SEARCH

SEARCH BY CITATION

Keywords:

  • urothelial carcinoma;
  • bladder cancer;
  • staging;
  • magnetic resonance imaging;
  • diagnosis;
  • prognosis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

What's known on the subject? and What does the study add?

According to current treatment guidelines, magnetic resonance imaging (MRI) or computed tomography (CT) can be used to assist in staging bladder cancer patients being considered for radical surgery.

In this article, we review the evidence supporting the use of MRI for bladder cancer staging. The ability of MRI to differentiate non-muscle invasive from muscle-invasive bladder cancer, to differentiate organ-confined from non-organ-confined bladder cancer, and to identify lymph node metastases is described in detail. Additionally, the role of MRI as a biomarker of chemotherapeutic response in bladder cancer is reviewed and summarized.

OBJECTIVES

  • • To evaluate the current status of magnetic resonance imaging (MR) as a staging tool for bladder cancer.

  • • To investigate the role of MR in assessing chemotherapeutic response in bladder cancer patients.

PATIENTS AND METHODS

  • • A Pubmed/MEDLINE search was conducted to identify original articles, review articles, and editorials regarding the use of MR in bladder cancer.

RESULTS

  • • Contrast-enhanced MR and diffusion weighted MR (DW-MRI) can likely distinguish between non-muscle invasive bladder cancer and muscle invasive cancer with >80% accuracy.

  • • Some advantages of DW-MRI are the differentiation of benign versus malignant tissue involvement without the need for intravenous contrast, and the possibility of obtaining information on histologic grade and T stage.

  • • Traditional MR sequence have low sensitivity for identifying small lymph node metastases but MR lymphography (MRL) using ultra-small paramagnetic iron oxide (USPIO) may enhance their detectin.

  • • There may be a role for DW-MRI in the evaluation of chemotherapeutic response in bladder cancer patients.

CONCLUSION

  • • To date, sample sizes and study designs are insufficient to clearly establish the role of MR in bladder cancer management, and to this end, well designed prospective trials are needed.


Abbreviations
NMIBC

non-muscle invasive bladder cancer

MIBC

muscle invasive bladder cancer

TUR

transurethral resection

RC

radical cystectomy

LN

lymph node

T1W

T1-weighted

T2W

T2-weighted

DCE-MRI

dynamic-contrast-enhanced MRI

DW-MRI

diffusion-weighted MRI

SI

signal intensity

ADC

apparent diffusion coefficient

MRL

magnetic resonance lymphography

USPIO

ultra-small paramagnetic iron oxide

MDCT

multi-detector row helical CT

EAU

European Association of Urology.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

An estimated 70 530 new cases of bladder cancer were diagnosed in the USA in 2010, resulting in 14 680 deaths [1]. Initially, 70% of patients present with non-muscle invasive bladder cancer (NMIBC), and 30% with muscle-invasive bladder cancer (MIBC) [2]. Despite transurethral resection (TUR) with or without intravesical chemotherapy, approximately 30% of patients with NMIBC experience disease progression [3]. One of the critical questions in bladder cancer is to determine which patients with NMIBC are at high risk of disease progression, so that early, aggressive treatment can be applied to potentially improve survival. For patients with non-metastatic MIBC, up to 50% will experience disease progression and eventual death, despite adequate radical cystectomy (RC) and bilateral pelvic lymph node (LN) dissection [4–6]. Neo-adjuvant cisplatin-based combination chemotherapy has been shown to improve survival in patients with MIBC [7,8]. However, this effective treatment is withheld from some patients based on the argument that RC alone may cure some of them, and the addition of chemotherapy would result in unnecessary overtreatment and avoidable side effects.

The strongest predictors of treatment success are local and regional disease burden. However, there is a large discrepancy between the clinical preoperative stage and the pathological stage, with approximately 25% of patients having LN metastases that are missed on current preoperative staging [9,10]. Outcome prediction based on current clinical staging, an integration of TUR pathology, bimanual examination and conventional cross-sectional imaging, is insufficient to allow accurate informed decision making when selecting those non-metastatic MIBC patients most likely to benefit from multimodal therapy with neo-adjuvant cisplatin-based combination chemotherapy. Newer imaging tools such as MRI promise to overcome some of the limitations of current staging methods, thereby allowing better risk-stratification of patients with bladder cancer.

