional cell tumors of the urinary bladder. (A) Volume-rendered reformation and (B, C, and D) coronal excretory-phase images from a computed tomography urogram demonstrate one large (long arrow) and multiple small (short arrows) bladder filling defects. There were multiple papillary transitional cell carcinomas at cystoscopy.
Node Staging Locoregional lymph node metastasis is an important prognostic factor in patients with bladder cancer, as patients with positive lymph nodes have worse survival rates.49,58 Lymph node metastasis also has a strong correlation to tumor stage.49,58 Lymph node involvement in patients with superficial tumors is rare, but if the deep muscle layer is involved or if extravesical invasion is present, the incidence of lymph node metastasis increases to 20%–30% and 50%– 60%, respectively.59 CT and MRI are the modalities of choice for assessing lymph nodes before surgery in patients with bladder cancer. The accuracy range for lymph node staging is 70% to 90% for CT with false-negative rates of 25% to 40%; MRI accuracy ranges from 64% to 92%.60 Unlike in primary tumor detection, contrast-enhanced images do
not appear to improve detection of lymph node involvement.50 Both CT and MRI rely predominantly on nodal size and morphology for detecting metastases; however, there is considerable overlap in size between benign and malignant nodes, resulting in suboptimal sensitivity and specificity for these imaging modalities.61,62 Studies have shown that meticulous lymph node dissection in patients with bladder or prostate cancer identifies a relatively high rate of metastases (25%) in patients with negative preoperative imaging.62 Although PET with 2-deoxy-2 [F] fluoro-D-glucose (FDG) in combination with CT (FDG-PET/CT) is an important imaging modality for the preoperative staging of various neoplasms, the use of FDG-PET/CT for detecting primary urothelial tract malignancies is limited. The urinary excretion and concentration of FDG
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Figure 8. Muscle-invasive infiltrating transitional cell carcinoma of the bladder. A discrete plaque-like wall thickening is seen along the left lateral and posterior aspects of the bladder wall (long arrow), causing ureteral dilation (short arrow).
in the urinary bladder prevent PET imaging from detecting primary tumors. Administration of furosemide, aggressive hydration, and Foley catheter placement have been attempted to decrease the amount of tracer in the bladder lumen that obscures important findings.49 Studies to date have not demonstrated significant advantage of PET/CT over CT alone or MRI in the evaluation of lymph node metastasis (Figure 19).60,63,64
Figure 10. Squamous cell carcinoma of the bladder. Axial images show an infiltrative mass of the superolateral bladder wall (arrows, A and B). Although calcifications often associated with this type of tumor were not present, the patient’s history of schistosomiasis was highly suggestive of a squamous cell carcinoma.
Figure 9. Infiltrating transitional cell carcinoma of the bladder. This infiltrating tumor (long thin arrow) can be seen extending outside the bladder wall to involve the seminal vesicle (short thick arrow).
Although PET theoretically permits the recognition of positive lymph nodes independent of size, the sensitivity of this imaging modality is limited in the evaluation of small microscopic metastases. Drieskens et al examined the value of preoperative FDG-PET/CT in identifying locoregional lymph node metastasis and other distant metastasis in 55 patients with bladder cancer.63 The sensitivity, specificity, and accuracy of PET/CT for staging of both types of metastases were 60%, 88%, and 78%, respectively. Although PET/CT was superior in identifying distant metastases, PET/CT was no better than CT alone in detecting locoregional lymph node metastasis. Swinnen et al found FDG-PET/CT to have an
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Figure 11. Adenocarcinoma of the urinary bladder. Adenocarcinoma of the bladder can occur in patients with bladder exstrophy or in those with an urachal remnant, as in this patient (arrow). Adenocarcinoma of the urachal remnant will be seen anteriorly and superiorly in the bladder at the urachal ligament.
accuracy, sensitivity, and specificity for diagnosing node-positive disease of 84%, 46%, and 97%, respectively.60 The accuracy, sensitivity, and specificity of CT alone were 80%, 46%, and 92%, respectively. The difference between FDG-PET/CT and CT alone was not statistically significant. PET tracers that are not excreted by the urinary system, such as 11C-methionine and 11C-choline, have been suggested as alternatives for evaluating urothelial
Figure 12. Papillary transitional cell carcinoma within a urinary bladder diverticulum. A papillary tumor is noted within a diverticulum of the lateral urinary bladder wall (arrow). The presence of contrast-opacified urine inside the diverticulum allowed the tumor to be detected.
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Figure 13. Non-Hodgkin lymphoma of the urinary bladder. Lymphoma of the bladder can show an infiltrating growth pattern (arrow); bladder margins are no longer seen. Biopsy is needed to distinguish lymphoma from other infiltrating bladder neoplasms.
tumors using PET/CT. One study of 11C-choline reported an accuracy of 62% for the detection of metastatic lymph nodes and a sensitivity of 96% for the detection of residual cancer after TURB.65 Although these recent data are promising, the short (20-minute) half-lives of these agents restrict their practical use in the clinical setting.60,65 Ferumoxtran-10, another agent for detecting lymph node metastases, is a reticuloendothelial system-targeted MRI contrast agent that consists of ultrasmall superparamagnetic particles of iron oxide (USPIO).
Figure 14. Bladder leiomyoma. Axial T2-weighted magnetic resonance image shows a lobulated mass projecting intraluminally (white arrow). A fluid-filled Foley catheter is seen (black arrow).
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matogenous spread are the lungs, bone, liver, and brain (Figure 20).12 Chest radiograph is an effective, inexpensive, method for evaluating lung metastasis in patients with muscle-invasive tumors.12,70 However, patients with equivocal chest radiographs and those who are thought to be at high risk for lung metastasis should undergo chest CT. MRI is more sensitive and specific for diagnosing bone metastasis than bone scintigraphy, but MRI is more expensive and time consuming, which limits its use as a screening tool.7 Currently, there is no recommendation for routine evaluation of bone metastasis in patients with bladder cancer, even for those with muscle-invasive tumors. Bone scintigraphy may be limited Figure 15. Transitional cell carcinoma of the bladder on computed tomography (CT). This bladder tumor presents as asymmetric thickening of the right posterior bladder wall (arrows). The lack of distinction between the bladder wall layers on CT precludes adequate characterization of muscle invasion, limiting local staging by CT.
Ferumoxtran-10 – enhanced MRI has been shown to be sensitive and specific for the detection of lymph node metastasis for various tumors. This technique offers higher diagnostic precision than does unenhanced MRI for the detection of lymph node metastases and provides functional and anatomic definition.66 The uptake of USPIO in normal lymph nodes results in a signal decrease on T2/T2*- weighted sequences; in lymph node regions containing malignant cells, the absence of macrophage activity results in a lack of signal decrease, leaving affected nodes with hyperintense signal.61,67,68 Unfortunately, using ferumoxtran-10 is expensive and time-consuming: a 30-minute administration period with medical supervision is required, and two separate MRI examinations must be performed within 24 to 36 hours. The reading of the results also requires special expertise, as a lengthy node-by-node comparison must be made between the native MRI and a second MRI after USPIO. USPIO has not yet received approval from the US Food and Drug Administration but is used in several European countries.
Metastasis Staging Approximately 10% to 15% of patients with bladder cancer already have metastatic disease at the time of diagnosis.69 TCC in the bladder spreads by local extension through the basement membrane into the muscular layer and then to the perivesical fat. Progressive extension into the muscular layer allows for vascular and lymphatic invasion and consequently more distant spread. The most common sites of he-
Figure 16. Papillary non–muscle-invasive transitional cell carcinoma of the bladder. The tumor (arrow) shows intermediate to high signal intensity on axial T2-weighted sequence (A), enhancing after intravenous administration of gadolinium-based contrast agent on axial T1-weighted sequence (B).
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Figure 17. Muscle-invasive transitional cell carcinoma of the bladder on magnetic resonance imaging. Coronal T2weighted image demonstrates a muscle-invasive tumor (asterisk) in the left lateral bladder wall, with extension into the perivesical fat (arrows). Notice interruption of the normal bladder wall at the site of maximal invasion (arrow head).
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Because most urinary bladder tumors (70%) show papillary growth, the tumors can be visualized with VC.74 The tumor’s size can be measured objectively with VC so that treatment response can be evaluated in unresectable tumors or in patients with other contraindications for conventional cystoscopy.40 Periodic imaging surveillance of the upper urinary tract is not recommended in patients with non–muscle-invasive tumors, except for those with a high risk of recurrence.10,75 In patients with invasive bladder cancer, radical cystectomy is performed with curative intent, and follow-up imaging choices depend on the pathologic stage of the tumor after cystectomy. Patients with more advanced disease undergo routine and frequent imaging particularly within the first 2 to 3 years, as 90% of recurrences occur during this period.71,76 Either CTU or
to patients with bone pain and/or elevated levels of serum alkaline phosphatase, and if necessary, further evaluation with radiographs, MRI, or even biopsy may be performed.12
FOLLOW-UP IMAGING Up to 70% of patients treated for bladder cancer will experience a recurrence after treatment.27 TCC recurrence can be attributed to multiple factors, including incomplete resection, implantation at traumatized sites in the bladder, and rapid growth of epithelial malignancy (Figure 21).71 The high frequency of recurrence and the potential for stage progression even after several years justify frequent and potentially lifelong surveillance with cystoscopy for patients with non–muscle-invasive bladder cancer.10 The need for frequent and long-term follow-up, in addition to the expense of treating bladder cancer, renders the per-patient cost of bladder cancer among the most expensive malignancies, and the fifth most expensive cancer in terms of annual medical care expenditures, accounting for almost $4 billion in direct costs per year in the United States.72,73 Imaging of bladder cancer after treatment is particularly challenging. Intravesical medication, transurethral resection or biopsy of the tumor often cause inflammation and edema, leading to vesical and perivesical changes that may mimic tumor, as previously discussed. Currently, no noninvasive imaging modality can replace cystoscopy.26,27 Some investigators have suggested the use of VC, alternated with conventional cystoscopy, as a more cost-effective and less invasive follow-up measure for patients with bladder cancer.39,43
Figure 18. Extensive muscle-invasive bladder carcinoma on magnetic resonance imaging. The tumor (arrowheads) demonstrates multifocal bladder wall thickening on T2weighted image (A) and restricted diffusion (high signal) on diffusion-weighted image (B). This tumor was associated with multiple enlarged lymph nodes (arrows).