The primary purpose of this review was to evaluate the current status of MRI as a staging tool for bladder cancer. The use of MRI will be considered in the context of the standard evaluation that ensues after a diagnosis of bladder cancer. We begin with the evaluation of the bladder wall itself, including detection of extravesical extension, as well as a regional LN evaluation. Finally, the evolving role of MRI in assessing chemotherapy response will be addressed.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

A non-systematic literature search using the Medline/PubMed database was conducted to identify original articles, review articles, and editorials regarding the use of MRI in bladder cancer. Searches were limited to the English language, humans and adults, and used the key words ‘magnetic resonance imaging’, ‘bladder cancer’ and ‘staging’. Substitution of the term ‘transitional cell carcinoma’ or ‘urothelial carcinoma of bladder’ for the term ‘bladder cancer’, yielded results that were subsets of the original search, which found 110 publications. All abstracts were reviewed and the corresponding full-length articles for those that were most relevant to bladder cancer staging and evaluation of chemotherapeutic response in bladder cancer were analysed. Articles written before 2000 were excluded unless they were later found to be widely referenced in the literature in which case they were fully reviewed for contemporary relevance and were selectively included. Case reports and studies with only a limited focus on MRI application to bladder cancer were also omitted. Studies of additional interest that were referenced in the full-length articles originally retrieved were located by hand search and were reviewed as well. Ultimately, 30 articles were chosen for discussion in this review based on these criteria. As most studies reviewed investigated urothelial carcinomas, when we use the term bladder cancer, we are referring to urothelial carcinoma of the bladder.

MRI TECHNOLOGIES

Quality MRI of the bladder requires multiple sequences and in general, the current roles for the most commonly used sequences are as follows. T1-weighted (T1W) imaging is helpful in identifying gross extravesical infiltration and lymphadenopathy. T2-weighted (T2W) imaging can give information on tumour depth and involvement of adjacent structures. Dynamic-contrast-enhanced MRI (DCE-MRI) is useful in evaluating the enhancement pattern of bladder lesions [11,12].

Recently, there has been great interest in the use of diffusion-weighted MRI (DW-MRI) for bladder cancer staging, an imaging modality that can aid in differentiation of benign from malignant tissue without implementing intravenous contrast material. The images made by DW-MRI are constructed by quantifying the diffusion of water molecules in tissues [13,14]. In malignant tissues water diffusion is restricted because of greater cellularity and decreased extracellular space, resulting in relatively higher signal intensity (SI). The freedom for water molecules to diffuse is inversely proportional to the degree of tissue cellularity, and in benign tissue where diffusion freedom is greater, the SI is relatively lower.

An apparent diffusion coefficient (ADC) measurement can be reported as a component of a DW-MRI study and relative decreases in this value are potentially a biomarker for morphological disorganization and cellular differentiation (grade) [15]. Increases in ADC reflect increases in the mobility of water and in general, higher-grade malignancies have lower ADC measurements. The actual diffusion coefficient cannot be measured by MRI, so the ‘apparent’ value is used. Unfortunately, ADC values are difficult to reproduce from system to system and are dependent upon the coil system, vendor and imaging protocol [16]. Some have suggested that a more reproducible value to report would be an ADC ratio, calculated with respect to surrounding normal tissues.

Magnetic resonance lymphography (MRL) using ultra-small paramagnetic iron oxide (USPIO) particles holds promise for improving the detection of lymphadenopathy, but this technology is not commercially available in the USA or in Europe [17]. The USPIO particles (Ferumoxtran-10) localize to the reticulo-endothelial system [18]. In benign LN, the macrophages that colonize the tissue take up these iron-based particles, and on T2W imaging, the SI correspondingly decreases in these nodes. In contrast, the macrophages in metastatic LN have been replaced by tumour tissue, which lacks a reticulo-endothelial system and the particles are not absorbed. The SI of these nodes therefore remains unchanged on serial T2W imaging.