Radiologic imaging of patients with bladder cancer
Figure 19. Pelvic recurrence of bladder cancer on positron emission tomography/computed tomography (PET/CT). Fused PET-CT image displays increased 2-deoxy-2 [F] fluoro-D-glucose (FDG) uptake in an enlarged left iliac lymph node (arrow) consistent with metastatic involvement.
MRI may be used to assess for local and distant recurrence. Although the risk of recurrence in the upper urinary tract is small (2%–7%), routine surveillance of the upper urinary tract in patients with muscle-invasive bladder cancer is recommended.76,77 CTU is the preferred modality for this indication, as it allows assessment of the urinary tract and metastatic disease in other sites in the same study. Recent research has shown that MRI of the bladder with DWI may help to predict treatment response in
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Figure 21. Recurrent transitional cell carcinoma on follow-up computed tomography (CT) 6 months after left nephrectomy and incomplete resection of the ipsilateral ureter. Coronal oblique CT reformation image shows recurrent tumor in the left ureteral stump (white arrow), and multiple papillary lesions in the bladder (black arrows).
patients receiving chemotherapy before cystectomy, which would allow more optimal patient selection in bladder-sparing protocols.77
CONCLUSION Imaging plays an important role in the detection, staging, and follow-up of patients with bladder cancer. CTU is currently the most common imaging modality used for the initial evaluation of patients with a suspected or proven bladder tumor. MRI provides the best local staging compared with other imaging modalities, and its role will continue to grow with refinements of techniques, particularly DWI. The use of PET/CT in patients with bladder cancer is currently best reserved for detecting lymphadenopathy and metastatic disease. New radioactive tracers may help to overcome current PET/CT limitations for the primary evaluation of the urinary tract.
REFERENCES
Figure 20. Bone metastasis in a patient with bladder cancer. Axial computed tomography image shows a mixed lythic and blastic lesion of the first lumbar vertebral body.
1. Kohler BA, Ward E, McCarthy BJ, et al. Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103:714 –36. 2. Murphy WM, Grignon DJ, Perlman EJ. Tumors of the kidney, bladder, and related urinary structures. Washington, DC: American Registry of Pathology; 2004:394. 3. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011; 306:737– 45.
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4. Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66 Suppl 1:4 –34. 5. Sutton JM. Evaluation of hematuria in adults. JAMA. 1990;263:2475– 80. 6. Cohan RH, Caoili EM, Cowan NC, Weizer AZ, Ellis JH. MDCT urography: exploring a new paradigm for imaging of bladder cancer. AJR Am J Roentgenol. 2009;192: 1501– 8. 7. Stenzl A, Witjes JA, Cowan NC, et al. Guidelines on bladder cancer muscle—invasive and metastatic. European Association of Urology; 2011. Available from: www.uroweb.org. 8. Lopes RI, Nogueira L, Albertotti CJ, Takahashi DY, Lopes RN. Comparison of virtual cystoscopy and transabdominal ultrasonography with conventional cystoscopy for bladder tumor detection. J Endourol. 2008;221725–9. 9. Grossfeld GD, Wolf JS Jr, Litwan MS, et al. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. Am Fam Physician. 2001;63:1145–54. 10. American Urological Association. Bladder Cancer Clinical Guideline Update Panel. The management of bladder cancer: diagnosis and treatment recommendations. American Urological Association Education and Research, Inc; 2007 (reviewed and validity confirmed 2010). Available from: www.auanet.org. 11. Hillman BJ, Silvert M, Cook G, et al. Recognition of bladder tumors by excretory urography. Radiology. 1981;138:319 –23. 12. ACR Appropriateness Criteria. Pretreatment staging of invasive bladder cancer. American College of Radiology; 2009. Available from: www.acr.org. 13. O’Malley ME, Hahn PF, Yoder IC, Gazelle GS, McGovern FJ, Mueller PR. Comparison of excretory phase, helical computed tomography with intravenous urography in patients with painless haematuria. Clin Radiol. 2003;58: 294 –300. 14. Herranz-Amo F, Diez-Cordero JM, Verdu-Tartajo F, Bueno-Chomon G, Leal-Hernandez F, Bielsa-Carillo A. Need for intravenous urography in patients with primary transitional carcinoma of the bladder? Eur Urol. 1999;36: 221– 4. 15. Datta SN, Allen GM, Evans R, Vaughton KC, Lucas MG. Urinary tract ultrasonography in the evaluation of haematuria: a report of over 1,000 cases. Ann R Coll Surg Engl. 2002;84:203–5. 16. Edwards TJ, Dickinson AJ, Natale S, Gosling J, McGrath JS. A prospective analysis of the diagnostic yield resulting from the attendance of 4020 patients at a protocoldriven haematuria clinic. BJU Int. 2006;97:301–5. 17. Nicolau C, Bunesch L, Sebastia C, Salvador R. Diagnosis of bladder cancer: contrast-enhanced ultrasound. Abdom Imaging. 2010;35:494 –503. 18. ACR Appropriateness Criteria. Hematuria. American College of Radiology; 2008. Available from: www.acr.org. 19. Francica G, Bellini SA, Scarano F, Miragliuolo A, De Marino FA, Maniscalco M. Correlation of transabdominal sonographic and cystoscopic findings in the diagnosis of focal abnormalities of the urinary bladder wall: a prospective study. J Ultrasound Med. 2008;27: 887–94.
A.S. Purysko, H.M. Leão Filho, and B.R. Herts
20. Itzchak Y, Singer D, Fischelovitch Y. Ultrasonographic assessment of bladder tumors. 1. Tumor detection. J Urol. 1981;126:31–3. 21. Ozden E, Turgut AT, Turkolmez K, Resorlu B, Safak M. Effect of bladder carcinoma location on detection rates by ultrasonography and computed tomography. Urology. 2007;69:889 –92. 22. Abu-Yousef MM, Narayana AS, Franken EA Jr, Brown RC. Urinary bladder tumors studied by cystosonography. Part I: detection. Radiology. 1984;153:223– 6. 23. Kocakoc E, Kiris A, Orhan I, Poyraz AK, Artas H, Firdolas F. Detection of bladder tumors with 3-dimensional sonography and virtual sonographic cystoscopy. J Ultrasound Med. 2008;27:45–53. 24. Joffe SA, Servaes S, Okon S, Horowitz M. Multi-detector row CT urography in the evaluation of hematuria. Radiographics. 2003;23:1441–55. 25. Silverman SG, Leyendecker JR, Amis ES Jr. What is the current role of CT urography and MR urography in the evaluation of the urinary tract? Radiology. 2009;250: 309 –23. 26. Turney BW, Willatt JM, Nixon D, Crew JP, Cowan NC. Computed tomography urography for diagnosing bladder cancer. BJU Int. 2006;98:345– 8. 27. Sadow CA, Silverman SG, O’Leary MP, Signorovitch JE. Bladder cancer detection with CT urography in an academic medical center. Radiology. 2008;249:195–202. 28. Jinzaki M, Tanimoto A, Shinmoto H, et al. Detection of bladder tumors with dynamic contrast-enhanced MDCT. AJR Am J Roentgenol. 2007;188:913– 8. 29. Kim JK, Park SY, Ahn HJ, Kim CS, Cho KS. Bladder cancer: analysis of multi-detector row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging. Radiology. 2004;231:725–31. 30. Park SB, Kim JK, Lee HJ, Choi HJ, Cho KS. Hematuria: portal venous phase multi detector row CT of the bladder: a prospective study. Radiology. 2007;245:798 – 805. 31. Kim B, Semelka RC, Ascher SM, Chalpin DB, Carroll PR, Hricak H. Bladder tumor staging: comparison of contrastenhanced CT, T1- and T2-weighted MR imaging, dynamic gadolinium-enhanced imaging, and late gadolinium-enhanced imaging. Radiology. 1994;193:239 – 45. 32. Tanimoto A, Yuasa Y, Imai Y, et al. Bladder tumor staging: comparison of conventional and gadolinium-enhanced dynamic MR imaging and CT. Radiology. 1992; 185:741–7. 33. Thomsen HS. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am. 2009;47:827–31. 34. Matsuki M, Inada Y, Tatsugami F, Tanikake M, Narabayashi I, Katsuoka Y. Diffusion-weighted MR imaging for urinary bladder carcinoma: initial results. Eur Radiol. 2007;17:201– 4. 35. Takahara T, Imai Y, Yamashita T, Yasuda S, Nasu S, Van Cauteren M. Diffusion weighted whole body imaging with background body signal suppression (DWIBS): technical improvement using free breathing, STIR and high-resolution 3D display. Radiat Med. 2004;22:275– 82. 36. Abou-El-Ghar ME, El-Assmy A, Refaie HF, El-Diasty T. Bladder cancer: diagnosis with diffusion-weighted MR imaging in patients with gross hematuria. Radiology. 2009;251:415–21.
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37. El-Assmy A, Abou-El-Ghar ME, Mosbah A, et al. Bladder tumour staging: comparison of diffusion- and T2weighted MR imaging. Eur Radiol. 2009;19:1575– 81. 38. Avcu S, Koseoglu MN, Ceylan K, Bulut MD, Unal O. The value of diffusion-weighted MRI in the diagnosis of malignant and benign urinary bladder lesions. Br J Radiol. 2011;84:875– 82. 39. Song JH, Francis IR, Platt JF, et al. Bladder tumor detection at virtual cystoscopy. Radiology. 2001;218:95–100. 40. Vining DJ, Zagoria RJ, Liu K, Stelts D. CT cystoscopy: an innovation in bladder imaging. AJR Am J Roentgenol. 1996;166:409 –10. 41. Narumi Y, Kumatani T, Sawai Y, et al. The bladder and bladder tumors: imaging with three-dimensional display of helical CT data. AJR Am J Roentgenol. 1996;167: 1134 –5. 42. Kim JK, Ahn JH, Park T, Ahn HJ, Kim CS, Cho KS. Virtual cystoscopy of the contrast material-filled bladder in patients with gross hematuria. AJR Am J Roentgenol. 2002; 179:763– 8. 43. Basak M, Ozkurt H, Tanriverdi O, Cay E, Aydin M, Miroglu C. Sixteen-slice multidetector computed tomographic virtual cystoscopy in the evaluation of a patient with suspected bladder tumor and history of bladder carcinoma operation. J Comput Assist Tomogr. 2009;33: 867–71. 44. Wong-You-Cheong JJ, Woodward PJ, Manning MA, Sesterhenn IA. From the Archives of the AFIP: neoplasms of the urinary bladder: radiologic-pathologic correlation. Radiographics. 2006;26:553– 80. 45. Saga Y, Numata A, Tokumitsu M, et al. Comparative study of novel endoluminal ultrasonography and conventional transurethral ultrasonography in staging of bladder cancer. Int J Urol. 2004;11:597– 601. 46. Tomita Y, Kobayashi K, Saito T, Tanikawa T, Kimura M, Takahashi K. Use of miniature ultrasonic probe system for intravesical ultrasonography for transitional cell cancer of the urinary tract. Scand J Urol Nephrol. 2000;34: 313– 6. 47. Barentsz JO, Ruijs SH, Strijk SP. The role of MR imaging in carcinoma of the urinary bladder. AJR Am J Roentgenol. 1993;160:937– 47. 48. Caruso G, Salvaggio G, Campisi A, et al. Bladder tumor staging: comparison of contrast-enhanced and gray-scale ultrasound. AJR Am J Roentgenol. 2010;194:151– 6. 49. Kibel AS, Dehdashti F, Katz MD, et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma. J Clin Oncol. 2009;27:4314 –20. 50. Barentsz JO, Jager GJ, van Vierzen PB, et al. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology. 1996;201:185–93. 51. Tachibana M, Baba S, Deguchi N, et al. Efficacy of gadolinium-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging for differentiation between superficial and muscle-invasive tumor of the bladder: a comparative study with computerized tomography and transurethral ultrasonography. J Urol. 1991;145:1169 –73. 52. Tekes A, Kamel I, Imam K, et al. Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am J Roentgenol. 2005;184:121–7.
557
53. Narumi Y, Kadota T, Inoue T, et al. Bladder tumors: staging with gadolinium-enhanced oblique MR imaging. Radiology. 1993;187:145–50. 54. Hayashi N, Tochigi H, Shiraishi T, Takeda K, Kawamura J. A new staging criterion for bladder carcinoma using gadolinium-enhanced magnetic resonance imaging with an endorectal surface coil: a comparison with ultrasonography. BJU Int. 2000;85:32– 6. 55. Takeuchi M, Sasaki S, Ito M, et al. Urinary bladder cancer: diffusion-weighted MR imaging: accuracy for diagnosing T stage and estimating histologic grade. Radiology. 2009; 251:112–21. 56. Scattoni V, Da Pozzo LF, Colombo R, et al. Dynamic gadolinium-enhanced magnetic resonance imaging in staging of superficial bladder cancer. J Urol. 1996;155: 1594 –9. 57. Kobayashi S, Koga F, Yoshida S, et al. Diagnostic performance of diffusion-weighted magnetic resonance imaging in bladder cancer: potential utility of apparent diffusion coefficient values as a biomarker to predict clinical aggressiveness. Eur Radiol. 2011;21:2178 – 86. 58. Leissner J, Hohenfellner R, Thuroff JW, Wolf HK. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: significance for staging and prognosis. BJU Int. 2000;85:817–23. 59. Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Riujs SJ. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional T1weighted magnetization-prepared-rapid gradient-echo sequence. AJR Am J Roentgenol. 1996;167:1503–7. 60. Swinnen G, Maes A, Pottel H, et al. FDG-PET/CT for the preoperative lymph node staging of invasive bladder cancer. Eur Urol. 2010;57:641–7. 61. Deserno WM, Harisinghani MG, Taupitz M, et al. Urinary bladder cancer: preoperative nodal staging with ferumoxtran-10-enhanced MR imaging. Radiology. 2004;233: 449 –56. 62. Thoeny HC, Triantafyllou M, Birkhaeuser FD, et al. Combined ultrasmall superparamagnetic particles of iron oxide– enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients. Eur Urol. 2009;55:761–9. 63. Drieskens O, Oyen R, Van Poppel H, Vankan Y, Flamen P, Mortelmans L. FDG-PET for preoperative staging of bladder cancer. Eur J Nucl Med Mol Imaging. 2005;32: 1412–7. 64. Jensen TK, Holt P, Gerke O, et al. Preoperative lymphnode staging of invasive urothelial bladder cancer with 18F-fluorodeoxyglucose positron emission tomography/ computed axial tomography and magnetic resonance imaging: correlation with histopathology. Scand J Urol Nephrol. 2011;45:122– 8. 65. Picchio M, Treiber U, Beer AJ, et al. Value of 11C-choline PET and contrast-enhanced CT for staging of bladder cancer: correlation with histopathologic findings. J Nucl Med. 2006;47:938 – 44. 66. Will O, Purkayastha S, Chan C, et al. Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis. Lancet Oncol. 2005;7:52– 60. 67. Thoeny HC, Triantafyllou M, Birkhaeuser FD, et al. Combined ultrasmall superparamagnetic particles of iron oxide-
558
68.
69.
70.
71.
72.
A.S. Purysko, H.M. Leão Filho, and B.R. Herts
enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients. Eur Urol. 2009;55:761–9. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med. 2003;348:2491–9. Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urol. 2005;174: 14 –20. Kuroda M, Meguro N, Maeda O, et al. Stage specific follow-up strategy after cystectomy for carcinoma of the bladder. Int J Urol. 2002;9:129 –33. Oosterlinck W, Lobel B, Jaske G, Malmstrom PU, Stockle M, Sternberg C; European Association of Urology (EAU) Working Group on Oncological Urology. Guidelines on bladder cancer. Eur Urol. 2002;41:105–12. Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R. The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics. 2003;21:1315–30.
73. Kamat AM, Karam JA, Grossman HB, Kader AK, Munsell M, Dinney CP. Prospective trial to identify optimal bladder cancer surveillance protocol: reducing costs while maximizing sensitivity. BJU Int. 2011;108:1119 –23. 74. Beer A, Saar B, Rummeny EJ. Tumors of the urinary bladder: technique, current use, and perspectives of MR and CT cystography. Abdom Imaging. 2003;28:868 –76. 75. Brausi M, Witjes JA, Lamm D, et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J Urol. 2011; 186:2158 – 67. 76. Beyersdorff D, Zhang J, Schöder H, Bochner B, Hricak H. Bladder cancer: can imaging change patient management? Curr Opin Urol. 2008;18:98 –104. 77. Yoshida S, Koga F, Kawakami S, et al. Initial experience of diffusion-weighted magnetic resonance imaging to assess therapeutic response to induction chemoradiotherapy against muscle-invasive bladder cancer. Urology. 2010;75:387–91.
B
ladder cancer is the most common malignancy of the urinary tract, and according to the most recent analysis of cancer cases in the United States, it is the fifth most common malignancy overall, with a stable incidence in men and a declining incidence in women.1 Approximately 90% to 95% of bladder cancers are primary and epithelial in origin (ie, transitional cell carcinomas).2 The most common risk factor for bladder cancer is cigarette smoking.3 The gold standard for the diagnosis of bladder cancer is cystoscopy; however, imaging also plays an important role in the evaluation and management of patients with bladder cancer. For years, intravenous urography (IVU) was the mainstay for imaging the upper urinary tract and bladder; more recently, computed tomography (CT) and, to a lesser extent, magnetic resonance imaging (MRI) now play a greater role. Despite myriad technical advances in these imaging techniques, there are still several limitations and technical challenges when imaging the urinary bladder. In the following sections, we discuss the performance of aDepartment
of Radiology, Section of Abdominal Imaging, and Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. bRadiology Department, HCor—Hospital do Coração, São Paulo, SP, Brazil. Financial disclosures or conflicts of interest: Dr Herts receives research funding from Siemens Medical for the investigation of CT dose and dose reduction techniques. Address correspondence to Brian R. Herts, MD, Imaging Institute, Desk Hb6, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected] 0270-9295/ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2012.08.010
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various imaging modalities in the detection, staging, and post-treatment follow-up of bladder cancer.