BLADDER CANCER STAGING

To assess the role that MRI plays in the staging evaluation of a bladder lesion, there are a few clinical questions that need to be considered: How well does MRI differentiate ≤T1 bladder cancer from ≥T2 and what role can MRI play as a biomarker of aggressive disease? How well does MRI differentiate between T2 and ≥T3 disease? How can MRI enhance the detection of small, but malignant LN?

NMIBC vs MIBC

High-grade NMIBC is frequently under-staged at TUR [9,10]. In fact, guideline recommendations call for a repeat TUR if a T1 lesion is diagnosed even if muscularis propria is present in the specimen [19]. These procedures require anaesthesia and carry with them a significant cost, and a low but present complication rate [20]. As Kim et al. showed an overall staging accuracy of 23% for CT with tumours ≤pT3a, imaging with CT is unable to accurately distinguish between pTa and pT3a disease [21,22]. Could the improved discrete visualization of MRI have potential benefits in staging, possibly obviating the need for a repeat resection?

T1W and T2W images in multiple planes are required for staging bladder tumours using MRI [23]. On T1W imaging, the bladder tumour has an intermediate SI that is similar to that of muscle, making differentiation of these two structures potentially difficult on this sequence. But, the T1W sequence is helpful in delineating the luminal component of a tumour and additionally, the extent of gross perivesical fat infiltration [24]. More importantly for defining NMIBC, on T2W imaging, the bladder wall is low in SI [25]. Tumours have intermediate to high SI and the muscularis propria has relatively lower SI. Therefore, a normal underlying muscle wall near the tumour suggests an absence of muscle infiltration. With contrast enhancement, the tumour and submucosal SI increase, whereas uninvolved muscle SI is unchanged. On the other hand, an irregular, heterogeneously enhancing muscle layer represents muscular involvement. Applying these MRI criteria, Tekes et al. [25] (n= 71) studied patients with a known diagnosis of urothelial carcinoma of the bladder using T1W, T2W and DCE-MRI. Pathological confirmation shows that these MRI sequences together can identify a ≤pT1 lesion vs a ≥pT2 lesion with a sensitivity, specificity and accuracy of 95–97%, 55–67% and 85%, respectively. Table 1 summarizes the findings of this study, as well as those of other selected studies that examined MRI as a bladder cancer staging modality.

Table 1. Selected studies of magnetic resonance imaging for bladder cancer T-staging
Study (n) [Ref.]MRI techniquePathological confirmation with RC, n (%)Overall staging accuracy (%)Over-staging error rate (%)NMIBC vs MIBC (%)Organ-confined vs Non-organ-confined bladder cancer (%)
Acc.Sens.Spec.Acc.Sens.Spec.
  1. MRI, magnetic resonance imaging; RC, radical cystectomy; NMIBC, non-muscle invasive bladder cancer; MIBC, muscle invasive bladder cancer; Acc., accuracy; Sens., sensitivity; Spec., specificity; T1W, T1-weighted; T2W, T2-weighted; DCE-MRI, dynamic contrast-enhanced MRI; DW-MRI, diffusion-weighted MRI; CE-EMRI, contrast-enhanced endorectal MRI; NR, not reported. *When ranges are given throughout table, aggregate values were not reported; range reflects two radiologists reading imaging studies. **P < 0.022 compared with T2W, aP < 0.01 compared with T2W alone, bP < 0.001 compared with T2W, cover-staging rate for organ-confined tumours, dstaging accuracy for pT1; P < 0.001 compared with T2W, estaging accuracy for ≤pT2; P < 0.001 compared with T2W; accuracy for >pT2, 93% and 80% for DW-MRI and T2W, respectively, P > 0.05, fNo T-staging differences between DW-MRI and T2W; study showed that ADC was lower in high-grade and high-stage tumours; threshold apparent diffusion coefficient value could differentiate MIBC/High-Grade T1 from more indolent phenotypes with Acc. 87, Sens. 88, Spec. 85; area under receiver operating characteristic curve = 0.921, gall had transurethral resection of bladder tumour after MRI, hvalues for MRI sequences overall, istaging accuracy, sensitivity and specificity based on Ta–T3a vs T3b–T4.

Tekes et al. (71) [25]T1W + T2W + DCE-MRI39 (58)62328595–97*55–678279–8679–84
Hayashi et al. (71) [27]T1W + CE-EMRI19 (27)8316879187NR
Takeuchi et al. (40) [28]T2W17 (43)67NR798874855095
T2W + DCE-MRI79**889486908092
T2W + DW-MRI88**96a88100a927097
T2W + DCE-MRI + DW-MRI92**98a94100a948097
El-Assmy et al. (106) [29]T2W72 (68)4076c6NRNR15NRNR
DW-MRI78b29c64dNRNR70eNRNR
Kobayashi et al.f (117) [16]T2W0 (0)g79–82NR79–8368–7680–91NR
DW-MRI79–8279–8266–7183–91
Kim et al. (36) [22]T1W22 (61)75h25hNR78i7878
T2W808378
DCE-MRI818673
Late DCE-MRI8610072

The differentiation of MIBC from NMIBC can be hindered by non-malignant changes associated with recent TUR, resulting in over-staging of the cancer [22]. Although contrast enhancement can partially ameliorate over-staging, it remains a confounding factor in post-TUR imaging [26]. In the early phases of DCE-MRI sequences, the tumour, mucosa and submucosa enhance and the bladder wall remains hypo-intense [25]. Taking advantage of this observation, investigators have used this submucosal linear enhancement as the basis for staging criteria. Hayashi et al. [27] studied 71 patients with bladder tumours, using gadolinium-enhanced T1W-MRI with an endorectal coil. Their diagnostic algorithm defined NMIBC if the submucosal linear enhancement was intact and MIBC if the line was interrupted. Patients were pathologically staged with deep TUR or RC. The sensitivity, specificity and accuracy for detecting muscle invasion was 91%, 87% and 87%, respectively. Visualization of submucosal linear enhancement could not always differentiate between inflammatory tissue and tumour extension through the submucosal layer, resulting in over-staging error in 16% of cases. These results were promising but required both gadolinium administration as well as an endorectal coil.

Similarly, using DCE-MRI, Takeuchi et al. [28] noted that 60% of lesions (n= 40) showed similar enhancement in tumour and submucosal tissue, and submucosal linear enhancement was difficult to identify in these cases. Although this group did not report their over-staging error with DCE-MRI, the authors concluded that contrast-enhanced images may be limited in terms of differentiating pT1 tumours with intact submucosal linear enhancement from pT2 tumours with submucosal linear enhancement disruptions.

In a cohort of putative bladder cancer patients (n= 106) who had not yet undergone TUR, DW-MRI was prospectively compared with T2W-MRI for staging purposes [29]. Standard T2W-MRI proved inaccurate at diagnosing pT1 and pT2 disease, with accuracies of 6% and 24%, respectively. DW-MRI improved this dramatically, to 64% and 75%, respectively, and interestingly, as pathological stage increased, both modalities provided increasingly accurate staging. Of note, DW-MRI had a 24.3% over-staging error for pT2 tumours, but did not under-stage any of these tumours. The overall staging accuracy for T2W in this study was only 39.6%, significantly lower than other published studies, a fact that the authors attributed to a high incidence of perivesical inflammation in the cohort and a high rate of over-staging [29]. In fact, Takeuchi et al. [28] also found that DW-MRI had superior accuracy to T2W-MRI for differentiating NMIBC from MIBC, 96% and 79%, respectively. However, the differences in accuracy for both T2W and DW-MRI between these two series are striking and according to a recent review from Giannarini et al. [30], those differences were probably attributable to the superior image quality achieved in the former study through varying diffusion sequences.