BLADDER CANCER DETECTION The search for bladder cancer most often occurs in the context of hematuria, as approximately 85% of patients with bladder cancer present with painless macroscopic hematuria; however, only 15% of cases of macroscopic hematuria originate in the bladder.4,5 In general, the recommended evaluation of patients with hematuria includes urine cytology, cystoscopy, and at least one imaging study to evaluate both the upper and lower urinary tracts. There are few data to support any one bladder imaging modality as superior to the others for the detection of bladder neoplasms.6 The final diagnosis of bladder cancer ultimately depends on histologic evaluation of a biopsy specimen obtained during cystoscopy.7 However, cystoscopy is invasive, time-consuming, expensive, and often requires sedation or anesthesia. Cystoscopy also may lead to iatrogenic injuries. Additionally, cystoscopy examination may not be suitable in patients with severe urethral strictures or in those with active bleeding, and evaluation of lesions located in the base and neck of the bladder or within a bladder diverticulum is difficult because of the limited field of view.8
Intravenous Urography Historically, IVU has been the initial imaging study used to evaluate patients with hematuria (Figure 1). IVU is widely available and cost-effective.9 For patients diagnosed with bladder cancer, IVU is used to assess for the presence of synchronous urothelial tumors in 543
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Figure 1. Transitional cell carcinoma of the bladder on intravenous urography (IVU). Coned-down view of the bladder from IVU shows a mass-like filling defect along the left lateral bladder (arrowheads).
the upper urinary tract, although these tumors occur in less than 5% of patients with bladder cancer.10 Up to 60% of known bladder tumors are visualized by IVU, whereas 66.6% of the upper urinary tract lesions are detected.11–14 However, with the advent of modern multidetector row CT scanners, IVU has been almost entirely replaced by CT urography (CTU) for the evaluation of patients with hematuria.
Ultrasound Transabdominal ultrasound (US) is a safe, noninvasive, relatively low-cost imaging method that can be used to examine the kidneys and the urinary bladder when the latter is distended. US is the study of choice for the initial investigation of hematuria in some centers. Advocates of US for the evaluation of hematuria report that there are few differences between US and IVU for the detection of various renal and bladder pathologies, and US can be performed without the risks associated with intravenous iodinated contrast material or exposure to ionizing radiation.15–17 However, most centers reserve US for radiation-sensitive populations, specifically for children and pregnant women.18 Additionally, the ability of US to depict upper tract urothelial tumors is poor and US has a low sensitivity when detecting bladder cancers. Reported sensitivity of transabdominal US for bladder tumors has been found to vary from 26% to 91.4%.8,15,19 Diagnosing bladder cancer with US entails detection of either focal bladder wall thickening or the presence of a fixed bladder wall mass protruding into the bladder lumen (Figure 2). The accuracy of US in detecting bladder lesions depends on several factors, most notably the morphology, size, and location of the lesion. Sessile lesions, lesions less than 0.5 cm in diameter
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regardless of location, and lesions of any size located in the bladder neck or dome are difficult to detect.20 Ozden et al reported that up to 42% of cancers in the anterior lower bladder wall were missed by US.21 The accuracy of US is also limited by equipment quality, body habitus, bladder distension, and examiner experience.17,19,22 Three-dimensional (3D) virtual sonography and contrast-enhanced US (CEUS) are well-established refinements in US imaging that have more recently been tested in the evaluation of bladder cancer. Favorable results have been reported with both techniques, but the available data are currently limited. Kocakoc et al evaluated 31 patients with known or suspected bladder cancer using two-dimensional (2D) gray-scale sonography combined with multiplanar reconstructions and 3D virtual sonography.23 For tumor detection, combined 2D and 3D sonography had a sensitivity of 96.4%, a specificity of 88.8%, a positive predictive value (PPV) of 97.6%, and a negative predictive value (NPV) of 84.2%. Although these results correlated well with conventional cystoscopy findings, the study was unable to demonstrate a statistically significant improvement with these techniques versus with 2D gray-scale imaging. Other research has shown that CEUS has a reported sensitivity of 88.5%, specificity of 88.9%, PPV of 95.8%, and NPV of 72.7%.17
Computed Tomography/ Computed Tomographic Urography With widespread availability and dedicated protocols, CT has supplanted the use of IVU in many insti-
Figure 2. Papillary transitional cell carcinoma of the bladder on ultrasound. Transabdominal ultrasound shows a polypoid intraluminal bladder tumor (arrow) at the bladder trigone. P, prostate; SV, seminal vesicle.
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Figure 3. Transitional cell carcinoma of the bladder on CT urography (CTU). Coronal volume-rendered reformatted image from CTU demonstrates a large mass within the urinary bladders; reformatted images are created to simulate the more familiar intravenous urogram image. Coronal coned-down image of the bladder shows a predominantly intravesical mass (asterisk on B) arising from the right lateral wall with bladder wall thickening. Cystoscopic view of the bladder mass (C, arrows).
tutions for evaluation of the urinary tract. The most recent revision of the American College of Radiology appropriate criteria ranks CTU as the best initial imaging examination for the evaluation of patients with hematuria.18 Multidetector CT (MDCT) datasets composed of isotropic voxels allow images of equal spatial resolution to be obtained in any plane, and 3D reformation of the excretory-phase images can produce images that mimic the appearance of IVU (Figure 3).24,25 Protocols for CTU vary, but in general they include unenhanced, nephrographic, and excretory-phase imaging or unenhanced imaging with a combination of the latter two phases (split-bolus technique). Two studies comparing CTU with cystoscopy are noteworthy. Turney et al conducted a study in a fasttrack hematuria clinic in which 200 consecutive patients were prospectively evaluated with CTU and flexible cystoscopy on the same day.26 The prevalence of bladder cancer in these patients was 24%. The sensitivity, specificity, and NPV of CTU for the detection of
bladder cancer in this study were 93%, 99%, and 98%, respectively. In a different study, Sadow et al found in a retrospective study of 838 CTUs from patients who also had been evaluated by cystoscopy within a 6-month period, that the overall sensitivity, specificity, PPV, and NPV for CTU in detecting bladder cancer were 79%, 94%, 75%, and 95%, respectively. Higher specificity and NPV (96% and 98%, respectively) was noted in the subgroup of patients with hematuria.27 The sensitivity of CTU in this latter study was greater in patients with gross hematuria than in those with microscopic hematuria (83.3% v 42.9%).27 As with other imaging modalities, CT has limited ability to detect small bladder lesions. In one study evaluating the ability of dynamic contrast-enhanced MDCT to detect bladder cancer, the overall sensitivity achieved with thin-section images combined with multiplanar reconstructions was 90%; sensitivity decreased to 79% for lesions 1 cm or smaller and to 58% for lesions 5 mm or smaller.28 Some bladder cancers in initial stages may present as faint color changes in the
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mucosa and can only be detected on direct visualization. CT also has limited ability to distinguish tumors from changes related to biopsy or transurethral resection of the bladder (TURB) performed during cystoscopy. One study found that the frequency of concordance between findings at CT and findings from histologic examination was greater in patients with a time interval of 7 or more days between those procedures than in those with a time interval of fewer than 7 days.29 The use of CT to detect bladder cancer also is limited in patients with severely impaired renal function, patients with metallic prostheses in the pelvis that cause imaging artifacts, and patients with bladder lesions adjacent to the prostate, as these may be mistaken for a normal prostate or for a prostatic lesion.26,30 Positron emission tomography (PET)/CT is limited in its ability to provide evidence for a primary diagnosis of urothelial tumors because of tracer excretion into the urinary tract; however, PET/CT is often used for staging bladder cancer (as discussed later).