Kobayashi et al. [16] (n= 117) and Takeuchi et al. [28] used DW-MRI to predict T-stage and ADC to predict tumour grade. Important for interpretation, tumour, submucosal tissue and muscle show high, low and intermediate SI (Fig. 1A), respectively, on DW-MRI [28]. In both studies, ADC values were lower in high-grade tumours and decreased as tumour stage increased. At a threshold ADC value, clinically aggressive phenotypes such as MIBC and high-grade T1 tumours could be differentiated from more indolent phenotypes with sensitivity, specificity and accuracy of 88, 85 and 87%, respectively. The area under the receiver operating curve for predicting clinically aggressive tumours based on ADC value was 0.921 [16]. The mean ADC were (1.29 ± 0.21) × 10–3 mm2/s, (1.13 ± 0.24) × 10–3 mm2/s and (0.81 ± 0.11) × 10–3 mm2/s, for G1, G2 and G3 tumours, respectively [28]. A statistically significant difference was observed between G1 and G3 tumours and between G2 and G3 tumours, but not between G1 and G2 lesions [28]. Interobserver variability calculations favoured the use of DW-MRI over T2W-MRI in both studies with κ= 0.88 vs κ= 0.67, and κ= 0.88 vs κ= 0.70, respectively [16,28].

image

Figure 1. Stage pT1 papillary urothelial carcinoma in a 70-year-old man. (A) Transverse diffusion-weighted magnetic resonance image shows C-shaped high signal intensity (SI) area with a low SI stalk connecting to left side of bladder wall. (B) An inchworm creeping along a branch: diffusion-weighted magnetic resonance image finding resembles the arch-like shape of an inchworm. Reprinted from Takeuchi M, Sasaki S, Ito M, et al. Radiology 2009; 251: 112–21 with permission of the authors and the publisher, Radiological Society of North America ©2009.

Download figure to PowerPoint

A notable finding on DW-MRI, potentially pathognomonic for pT1 disease, is the ‘inchworm’ sign (Fig. 1A,B). This sign refers to the low SI stalk seen to invaginate into the high SI tumour on DW-MRI. In fact, the positive predictive value of this sign for pT1 disease was as high as 100% (28/28) in the series from Takeuchi et al., although potentially lacking in specificity [16,28]. The two radiologists reviewing images for the purpose of the study under-staged six histologically proven MIBC patients as NMIBC based on this imaging finding, for an under-staging rate of 24–27%. Interestingly, when an ADC threshold value differentiating MIBC from NMIBC was applied to the images with positive ‘inchworm’ sign, the under-staging rates dropped to 4–4.5% [16]. Seemingly, as has been shown in other malignancies, ADC reflects histological tumour grade and stage [13].

Organ-confined vs non-organ confined

Detecting extravesical extension of bladder cancer is the most important feature of the bladder wall evaluation before RC, as its presence negatively affects prognosis and may indicate the need for multimodal therapy with neo-adjuvant cisplatin-based combination chemotherapy when possible [31,32]. Contrast-enhanced CT is reasonably accurate at this assessment and perivesical fat invasion on multi-detector row helical CT (MDCT) has been shown to have sensitivity and specificity of 89% and 95%, respectively [33]. The updated European Association of Urology (EAU) Guidelines recommend either DCE-MRI or contrast-enhanced CT in patients being evaluated for radical treatment citing the increased sensitivity and decreased specificity for MRI versus CT [34].

Head-to-head studies comparing CT and MRI for staging of urothelial carcinoma of the bladder are rare. Kim et al. [22], in 1994, compared CT with several techniques of MRI for patients diagnosed with urothelial carcinoma of the bladder and reported the different modalities' ability to differentiate pTa–pT3a from pT3b–pT4a disease. The sensitivity, specificity and accuracy for CT and DCE-MRI were 93%, 71% and 83%, and 100%, 72% and 86%, respectively. Despite lack of significance, the authors concluded that DCE-MRI was a superior staging tool to CT and T1W or T2W MRI.

More recently, MDCT was used to predict perivesical invasion. Sixty-seven patients with urothelial carcinoma of the bladder were imaged before RC, and 16 bladder cancers with perivesical invasion were identified by pathology [33]. Identification of perivesical invasion with MDCT showed a sensitivity, specificity and accuracy of 89%, 95% and 93%, respectively. In comparing the MRI results reported by Kim et al. [22] with their results, these authors concluded that MRI provided greater sensitivity through its superior visualization of perivesical fat. However, this came at the cost of reduced specificity because of the misinterpretation of perivesical inflammation as a malignant process [22,33].

In a recent study from El-Assmy et al. [29] (n= 106) staging accuracy for ≤pT2 disease was 70% and 15%, for DW-MRI and T2W imaging, respectively (P < 0.001). Accuracy and sensitivity for diagnosing non-organ-confined bladder cancer (>pT2) was 92% and 80%, for DW-MRI and T2W imaging, respectively (P > 0.05). Specificity of MRI in diagnosing >T2 disease was not reported, but based on the published data, was limited by over-staging errors for pT1–pT2 lesions. DW-MRI and T2W-MRI over-staged 19/66(29%) and 50/66(76%) of pT1–T2 lesions, respectively.

Tekes et al. [25] (n= 71) found the sensitivity, specificity and accuracy to be 79–86%, 79–84% and 82% for differentiating ≤pT2b from ≥pT3 or greater disease using T2W and DCE-MRI. As in other studies, employing DCE-MRI resulted in over-staging error, 32% over all cases [25].

Takeuchi et al. [28] (n= 40) studied patients with T2W, DW-MRI and DCE-MRI. Diagnostic accuracy for differentiating ≤pT2 from ≥pT3 was tested for all combinations of these MRI sequences. Accuracies ranged from 85 to 94% and in terms of accuracy, no combination of sequences showed diagnostic superiority in differentiating organ-confined from non-organ-confined bladder cancer. However, the addition of DCE-MRI or DW-MRI sequences, or both, to T2W images, improved sensitivity for detecting non-organ-confined disease from 50% to 70–80%, although not reaching significance [28]. Specificity of the MRI finding of non-organ-confined disease was high for all sequences, 92–97%, with no inter-sequence statistical differences.

Lymph node evaluation

Bladder cancer metastatic to regional LN is strongly associated with poor prognosis despite effective local and systemic therapy [4–6]. Although patients with enlarged, biopsy-proven LN metastases are typically given definitive chemotherapy [35], micro-metastatic LN deposits escape detection. MRI and CT diagnoses of positive LN are based on size criteria where nodes >8 mm or >10 mm are considered positive for round and oval nodes, respectively [26,36]. Size criteria alone lack both sensitivity and specificity, because small metastatic nodes may be missed and enlarged benign nodes may be misclassified [37]. The accuracy of MRI for nodal staging has been reported in the range of 73–90%, which is similar to that reported for CT [11,26]. However, reports such as these should be considered in the context of the great variability in the LN dissections, the details of which are rarely reported in the radiological literature, that serve as the reference standard against which the imaging studies are measured. For example, while Kim et al. [33] reported on 67 RC patients imaged with MDCT before surgery, only five patients with a total of six LN metastases were found.

There is some evidence that MRI is superior to CT at identifying sub-centimetre pelvic LN but conventional MRI cannot distinguish between small benign nodes and those with micrometastatic deposits [38,39]. In a comparison study of the ability of CT and MRI to detect LN, MRI detected 271 vs 189 detected by CT (P < 0.001), and most of the difference was accounted for by nodes 1–5 mm in size [38]. However, tumour involvement in the identified nodes was not assessed so although more nodes overall were visualized, the study did not tell us whether more malignant nodes were seen. Moreover, in another study comparing positron emission tomography-CT with T2W/DCE-MRI for LN staging before RC, all three small metastatic nodes were missed by MRI and two of three were missed by positron emission tomography-CT [39].

A recent study investigated the use of DW-MRI for nodal staging in patients scheduled for RC [40]. One of the strengths of this study from Papalia et al. [40] is that all patients had an extended pelvic LN dissection with a mean nodal yield of 29. Values of ADC were obtainable for nodes in a total of 72 nodal basins. Histopathological evaluation of those nodal basins was then correlated with the recorded ADC values and a receiver operating characteristic curve analysis was performed. From the receiver operating characteristic curve, the authors determined that a threshold ADC of 0.86 × 10–3 mm3/s showed the clearest separation between metastatic and non-metastatic nodes. Using that value, the sensitivity, specificity and positive and negative predicted values were 76.4%, 89.4%, 86.6% and 71.4% [40]. The authors noted the variability of ADC readings from centre to centre and the operator dependency of reading these studies as a limitation of the technique.