Magnetic Resonance Imaging In recent years, MRI of the abdomen and pelvis has greatly improved with the development of faster imaging acquisition techniques that help overcome both respiratory and bowel motion artifacts. With MRI, multiplanar imaging acquisition and multiplanar imaging reconstruction with 3D sequences can be performed. MRI does not involve the risks of ionizing radiation; however, MRI is not as widely available as CT and is more expensive. Although studies have shown good sensitivity in the detection of bladder cancer, the role of MRI in the detection of urothelial lesions remains under investigation.18 In a prospective study of 36 patients with a history of bladder cancer comparing CT and MRI, the sensitivity and PPVs for tumor detection were 93% and 96%, respectively, for CT; 94% and 94%, respectively, for MRI on T2-weighted imaging; and 100% and 93%, respectively, for dynamic gadolinium-enhanced MRI.31 Another prospective study of 79 patients with 83 bladder tumors demonstrated that the detection of small (⬍1.0 cm) lesions significantly improved on MRI after the administration of intravenous contrast media, compared with detection on precontrast MRI images and CT.32 Although gadolinium-based contrast agents used on MRI are not nephrotoxic when administered at recommended doses, in patients with chronic kidney disease, these agents are associated with the development of nephrogenic systemic fibrosis (NSF), a severely debilitating and potentially fatal systemic fibrosis. It is accepted that patients with stage IV or V chronic kidney disease (estimated glomerular filtration rate [eGFR] ⬍30 mL/min) are at increased
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risk of developing NSF, and so the use of gadolinium agents should be avoided in these patients.7,33
New MRI Technique: Diffusion-Weighted Imaging Diffusion-weighted imaging (DWI) is a promising MRI technique for detecting and characterizing lesions in several organs of the abdomen and pelvis. Recent refinements allow this imaging to occur under free breathing, which enables longer scan times, thinner slices, and signal averaging; these factors in turn improve image quality.34,35 In DWI, image signal is based on the natural thermally induced Brownian motion of water molecules: the signal intensity is high if water molecules are restricted in their motion, which can be caused by cell membranes or, in the case of free fluid, by high viscosity.36 This diffusion of water molecules can be calculated and displayed on apparent diffusion coefficient (ADC) maps. The high cell density in tumors can produce restricted diffusion (Figure 4), although restricted diffusion does not occur exclusively in malignant tissues. In one study of 130 patients presenting with gross hematuria, the sensitivity, specificity, PPV, NPV, and accuracy of DWI were 98.1%, 92.3%, 100%, 92.3%, and 97%, respectively.36 Two false negatives on T2-weighted MRI were correctly diagnosed with DWI. The agreement between DWI and cystoscopic findings for identifying bladder neoplasm was excellent (K⫽ 0.94). In another prospective study evaluating the performance of DWI, 121 of 123 tumors noted on cystoscopy were detected on DWI, including 14 of 16 lesions smaller than 10 mm.37 DWI also may be beneficial in differentiating malignant from benign urinary bladder lesions based on the lower ADC values demonstrated by the malignant lesions.38
Virtual Cystoscopy Virtual endoscopic imaging also has been used for the detection of bladder cancer. Volumetric data obtained with either helical CT or MRI are computer rendered to generate 3D images, and with commercially available software, endoluminal visualization of any hollow viscus is then possible.39 Virtual cystoscopy (VC) is most commonly CT based, but regardless of the imaging modality used, adequate distension of the bladder with gas or contrast media is vital (Figure 5). This distension can be achieved by directly inserting the gas or contrast media through a catheter or by using the urine as a natural contrast or by using intravenous contrast that is then excreted into the urinary tract. Although this technique does not produce any new information apart from what is available on the axial CT slices, it does allow for rapid evaluation of the often complex morphology of hollow organs in a more intuitive fashion.40
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to the tumor size.39,41– 43 When compared to transabdominal US, VC has demonstrated favorable results: for tumors <1 cm, VC’s sensitivity was found to be 93.5% versus US’s sensitivity of 50%.8 Additionally, US frequently missed lesions in the anterior and posterior wall, whereas these lesions were identified by VC. There is no evidence to support the use of VC on a routine basis in patients with hematuria. VC requires extra time, both in the scanner and on post processing, and is associated with a higher cost and increased radiation exposure.42 Additionally, unless VC uses contrast excreted by the urinary system, it is an invasive study.
TYPES OF BLADDER NEOPLASMS
Figure 4. Transitional cell carcinoma of the urinary bladder on magnetic resonance imaging. Papillary tumor at the right ureterovesical junction with intermediate signal intensity on axial T2-weighted image (A, arrow). On corresponding diffusion-weighted image (B), the lesion (arrow) demonstrates high signal intensity, a characteristic of restricted diffusion.
Even when a urethral catheter is used, VC is less invasive than conventional cystoscopy and has a very low complication rate. This procedure also can depict extravesical anatomy, which is important for staging.8,36,39 VC images can be complementary to transverse images: some small lesions are better depicted or visible only on the virtual images, while areas of wall thickening are more readily apparent on transverse images.39 The reported sensitivity of VC for the detection of bladder cancer ranges from 60% to 100% and is related
The overwhelming majority (⬎90%) of bladder cancers are transitional cell carcinomas (TCC). These lesions can be papillary (Figures 6 and 7) or infiltrating (Figures 8 and 9) and can occur anywhere in the bladder. TCC of the bladder is rarely calcified; conversely, squamous cell tumors of the bladder, more common with chronic inflammation or associated with schistosomiasis and common in endemic areas, do demonstrate calcifications and are often mass-like, aggressive tumors (Figure 10). Adenocarcinomas are also masslike, aggressive tumors that arise in patients with bladder exstrophy or in those with an urachal remnant. In the latter case, tumors are located at the anterior and superior aspect of the bladder along the urachal ligament (Figure 11). When tumors arise in a bladder diverticulum, they more frequently invade perivesical fat because of the lack of muscularis mucosa in the wall of the diverticulum (Figure 12).4 Other than history and these basic imaging features, there is little to differentiate among the different primary bladder neoplasms, and so biopsy is usually needed.44 Other bladder tumors such as pheochromocytoma, lymphoma, and bladder leiomyosarcomas (Figures 13 and 14) are managed differently from TCC and are beyond the scope of this review.
STAGING The tumor-node-metastasis (TNM) system is the most common method for staging bladder cancer.10,12 CT and MRI allow for ready assessment of extravesical extension, lymph node enlargement, and distant metastases, all of which are used to determine the clinical stage, which allows clinicians to select the appropriate treatment and provide a prognosis.32
Tumor Staging In patients with bladder cancer, T stage refers to the depth of bladder wall invasion by the tumor. Clinical management of urinary bladder cancer is determined primarily on the basis of distinguishing superficial tu-
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A.S. Purysko, H.M. Leão Filho, and B.R. Herts
Figure 5. Papillary transitional cell carcinoma of the bladder on virtual cystoscopy. The lesion is not seen on a precontrast image (A) but becomes evident after the bladder is filled by the excreted contrast (black arrow, B). (C) Three-dimensional perspective volume-rendered image (virtual cystoscopy) simulating the conventional cystoscopy view of the tumor (black arrow), which is located near the left ureteral meatus (white arrow).
mors (stage T1 or lower) from invasive ones (stage T2 or higher). Infiltration beyond the lamina propria requires more aggressive treatment than transurethral resection. Approximately 70% to 75% of bladder cancers present as non–muscle-invasive tumors, and of these tumors, the majority (70% to 75%) are confined to the bladder mucosa (stage Ta).10 IVU and transabdominal US are not recommended for staging because of their lower sensitivity in detecting bladder tumors and their inability to accurately evaluate extravesical extension. Endoluminal or intravesical US (ELUS or IVUS), introduced by a rigid cystoscope for intravesical evaluation, provides greater bladder wall detail and is sensitive and specific in detecting muscle invasion in bladder cancer; however, this technique is still not widely available and is invasive.12,45,46
CT is the modality most commonly used for staging bladder cancer, as the same study performed for tumor detection (CTU) can also be used for staging. The reported accuracy of CT for bladder tumor staging ranges from 40% to 92%.37,47 However, CT does not depict individual layers of the bladder wall and therefore cannot be used to reliably estimate the depth of tumor infiltration (Figure 15).48 Additionally, CT is unable to accurately detect microscopic or small-volume extravesical tumor extension.12 The limitations of CT are most significant when CT is performed shortly after TURB49; for this reason, CT should precede cystoscopy when possible. Inflammatory changes after TURB, namely, bladder wall thickening and perivesical fat stranding, may limit accurate cancer detection and diagnosis of perivesical invasion.29,50
Radiologic imaging of patients with bladder cancer
Figure 6. Papillary transitional cell carcinoma of the urinary bladder. (A) Routine enhanced and (B) excretoryphase computed tomography (CT) images from a CT urogram show a papillary mass projecting into the bladder lumen arising near the left ureterovesical junction. Note the higher visibility of the lesion when the bladder is distended with contrast-opacified urine during the excretory phase (B).
Perivesical invasion is diagnosed on CT when the interface between the bladder cancer and perivesical fat is irregular or when the bladder cancer shows overt growth beyond the outer margin of the bladder wall. Using these criteria, Kim et al found CT to have a sensitivity and specificity for diagnosing perivesical invasion of 89% and 95%, respectively, with a time interval of less than 7 days between TURB and the CT study.29 These values increased to 92% and 98%, respectively, when the time interval was 7 or more days. Although CTU offers the potential for a “one-stopshopping” examination to assess local disease, lymph
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nodes, distant metastases, and the upper urinary tract, MRI may offer advantages over CT for local staging. The inherent soft tissue contrast on MRI helps to identify the bladder wall layers and the delineation between the bright perivesical fat and the intermediate signal-intensity bladder, which improves estimation of depth of invasion and extravesical extension, respectively (Figures 16 and 17).12,46,47 In a review of the literature, Barentsz et al found the accuracy of MRI ranging from 76% to 96% for T-staging in bladder cancer.47 A study by Tachibana et al demonstrated superior detection of small tumors (⬍10 mm) and better staging for superficial tumors with MRI than with US and CT.51 The MRI accuracy values reported in the literature are generally 10% to 33% higher than those obtained with CT.37 However, these values should be interpreted with caution, as the studies are not directly comparable because of varying patient populations, particularly regarding pre- and post-TURBT status. For differentiating between superficial (ⱕT1) and muscle-invasive (ⱖT2) bladder tumors, the accuracy of dynamic contrastenhanced MRI has ranged from 75% to 92%, with overall accuracy for diagnosing tumor stage ranging from 52% to 93%.31,32,52–56 Diffusion-weighted MRI shows promise for staging bladder cancer (Figure 18). In a study conducted by El-Assmy et al, bladder cancer was correctly staged in 83 of 106 patients (78.3%) by DWI, which was significantly better (P ⬍.001) than the results obtained with T2-weighted images (39.6%).37 Overstaging was the most common error seen in organ-confined tumors. The accuracy of DWI was 63.6% in differentiating superficial from invasive tumors and 69.6% in differentiating organ-confined from non– organ-confined tumors. On a stage-by-stage basis, DWI accuracy was 63.6%, 75.7%, 93.7%, and 87.5% for stages T1, T2, T3, and T4, respectively. The value of DWI in staging was also demonstrated by Takeuchi et al.55 The accuracy of DWI for diagnosing the tumor stage of bladder cancer was significantly improved when DW images and contrast-enhanced images were viewed in addition to T2weighted images (92% v 67%, P ⬍.01). Importantly, the investigators found that the specificity of DWI for the diagnosis of muscle invasion was 97%. Furthermore, the ADC value, a quantitative measurement of diffusion, was significantly lower in high-grade disease than in low-grade disease, thus providing further information about tumor staging.55,57 However, ADC values depend on multiple factors related to both the MRI hardware (such as the field strengths and coils used for imaging) and the patient, and so specific ADC values determined by these studies cannot be generalized to other sites.
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Figure 7. Multiple papillary transitional cell tumors of the urinary bladder. (A) Volume-rendered reformation and (B, C, and D) coronal excretory-phase images from a computed tomography urogram demonstrate one large (long arrow) and multiple small (short arrows) bladder filling defects. There were multiple papillary transitional cell carcinomas at cystoscopy.
Node Staging Locoregional lymph node metastasis is an important prognostic factor in patients with bladder cancer, as patients with positive lymph nodes have worse survival rates.49,58 Lymph node metastasis also has a strong correlation to tumor stage.49,58 Lymph node involvement in patients with superficial tumors is rare, but if the deep muscle layer is involved or if extravesical invasion is present, the incidence of lymph node metastasis increases to 20%–30% and 50%– 60%, respectively.59 CT and MRI are the modalities of choice for assessing lymph nodes before surgery in patients with bladder cancer. The accuracy range for lymph node staging is 70% to 90% for CT with false-negative rates of 25% to 40%; MRI accuracy ranges from 64% to 92%.60 Unlike in primary tumor detection, contrast-enhanced images do
not appear to improve detection of lymph node involvement.50 Both CT and MRI rely predominantly on nodal size and morphology for detecting metastases; however, there is considerable overlap in size between benign and malignant nodes, resulting in suboptimal sensitivity and specificity for these imaging modalities.61,62 Studies have shown that meticulous lymph node dissection in patients with bladder or prostate cancer identifies a relatively high rate of metastases (25%) in patients with negative preoperative imaging.62 Although PET with 2-deoxy-2 [F] fluoro-D-glucose (FDG) in combination with CT (FDG-PET/CT) is an important imaging modality for the preoperative staging of various neoplasms, the use of FDG-PET/CT for detecting primary urothelial tract malignancies is limited. The urinary excretion and concentration of FDG
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Figure 8. Muscle-invasive infiltrating transitional cell carcinoma of the bladder. A discrete plaque-like wall thickening is seen along the left lateral and posterior aspects of the bladder wall (long arrow), causing ureteral dilation (short arrow).
in the urinary bladder prevent PET imaging from detecting primary tumors. Administration of furosemide, aggressive hydration, and Foley catheter placement have been attempted to decrease the amount of tracer in the bladder lumen that obscures important findings.49 Studies to date have not demonstrated significant advantage of PET/CT over CT alone or MRI in the evaluation of lymph node metastasis (Figure 19).60,63,64
Figure 10. Squamous cell carcinoma of the bladder. Axial images show an infiltrative mass of the superolateral bladder wall (arrows, A and B). Although calcifications often associated with this type of tumor were not present, the patient’s history of schistosomiasis was highly suggestive of a squamous cell carcinoma.
Figure 9. Infiltrating transitional cell carcinoma of the bladder. This infiltrating tumor (long thin arrow) can be seen extending outside the bladder wall to involve the seminal vesicle (short thick arrow).
Although PET theoretically permits the recognition of positive lymph nodes independent of size, the sensitivity of this imaging modality is limited in the evaluation of small microscopic metastases. Drieskens et al examined the value of preoperative FDG-PET/CT in identifying locoregional lymph node metastasis and other distant metastasis in 55 patients with bladder cancer.63 The sensitivity, specificity, and accuracy of PET/CT for staging of both types of metastases were 60%, 88%, and 78%, respectively. Although PET/CT was superior in identifying distant metastases, PET/CT was no better than CT alone in detecting locoregional lymph node metastasis. Swinnen et al found FDG-PET/CT to have an
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Figure 11. Adenocarcinoma of the urinary bladder. Adenocarcinoma of the bladder can occur in patients with bladder exstrophy or in those with an urachal remnant, as in this patient (arrow). Adenocarcinoma of the urachal remnant will be seen anteriorly and superiorly in the bladder at the urachal ligament.
accuracy, sensitivity, and specificity for diagnosing node-positive disease of 84%, 46%, and 97%, respectively.60 The accuracy, sensitivity, and specificity of CT alone were 80%, 46%, and 92%, respectively. The difference between FDG-PET/CT and CT alone was not statistically significant. PET tracers that are not excreted by the urinary system, such as 11C-methionine and 11C-choline, have been suggested as alternatives for evaluating urothelial
Figure 12. Papillary transitional cell carcinoma within a urinary bladder diverticulum. A papillary tumor is noted within a diverticulum of the lateral urinary bladder wall (arrow). The presence of contrast-opacified urine inside the diverticulum allowed the tumor to be detected.
A.S. Purysko, H.M. Leão Filho, and B.R. Herts
Figure 13. Non-Hodgkin lymphoma of the urinary bladder. Lymphoma of the bladder can show an infiltrating growth pattern (arrow); bladder margins are no longer seen. Biopsy is needed to distinguish lymphoma from other infiltrating bladder neoplasms.
tumors using PET/CT. One study of 11C-choline reported an accuracy of 62% for the detection of metastatic lymph nodes and a sensitivity of 96% for the detection of residual cancer after TURB.65 Although these recent data are promising, the short (20-minute) half-lives of these agents restrict their practical use in the clinical setting.60,65 Ferumoxtran-10, another agent for detecting lymph node metastases, is a reticuloendothelial system-targeted MRI contrast agent that consists of ultrasmall superparamagnetic particles of iron oxide (USPIO).
Figure 14. Bladder leiomyoma. Axial T2-weighted magnetic resonance image shows a lobulated mass projecting intraluminally (white arrow). A fluid-filled Foley catheter is seen (black arrow).
Radiologic imaging of patients with bladder cancer
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matogenous spread are the lungs, bone, liver, and brain (Figure 20).12 Chest radiograph is an effective, inexpensive, method for evaluating lung metastasis in patients with muscle-invasive tumors.12,70 However, patients with equivocal chest radiographs and those who are thought to be at high risk for lung metastasis should undergo chest CT. MRI is more sensitive and specific for diagnosing bone metastasis than bone scintigraphy, but MRI is more expensive and time consuming, which limits its use as a screening tool.7 Currently, there is no recommendation for routine evaluation of bone metastasis in patients with bladder cancer, even for those with muscle-invasive tumors. Bone scintigraphy may be limited Figure 15. Transitional cell carcinoma of the bladder on computed tomography (CT). This bladder tumor presents as asymmetric thickening of the right posterior bladder wall (arrows). The lack of distinction between the bladder wall layers on CT precludes adequate characterization of muscle invasion, limiting local staging by CT.
Ferumoxtran-10 – enhanced MRI has been shown to be sensitive and specific for the detection of lymph node metastasis for various tumors. This technique offers higher diagnostic precision than does unenhanced MRI for the detection of lymph node metastases and provides functional and anatomic definition.66 The uptake of USPIO in normal lymph nodes results in a signal decrease on T2/T2*- weighted sequences; in lymph node regions containing malignant cells, the absence of macrophage activity results in a lack of signal decrease, leaving affected nodes with hyperintense signal.61,67,68 Unfortunately, using ferumoxtran-10 is expensive and time-consuming: a 30-minute administration period with medical supervision is required, and two separate MRI examinations must be performed within 24 to 36 hours. The reading of the results also requires special expertise, as a lengthy node-by-node comparison must be made between the native MRI and a second MRI after USPIO. USPIO has not yet received approval from the US Food and Drug Administration but is used in several European countries.
Metastasis Staging Approximately 10% to 15% of patients with bladder cancer already have metastatic disease at the time of diagnosis.69 TCC in the bladder spreads by local extension through the basement membrane into the muscular layer and then to the perivesical fat. Progressive extension into the muscular layer allows for vascular and lymphatic invasion and consequently more distant spread. The most common sites of he-
Figure 16. Papillary non–muscle-invasive transitional cell carcinoma of the bladder. The tumor (arrow) shows intermediate to high signal intensity on axial T2-weighted sequence (A), enhancing after intravenous administration of gadolinium-based contrast agent on axial T1-weighted sequence (B).
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Figure 17. Muscle-invasive transitional cell carcinoma of the bladder on magnetic resonance imaging. Coronal T2weighted image demonstrates a muscle-invasive tumor (asterisk) in the left lateral bladder wall, with extension into the perivesical fat (arrows). Notice interruption of the normal bladder wall at the site of maximal invasion (arrow head).
A.S. Purysko, H.M. Leão Filho, and B.R. Herts
Because most urinary bladder tumors (70%) show papillary growth, the tumors can be visualized with VC.74 The tumor’s size can be measured objectively with VC so that treatment response can be evaluated in unresectable tumors or in patients with other contraindications for conventional cystoscopy.40 Periodic imaging surveillance of the upper urinary tract is not recommended in patients with non–muscle-invasive tumors, except for those with a high risk of recurrence.10,75 In patients with invasive bladder cancer, radical cystectomy is performed with curative intent, and follow-up imaging choices depend on the pathologic stage of the tumor after cystectomy. Patients with more advanced disease undergo routine and frequent imaging particularly within the first 2 to 3 years, as 90% of recurrences occur during this period.71,76 Either CTU or
to patients with bone pain and/or elevated levels of serum alkaline phosphatase, and if necessary, further evaluation with radiographs, MRI, or even biopsy may be performed.12
FOLLOW-UP IMAGING Up to 70% of patients treated for bladder cancer will experience a recurrence after treatment.27 TCC recurrence can be attributed to multiple factors, including incomplete resection, implantation at traumatized sites in the bladder, and rapid growth of epithelial malignancy (Figure 21).71 The high frequency of recurrence and the potential for stage progression even after several years justify frequent and potentially lifelong surveillance with cystoscopy for patients with non–muscle-invasive bladder cancer.10 The need for frequent and long-term follow-up, in addition to the expense of treating bladder cancer, renders the per-patient cost of bladder cancer among the most expensive malignancies, and the fifth most expensive cancer in terms of annual medical care expenditures, accounting for almost $4 billion in direct costs per year in the United States.72,73 Imaging of bladder cancer after treatment is particularly challenging. Intravesical medication, transurethral resection or biopsy of the tumor often cause inflammation and edema, leading to vesical and perivesical changes that may mimic tumor, as previously discussed. Currently, no noninvasive imaging modality can replace cystoscopy.26,27 Some investigators have suggested the use of VC, alternated with conventional cystoscopy, as a more cost-effective and less invasive follow-up measure for patients with bladder cancer.39,43
Figure 18. Extensive muscle-invasive bladder carcinoma on magnetic resonance imaging. The tumor (arrowheads) demonstrates multifocal bladder wall thickening on T2weighted image (A) and restricted diffusion (high signal) on diffusion-weighted image (B). This tumor was associated with multiple enlarged lymph nodes (arrows).
Radiologic imaging of patients with bladder cancer
Figure 19. Pelvic recurrence of bladder cancer on positron emission tomography/computed tomography (PET/CT). Fused PET-CT image displays increased 2-deoxy-2 [F] fluoro-D-glucose (FDG) uptake in an enlarged left iliac lymph node (arrow) consistent with metastatic involvement.
MRI may be used to assess for local and distant recurrence. Although the risk of recurrence in the upper urinary tract is small (2%–7%), routine surveillance of the upper urinary tract in patients with muscle-invasive bladder cancer is recommended.76,77 CTU is the preferred modality for this indication, as it allows assessment of the urinary tract and metastatic disease in other sites in the same study. Recent research has shown that MRI of the bladder with DWI may help to predict treatment response in
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Figure 21. Recurrent transitional cell carcinoma on follow-up computed tomography (CT) 6 months after left nephrectomy and incomplete resection of the ipsilateral ureter. Coronal oblique CT reformation image shows recurrent tumor in the left ureteral stump (white arrow), and multiple papillary lesions in the bladder (black arrows).
patients receiving chemotherapy before cystectomy, which would allow more optimal patient selection in bladder-sparing protocols.77
CONCLUSION Imaging plays an important role in the detection, staging, and follow-up of patients with bladder cancer. CTU is currently the most common imaging modality used for the initial evaluation of patients with a suspected or proven bladder tumor. MRI provides the best local staging compared with other imaging modalities, and its role will continue to grow with refinements of techniques, particularly DWI. The use of PET/CT in patients with bladder cancer is currently best reserved for detecting lymphadenopathy and metastatic disease. New radioactive tracers may help to overcome current PET/CT limitations for the primary evaluation of the urinary tract.
REFERENCES
Figure 20. Bone metastasis in a patient with bladder cancer. Axial computed tomography image shows a mixed lythic and blastic lesion of the first lumbar vertebral body.
1. Kohler BA, Ward E, McCarthy BJ, et al. Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103:714 –36. 2. Murphy WM, Grignon DJ, Perlman EJ. Tumors of the kidney, bladder, and related urinary structures. Washington, DC: American Registry of Pathology; 2004:394. 3. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011; 306:737– 45.
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4. Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66 Suppl 1:4 –34. 5. Sutton JM. Evaluation of hematuria in adults. JAMA. 1990;263:2475– 80. 6. Cohan RH, Caoili EM, Cowan NC, Weizer AZ, Ellis JH. MDCT urography: exploring a new paradigm for imaging of bladder cancer. AJR Am J Roentgenol. 2009;192: 1501– 8. 7. Stenzl A, Witjes JA, Cowan NC, et al. Guidelines on bladder cancer muscle—invasive and metastatic. European Association of Urology; 2011. Available from: www.uroweb.org. 8. Lopes RI, Nogueira L, Albertotti CJ, Takahashi DY, Lopes RN. Comparison of virtual cystoscopy and transabdominal ultrasonography with conventional cystoscopy for bladder tumor detection. J Endourol. 2008;221725–9. 9. Grossfeld GD, Wolf JS Jr, Litwan MS, et al. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. Am Fam Physician. 2001;63:1145–54. 10. American Urological Association. Bladder Cancer Clinical Guideline Update Panel. The management of bladder cancer: diagnosis and treatment recommendations. American Urological Association Education and Research, Inc; 2007 (reviewed and validity confirmed 2010). Available from: www.auanet.org. 11. Hillman BJ, Silvert M, Cook G, et al. Recognition of bladder tumors by excretory urography. Radiology. 1981;138:319 –23. 12. ACR Appropriateness Criteria. Pretreatment staging of invasive bladder cancer. American College of Radiology; 2009. Available from: www.acr.org. 13. O’Malley ME, Hahn PF, Yoder IC, Gazelle GS, McGovern FJ, Mueller PR. Comparison of excretory phase, helical computed tomography with intravenous urography in patients with painless haematuria. Clin Radiol. 2003;58: 294 –300. 14. Herranz-Amo F, Diez-Cordero JM, Verdu-Tartajo F, Bueno-Chomon G, Leal-Hernandez F, Bielsa-Carillo A. Need for intravenous urography in patients with primary transitional carcinoma of the bladder? Eur Urol. 1999;36: 221– 4. 15. Datta SN, Allen GM, Evans R, Vaughton KC, Lucas MG. Urinary tract ultrasonography in the evaluation of haematuria: a report of over 1,000 cases. Ann R Coll Surg Engl. 2002;84:203–5. 16. Edwards TJ, Dickinson AJ, Natale S, Gosling J, McGrath JS. A prospective analysis of the diagnostic yield resulting from the attendance of 4020 patients at a protocoldriven haematuria clinic. BJU Int. 2006;97:301–5. 17. Nicolau C, Bunesch L, Sebastia C, Salvador R. Diagnosis of bladder cancer: contrast-enhanced ultrasound. Abdom Imaging. 2010;35:494 –503. 18. ACR Appropriateness Criteria. Hematuria. American College of Radiology; 2008. Available from: www.acr.org. 19. Francica G, Bellini SA, Scarano F, Miragliuolo A, De Marino FA, Maniscalco M. Correlation of transabdominal sonographic and cystoscopic findings in the diagnosis of focal abnormalities of the urinary bladder wall: a prospective study. J Ultrasound Med. 2008;27: 887–94.
A.S. Purysko, H.M. Leão Filho, and B.R. Herts
20. Itzchak Y, Singer D, Fischelovitch Y. Ultrasonographic assessment of bladder tumors. 1. Tumor detection. J Urol. 1981;126:31–3. 21. Ozden E, Turgut AT, Turkolmez K, Resorlu B, Safak M. Effect of bladder carcinoma location on detection rates by ultrasonography and computed tomography. Urology. 2007;69:889 –92. 22. Abu-Yousef MM, Narayana AS, Franken EA Jr, Brown RC. Urinary bladder tumors studied by cystosonography. Part I: detection. Radiology. 1984;153:223– 6. 23. Kocakoc E, Kiris A, Orhan I, Poyraz AK, Artas H, Firdolas F. Detection of bladder tumors with 3-dimensional sonography and virtual sonographic cystoscopy. J Ultrasound Med. 2008;27:45–53. 24. Joffe SA, Servaes S, Okon S, Horowitz M. Multi-detector row CT urography in the evaluation of hematuria. Radiographics. 2003;23:1441–55. 25. Silverman SG, Leyendecker JR, Amis ES Jr. What is the current role of CT urography and MR urography in the evaluation of the urinary tract? Radiology. 2009;250: 309 –23. 26. Turney BW, Willatt JM, Nixon D, Crew JP, Cowan NC. Computed tomography urography for diagnosing bladder cancer. BJU Int. 2006;98:345– 8. 27. Sadow CA, Silverman SG, O’Leary MP, Signorovitch JE. Bladder cancer detection with CT urography in an academic medical center. Radiology. 2008;249:195–202. 28. Jinzaki M, Tanimoto A, Shinmoto H, et al. Detection of bladder tumors with dynamic contrast-enhanced MDCT. AJR Am J Roentgenol. 2007;188:913– 8. 29. Kim JK, Park SY, Ahn HJ, Kim CS, Cho KS. Bladder cancer: analysis of multi-detector row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging. Radiology. 2004;231:725–31. 30. Park SB, Kim JK, Lee HJ, Choi HJ, Cho KS. Hematuria: portal venous phase multi detector row CT of the bladder: a prospective study. Radiology. 2007;245:798 – 805. 31. Kim B, Semelka RC, Ascher SM, Chalpin DB, Carroll PR, Hricak H. Bladder tumor staging: comparison of contrastenhanced CT, T1- and T2-weighted MR imaging, dynamic gadolinium-enhanced imaging, and late gadolinium-enhanced imaging. Radiology. 1994;193:239 – 45. 32. Tanimoto A, Yuasa Y, Imai Y, et al. Bladder tumor staging: comparison of conventional and gadolinium-enhanced dynamic MR imaging and CT. Radiology. 1992; 185:741–7. 33. Thomsen HS. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am. 2009;47:827–31. 34. Matsuki M, Inada Y, Tatsugami F, Tanikake M, Narabayashi I, Katsuoka Y. Diffusion-weighted MR imaging for urinary bladder carcinoma: initial results. Eur Radiol. 2007;17:201– 4. 35. Takahara T, Imai Y, Yamashita T, Yasuda S, Nasu S, Van Cauteren M. Diffusion weighted whole body imaging with background body signal suppression (DWIBS): technical improvement using free breathing, STIR and high-resolution 3D display. Radiat Med. 2004;22:275– 82. 36. Abou-El-Ghar ME, El-Assmy A, Refaie HF, El-Diasty T. Bladder cancer: diagnosis with diffusion-weighted MR imaging in patients with gross hematuria. Radiology. 2009;251:415–21.
Radiologic imaging of patients with bladder cancer
37. El-Assmy A, Abou-El-Ghar ME, Mosbah A, et al. Bladder tumour staging: comparison of diffusion- and T2weighted MR imaging. Eur Radiol. 2009;19:1575– 81. 38. Avcu S, Koseoglu MN, Ceylan K, Bulut MD, Unal O. The value of diffusion-weighted MRI in the diagnosis of malignant and benign urinary bladder lesions. Br J Radiol. 2011;84:875– 82. 39. Song JH, Francis IR, Platt JF, et al. Bladder tumor detection at virtual cystoscopy. Radiology. 2001;218:95–100. 40. Vining DJ, Zagoria RJ, Liu K, Stelts D. CT cystoscopy: an innovation in bladder imaging. AJR Am J Roentgenol. 1996;166:409 –10. 41. Narumi Y, Kumatani T, Sawai Y, et al. The bladder and bladder tumors: imaging with three-dimensional display of helical CT data. AJR Am J Roentgenol. 1996;167: 1134 –5. 42. Kim JK, Ahn JH, Park T, Ahn HJ, Kim CS, Cho KS. Virtual cystoscopy of the contrast material-filled bladder in patients with gross hematuria. AJR Am J Roentgenol. 2002; 179:763– 8. 43. Basak M, Ozkurt H, Tanriverdi O, Cay E, Aydin M, Miroglu C. Sixteen-slice multidetector computed tomographic virtual cystoscopy in the evaluation of a patient with suspected bladder tumor and history of bladder carcinoma operation. J Comput Assist Tomogr. 2009;33: 867–71. 44. Wong-You-Cheong JJ, Woodward PJ, Manning MA, Sesterhenn IA. From the Archives of the AFIP: neoplasms of the urinary bladder: radiologic-pathologic correlation. Radiographics. 2006;26:553– 80. 45. Saga Y, Numata A, Tokumitsu M, et al. Comparative study of novel endoluminal ultrasonography and conventional transurethral ultrasonography in staging of bladder cancer. Int J Urol. 2004;11:597– 601. 46. Tomita Y, Kobayashi K, Saito T, Tanikawa T, Kimura M, Takahashi K. Use of miniature ultrasonic probe system for intravesical ultrasonography for transitional cell cancer of the urinary tract. Scand J Urol Nephrol. 2000;34: 313– 6. 47. Barentsz JO, Ruijs SH, Strijk SP. The role of MR imaging in carcinoma of the urinary bladder. AJR Am J Roentgenol. 1993;160:937– 47. 48. Caruso G, Salvaggio G, Campisi A, et al. Bladder tumor staging: comparison of contrast-enhanced and gray-scale ultrasound. AJR Am J Roentgenol. 2010;194:151– 6. 49. Kibel AS, Dehdashti F, Katz MD, et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma. J Clin Oncol. 2009;27:4314 –20. 50. Barentsz JO, Jager GJ, van Vierzen PB, et al. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology. 1996;201:185–93. 51. Tachibana M, Baba S, Deguchi N, et al. Efficacy of gadolinium-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging for differentiation between superficial and muscle-invasive tumor of the bladder: a comparative study with computerized tomography and transurethral ultrasonography. J Urol. 1991;145:1169 –73. 52. Tekes A, Kamel I, Imam K, et al. Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am J Roentgenol. 2005;184:121–7.
557
53. Narumi Y, Kadota T, Inoue T, et al. Bladder tumors: staging with gadolinium-enhanced oblique MR imaging. Radiology. 1993;187:145–50. 54. Hayashi N, Tochigi H, Shiraishi T, Takeda K, Kawamura J. A new staging criterion for bladder carcinoma using gadolinium-enhanced magnetic resonance imaging with an endorectal surface coil: a comparison with ultrasonography. BJU Int. 2000;85:32– 6. 55. Takeuchi M, Sasaki S, Ito M, et al. Urinary bladder cancer: diffusion-weighted MR imaging: accuracy for diagnosing T stage and estimating histologic grade. Radiology. 2009; 251:112–21. 56. Scattoni V, Da Pozzo LF, Colombo R, et al. Dynamic gadolinium-enhanced magnetic resonance imaging in staging of superficial bladder cancer. J Urol. 1996;155: 1594 –9. 57. Kobayashi S, Koga F, Yoshida S, et al. Diagnostic performance of diffusion-weighted magnetic resonance imaging in bladder cancer: potential utility of apparent diffusion coefficient values as a biomarker to predict clinical aggressiveness. Eur Radiol. 2011;21:2178 – 86. 58. Leissner J, Hohenfellner R, Thuroff JW, Wolf HK. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: significance for staging and prognosis. BJU Int. 2000;85:817–23. 59. Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Riujs SJ. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional T1weighted magnetization-prepared-rapid gradient-echo sequence. AJR Am J Roentgenol. 1996;167:1503–7. 60. Swinnen G, Maes A, Pottel H, et al. FDG-PET/CT for the preoperative lymph node staging of invasive bladder cancer. Eur Urol. 2010;57:641–7. 61. Deserno WM, Harisinghani MG, Taupitz M, et al. Urinary bladder cancer: preoperative nodal staging with ferumoxtran-10-enhanced MR imaging. Radiology. 2004;233: 449 –56. 62. Thoeny HC, Triantafyllou M, Birkhaeuser FD, et al. Combined ultrasmall superparamagnetic particles of iron oxide– enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients. Eur Urol. 2009;55:761–9. 63. Drieskens O, Oyen R, Van Poppel H, Vankan Y, Flamen P, Mortelmans L. FDG-PET for preoperative staging of bladder cancer. Eur J Nucl Med Mol Imaging. 2005;32: 1412–7. 64. Jensen TK, Holt P, Gerke O, et al. Preoperative lymphnode staging of invasive urothelial bladder cancer with 18F-fluorodeoxyglucose positron emission tomography/ computed axial tomography and magnetic resonance imaging: correlation with histopathology. Scand J Urol Nephrol. 2011;45:122– 8. 65. Picchio M, Treiber U, Beer AJ, et al. Value of 11C-choline PET and contrast-enhanced CT for staging of bladder cancer: correlation with histopathologic findings. J Nucl Med. 2006;47:938 – 44. 66. Will O, Purkayastha S, Chan C, et al. Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis. Lancet Oncol. 2005;7:52– 60. 67. Thoeny HC, Triantafyllou M, Birkhaeuser FD, et al. Combined ultrasmall superparamagnetic particles of iron oxide-
558
68.
69.
70.
71.
72.
A.S. Purysko, H.M. Leão Filho, and B.R. Herts
enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients. Eur Urol. 2009;55:761–9. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med. 2003;348:2491–9. Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urol. 2005;174: 14 –20. Kuroda M, Meguro N, Maeda O, et al. Stage specific follow-up strategy after cystectomy for carcinoma of the bladder. Int J Urol. 2002;9:129 –33. Oosterlinck W, Lobel B, Jaske G, Malmstrom PU, Stockle M, Sternberg C; European Association of Urology (EAU) Working Group on Oncological Urology. Guidelines on bladder cancer. Eur Urol. 2002;41:105–12. Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R. The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics. 2003;21:1315–30.
73. Kamat AM, Karam JA, Grossman HB, Kader AK, Munsell M, Dinney CP. Prospective trial to identify optimal bladder cancer surveillance protocol: reducing costs while maximizing sensitivity. BJU Int. 2011;108:1119 –23. 74. Beer A, Saar B, Rummeny EJ. Tumors of the urinary bladder: technique, current use, and perspectives of MR and CT cystography. Abdom Imaging. 2003;28:868 –76. 75. Brausi M, Witjes JA, Lamm D, et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J Urol. 2011; 186:2158 – 67. 76. Beyersdorff D, Zhang J, Schöder H, Bochner B, Hricak H. Bladder cancer: can imaging change patient management? Curr Opin Urol. 2008;18:98 –104. 77. Yoshida S, Koga F, Kawakami S, et al. Initial experience of diffusion-weighted magnetic resonance imaging to assess therapeutic response to induction chemoradiotherapy against muscle-invasive bladder cancer. Urology. 2010;75:387–91.