Several trials have investigated the utility of MRL for bladder cancer LN staging, using USPIO particles as a contrast material [18]. Deserno et al.[37] (n= 58), in a prospective study of patients scheduled for RC, showed that the use of MRL substantially improved MRI sensitivity and negative predictive value for nodal involvement. Comparing pre-contrast with post-contrast images, sensitivity went from 76% to 96% and negative predictive value from 91% to 98% (P < 0.01). Remarkably, 10/12 metastatic nodes measuring 6–9 mm at pathological review were identified preoperatively. An obvious criticism of the technique is the length of time required for study completion (24–36 h between pre- and post-contrast). Additionally, the images obtained may be difficult to interpret requiring highly specialized expertise [41]. Also, as previously noted, another limitation of this study seems to be the lack of a clearly defined standard template for lymphadenectomy, possibly creating a detection bias.

A recent study from Thoeny et al. [42] (n= 21), which served as a pilot for a larger clinical trial (NCT00622973) improved upon this technique by incorporating the benefits of DW-MRI with those of USPIO administration. The restricted diffusion capability of water molecules in malignant nodes leads to increased SI on DW-MRI, as does the impaired USPIO uptake in these nodes. The authors hypothesized that the hyperintense signal in malignant nodes resulting from the use of this combined modality would improve the ability to differentiate from benign nodes [42].

The cohort, who had either a diagnosis of prostate or bladder cancer, was studied with conventional MRI sequences and DW-MRI sequences both pre-contrast and post-contrast infusion with Ferumoxtran-10. Images were interpreted in two ways: using the technique of pre- and post-contrast comparison, as in Deserno et al. [37]; and using the technique of the USPIO-enhanced MRI and DW-MRI (USPIO-DW-MRI) with subsequent morphological correlation. All patients underwent an extended pelvic LN dissection identifying a total of 26 malignant nodes. Overall, 24/26 were correctly identified with USPIO-DW-MRI and although diagnostic accuracies were of similarly high quality in the first method, and both methods require a second set of MRI images 24–36 h after Ferumoxtran is infused, the time spent interpreting the images was significantly less using the new method (13 min/patient vs 80 min; P < 0.001) [42]. Additionally, the USPIO-DW-MRI images seem relatively easy to interpret in that the radiologists who served as readers in this study were not previously familiar with the technique [42]. Taken together, these studies show that USPIO can significantly improve the accuracy of detecting LN metastasis in pelvic malignancies. However, image acquisition time is long, but the addition of DW-MRI techniques may increase the ease and the speed with which these images are interpreted. Despite some encouraging findings, further trials are necessary before FDA approval and widespread inclusion into clinical practice is considered.

EVALUATING CHEMOTHERAPY RESPONSE

MRI has been used for several years in patients after radiation for bladder cancer to identify residual active malignancy. DCE-MRI has a high negative predictive value for this purpose, but false positives are high because of inflammatory changes [43]. Some investigators have employed DCE-MRI to predict response to chemotherapy to individualize therapy. A positive early response would provide support for continuing with chemotherapy, whereas disease progression would indicate the need for a change in therapy [44]. Schrier et al. [44] (n= 40) studied patients with clinical N1–N2 disease who were undergoing chemotherapy. After their second and fourth of six chemotherapy courses, evidence of an early response was assessed with DCE-MRI. The rapidity with which the bladder tumour and LN (if visible) enhanced with contrast was the marker of clinical response. The investigators found that if the cancerous tissue enhanced >10 s after arterial enhancement (aorta), the patients could be considered responders after two chemotherapy sessions (sensitivity 91%, specificity 93%, accuracy 92%). This significantly improved upon the use of size criteria alone.

An evolving body of work is showing that DW-MRI can serve as a radiographic biomarker assessing response to chemotherapy. Several studies of non-urological malignancies (brain, liver, breast) have shown the ADC to be predictive of chemotherapy response [15]. As the diffusion coefficient reflects the activity of diffusing water molecules, effective cancer treatments augment the space within which water can diffuse, with a corresponding increase in ADC [14]. From an oncological standpoint, these increases in the mobility of water probably reflect cell membrane disruption that would occur in apoptosis, as well as the decrease in cellular volume from necrosis [15]. In breast cancer, ADC has been shown to increase in patients positively responding to chemotherapy, before any decrease in tumour volume is detectable on conventional imaging [15].

A recent study by Yoshida et al. [45] (n= 20) examined the therapeutic response to chemoradiotherapy for MIBC using DW-MRI. This was studied in the clinical setting of a protocol in which patients with a complete response entered a bladder preservation protocol, and those with a poor response underwent RC [46,47]. While DW-MRI, DCE-MRI and T2W imaging all showed poor sensitivity (43–57%) for detecting residual disease, the specificity and accuracy for DW-MRI in predicting pathological complete response was 92% and 80%, respectively, both significantly better than the other sequences.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

The clearest advantage of MRI over CT in bladder cancer imaging is its ability to differentiate NMIBC from MIBC [22,27–29]. DCE-MRI and DW-MRI are both capable of identifying the depth of bladder tumour invasion although both are susceptible to over-staging [27–29]. Additionally, the inclusion of ADC criteria in DW-MRI evaluation can improve the staging accuracy [16].

Both MRI and CT have approximately similar accuracy when used to diagnose non-organ-confined bladder cancer [28,33]. Older studies showed the sensitivity for perivesical invasion to be higher for MRI than for CT [22]; but newer MDCT, DCE-MRI and DW-MRI studies have shown sensitivities for non-organ-confined disease of 89% [33], 79–86% [25,28] and 70–92% [28,29], respectively. Regarding specificity, the EAU guidelines concluded that CT was the superior modality based on a comparison of a relatively new MDCT study [33] to the MRI findings of an older study [22,34], in which the specificity of MDCT and MRI were 95% and 71%, respectively. In more contemporary MRI studies, this trend may persist, although the difference may be smaller with specificities as high as 92–97% for DW-MRI and DCE-MRI having been reported [28,29]. Although EAU guidelines recommended either a contrast-enhanced CT or a DCE-MRI for evaluation in the patient being considered for RC [34], DW-MRI may be a reasonable alternative, particularly in the patient with renal impairment, in whom intravenous contrast material is contraindicated.

Conventional MRI and CT have similarly limited sensitivity for LN metastases <8 mm in size [36] although overall sensitivity for both modalities has been reported at a similarly high range, between 73 and 90% [11,48]. However, the reports for both modalities are fraught with potential inaccuracy stemming from the variation in the extent of pelvic node dissection during RC. To address that issue, Papalia et al. [40] performed extended pelvic LN dissection in patients who underwent DW-MRI before surgery. Their calculated ideal threshold value for determining LN metastases based on ADC requires external validation, which raises one of the fundamental problems in reporting ADC values, which is the difficulty of reproducing the same values from one system and protocol to another [16].

Another promising method of LN evaluation is MRL employing USPIO, which dramatically improves the sensitivity for the detection of small LN [37]. Diffusion-weighted imaging may enhance MRL capabilities and also probably plays an important role in other aspects of image-based bladder cancer staging [42]. As described, an important and evolving role for DW-MRI is that of the diffusion coefficient as an early marker of chemotherapy response in advanced bladder cancer [45].

There is no doubt that we need accurate biomarkers to individualize management and improve outcomes of bladder cancer patients. MRI, in its various forms, might serve as such a biomarker. However, to date, the sample size and design of studies are insufficient to draw definite conclusions on the role of MRI in bladder cancer management. As in the whole field of urology, well-designed prospective trials are needed to define the role and benefit of MRI in the management of bladder cancer.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

None declared. Source of funding: supported by the Frederick J. and Theresa Dow Wallace fund of the New York Community Trust.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES