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International Journal of Urology (2014)
doi: 10.1111/iju.12587
Review Article
Role of diffusion-weighted magnetic resonance imaging as an imaging biomarker of urothelial carcinoma Soichiro Yoshida,1 Fumitaka Koga,2 Hitoshi Masuda,3 Yasuhisa Fujii1 and Kazunori Kihara1 1
Department of Urology, Tokyo Medical and Dental University Graduate School, 2Department of Urology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, and 3Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
Abbreviations & Acronyms ADC = apparent diffusion coefficient BC = bladder cancer CCRCC = clear cell renal cell carcinoma CRT = chemoradiotherapy DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging DW-MRI = diffusion-weighted magnetic resonance imaging G = grade Ki-67 LI = Ki-67 labeling index MIBC = muscle-invasive bladder cancer MRI = magnetic resonance imaging NMIBC = non-muscle invasive bladder cancer NR = not reported P = pelvis Pts = patients ROI = regions of interest T2W-MRI = T2-weighted magnetic resonance imaging TURB = transurethral resection of the bladder U = ureter U/C = urinary cytology UTUC = upper tract urothelial carcinoma Correspondence: Soichiro Yoshida M.D., Ph.D., Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Email: [email protected] Received 23 May 2014; accepted 4 July 2014. © 2014 The Japanese Urological Association
Abstract: Diffusion-weighted magnetic resonance imaging is a type of functional imaging that is increasingly being applied in the management of upper tract urothelial carcinoma and bladder cancer. The image contrast is derived from differences in the Brownian motion of water molecules in tissues. The homogenous high signal intensity of upper tract urothelial carcinoma and bladder cancer on diffusion-weighted magnetic resonance imaging provides helpful diagnostic information for the presence of cancerous lesions in a non-invasive manner. Recently, growing evidence has emerged showing that diffusion-weighted magnetic resonance imaging can serve as an imaging biomarker for characterizing cancer pathophysiology, because the signal reflects biophysical information about the tissues. Quantitative analysis by evaluating the apparent diffusion coefficient values potentially reflects the histological grade and the biological aggressiveness of urothelial carcinoma. The apparent diffusion coefficient value could be a biomarker predicting the clinical course of upper tract urothelial carcinoma and bladder cancer. In addition, in chemoradiotherapy-based bladdersparing approaches against muscle-invasive bladder cancer, the role of diffusion-weighted magnetic resonance imaging for predicting the chemoradiosensitivity and for monitoring therapeutic response has been shown. Diffusion-weighted magnetic resonance imaging is expected to improve the diagnostic accuracy, and this qualitative information might allow individualized treatment strategies for patients with urothelial carcinoma. Key words: biological marker, carcinoma, diffusion magnetic resonance imaging, transitional cell, ureteral neoplasms, urinary bladder neoplasms.
Introduction Urothelial carcinomas are mainly located in the bladder or upper urinary tract. Bladder cancer and upper urinary tract cancer account for 90–95% and 5–10% of urothelial carcinomas, respectively.1,2 In recent clinical practice, contrast-enhanced computed tomography and MRI have become the most widely-used imaging modalities for radiological evaluation of the upper urinary tract and bladder.3 Generally, MRI is superior to computed tomography in locoregional staging because of its superior soft tissue delineation.4,5 Urothelial carcinoma of the bladder and UTUC share some significant characteristics, and their radiological findings are similar. However, an important point is that the treatment approaches differ significantly between these two diseases because of distinct differences in inherent anatomical locations.1,2,6,7 DW-MRI is a type of functional imaging, which is increasingly being applied in the management of UTUC and bladder cancer, and provides helpful information for the diagnosis of urothelial carcinoma in a non-invasive manner.8,9 Growing evidence has emerged showing that DW-MRI can serve as an imaging biomarker for characterizing the pathophysiology of cancer, which is requested for customizing therapeutic approaches for UTUC and bladder cancer.10 Thus, the present review focuses on the potential role of DW-MRI in detecting and characterizing UTUC and bladder cancer.
DW-MRI: Biophysical basis DW-MRI is a non-invasive functional imaging technique; the image contrast is derived from differences in the Brownian motion of water molecules in tissues.9,10 The imaging signal confers information about the biophysical properties of tissues, such as cell organization and density. A lesion where water molecules can diffuse freely shows low-signal intensity on DW-MRI. Stejskal and Tanner initially devised the DW-MRI technique in 1965. Since Le Bihan reported the first 1
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images of water diffusion in the human brain in 1986, DW-MRI has been applied in the early detection of microstructural and functional changes.11 DW-MRI can detect acute cerebral infarction before secondary morphological changes are observed by conventional imaging. In a similar manner, malignant lesions characteristically show high signal intensity because of the dense cellularity, tissue disorganization and decreased extracellular space that are typical characteristics of cancerous tissue, all of which restrict water diffusion.9,10 As the DW-MRI signal is derived from the inherent tissue contrast, the administration of intravenous contrast media is not required in this imaging technique. Therefore, DW-MRI is applicable in patients with allergies to contrast agents and those with renal insufficiency. The addition of DW-MRI to a routine MRI protocol requires only a few minutes, and it can be acquired using most current clinical MRI scanners.
Applications of DW-MRI in the abdominal and pelvic organs The application of DW-MRI to the abdominal organs is challenging because of physiological motion artifacts, such as respiratory movements, pulsation and bowel motion. However, a single-shot echo planar sequence with parallel imaging techniques, high-gradient amplitudes and multichannel coils allows for rapid data acquisition with improved image quality.12 Takahara et al. reported a procedure for body DW-MRI under free breathing conditions.13 Such approaches enable longer scan times and more thin-slice images with multiple signal averaging, and provide a high-quality multiplanar display. These technological improvements have allowed DW-MRI to be increasingly applied in abdominal and pelvic examinations, and it was quickly introduced as an important diagnostic imaging tool for detecting various types of tumors, including UTUC and bladder cancer.9
Degree of water diffusion as an imaging biomarker DW-MRI offers unique information reflecting the physiological characteristics of tissues by quantifying the diffusion of water molecules. The degree of water molecule diffusion is represented by the ADC value. The sensitivity of the diffusion is changed by using various “b-values,” which are proportional to the gradient amplitude, the duration of the applied gradient and the time interval between the paired gradients.9,10 The ADC value is calculated by evaluating the signal attenuation on DW-MRI with increasing b-values. Although a visual assessment of DW-MRI is carried out qualitatively, restriction of diffusion can be quantitatively assessed by evaluating the ADC values of a lesion. As DW-MRI provides biophysical information about cell organization, density and microstructure, tumor ADC values are expected to reflect the characteristics of the lesion.9,10 Various researchers have pointed out that ADC values could be a useful adjunct to characterize tumors in different regions, including the genitourinary organs. On an ADC map, the ADC values are calculated automatically for each pixel of the image and displayed. By setting ROI on the ADC map, profiles of the ADC values within the delineated regions are obtained. 2
However, the reproducibility of the ADC value is an intrinsic limitation of ADC measurements. Because the ADC value depends on the MRI system and imaging protocol, standardization of ADC assessment is essential to use ADC values as biomarkers to characterize cancerous lesions.10
Features of urothelial carcinoma on DW-MRI On DW-MRI with high b-values of 800–1000 s/mm2, urothelial carcinomas in the upper urinary tract and bladder generally show a homogenous, hyperintense signal reflecting homogenous histological characteristics, whereas the signals from the surrounding tissues, including the urine, renal parenchyma and surrounding tissues, are well-restrained.14 In most UTUC and bladder cancer patients, the intratumoral distribution of ADC values are homogenous on the ADC map. Homogenous diffusion environments within UTUC and bladder cancer lesions has been shown by a histogram analysis within a ROI positioned to maximally cover the tumor. Histogram analyses of intratumoral ADC values showed a single prominent peak in 82% of UTUC and 83% of bladder cancer lesions (Fig. 1).15,16 Compared with renal cell carcinoma that shows a heterogeneous signal on DW-MRI and on the ADC map, a ROI is relatively easy to set within a UTUC or bladder cancer lesion.17 The method of positioning a ROI for measuring ADC values of urothelial carcinoma is not standardized. However, Sufana Iancu et al. reported that there was no significant difference between the ADC values of UTUC obtained by drawing a large ROI covering the greatest part of the tumor and those measured from a small ROI in the most restricted part of the tumor.18 Because of the clear contrast between tumors and normal lesions, and the homogenous diffusion environment within the tumor, interobserver variability of measuring ADC values of UTUC and bladder cancers can be relatively small, although no study has evaluated this point.
Clinical applications of DW-MRI in bladder cancer Detection of bladder cancer The usefulness of DW-MRI in the diagnosis of bladder cancer has been shown in recent studies.8 On DW-MRI with a high b-value, bladder cancers generally show a hyperintense signal, whereas the signals of the surrounding tissue, including the urine and normal tissues, are well-restrained. Matsuki et al. first reported the feasibility of DW-MRI in detecting bladder cancer.19 In that study, all 15 known bladder cancers were clearly shown to have a high signal intensity compared with the surrounding tissue. A clear contrast was obtained between bladder cancer and the surrounding tissue. The same findings were reported in the following studies using a cohort composed of patients with known bladder cancer, showing the high sensitivity of DW-MRI in terms of detecting cancer. Details of the published studies are shown in Table 1.19–26 In a study of 123 cystoscopy-identified bladder cancers in 106 patients, El-Assmy et al. reported that 98% of the cancers were correctly identified, whereas two polypoid lesions less than 4 mm in diameter could not be identified, even when viewed © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
Bladder cancer
UTUC DW-MRI
DW-MRI
DW-MRI
ADC map
ADC map
ADC map
Histogram
Histogram 10
Table 1
Histogram
1.1
1.7
Pixel number
21
Pixel number
11
Pixel number
Fig. 1 DW-MRI, ADC map, and the ADC value histogram of a representative case of bladder cancer, UTUC and CCRCC. On DW-MRI with a b-value of 800 s/mm2, bladder cancer and UTUC show a homogenously high signal intensity, whereas CCRCC shows a heterogeneous signal intensity. A ROI was positioned to contain the whole part of the tumor on the ADC map. Histograms for ADC value distribution in bladder cancer and UTUC show a single prominent peak, whereas the histogram of CCRCC shows several peaks.
CCRCC
0.6
ADC values (10–3 mm2/s)
1.3
0.9
ADC values (10–3 mm2/s)
2.0 ADC values (10–3 mm2/s)
Studies of DW-MRI reporting detectability and apparent diffusion coefficient value for bladder cancer
Investigator (year)
19
b-values, (s/mm2)
Matsuki (2007) El-Assymy (2008)24 Kılıckesmez (2009)25 El-Assymy (2009)23 Abou-El-Ghar (2009)20 Kobayashi (2011)526
0, 800 0, 800 0, 500, 1000 0, 800 0. 800 0, 500, 1000, 2000
Avcu (2011)21 Dag˘gülli (2011)22
0, 500, 1000 100, 600, 1000
Inclusion criteria
Pts with known BC Pts with known BC Pts with known BC Pts with known BC Pts with gross hematuria Pts with known BC and/or positive U/C Pts with known BC Pts with hematuria
No. controls
No. BC
– – 50 – – –
17 43 14 123 130 121
20 30
46 35
ADC value, ×10−3 mm2/s (mean ± SD)
Sensitivity (%)
Specificity (%)
BC
Bladder wall
Urine
1.18 ± 0.19 1.40 ± 0.51 0.94 ± 0.18 – – 0.86 (0.39–2.07)†
2.27 ± 0.24 2.29 ± 0.78 2.08 ± 0.22 – – –
3.28 ± 0.20 3.50 ± 0.43 – – – –
NR NR NR 98.4 98.1 91.3–92.3
NR NR NR NR 92.3 NR
1.07 ± 0.26 –
– –
2.02 ± 0.11 –
100 94.2
76.5 85
†Data are expressed as median (range).
retrospectively.23 In another study carried out by our group on 143 patients with bladder cancer, a sensitivity level of 99% was reported in detecting bladder cancers larger than 7 mm.26 This level of bladder cancer detectability was equivalent to that of T2W-MRI, whereas the interobserver agreement using DW-MRI (κ score, 0.88) in detecting bladder cancer was superior to that of T2W-MRI (κ score, 0.67). Other studies have also reported high specificities in discriminating bladder cancers from benign conditions. In a prospective study includ© 2014 The Japanese Urological Association
ing 130 consecutive patients with gross hematuria, Abou-ElGhar et al. reported that DW-MRI had a 98.1% sensitivity and 92.3% specificity to discriminate bladder cancers from benign conditions.20 In a smaller study including 45 patients presenting with hematuria, Dag˘gülli et al. reported the sensitivity and specificity of DW-MRI for detecting bladder cancer to be 94.2% and 85.0%, respectively.22 Several studies showed restricted diffusion in bladder cancer by analyzing ADC values. Bladder cancers were consistently 3
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Table 2
Studies of DW-MRI for staging and characterizing bladder cancer
Investigator (year)
27
b-values, (s/mm2)
52
ADC value, ×10−3 mm2/s (mean ± SD)
Staging accuracy (%)
pTa-1 vs pT2-4
pTa-2 vs pT3-4
Grade
T2W: 85, T2W+DW: 92, T2W+DCE: 90, T2W+DW+DCE: 94 69.6 – –
–
G1: 1.29 ± 0.27, G2: 1.13 ± 0.24, G3: 0.81 ± 0.11; G1 vs G3; P < 0.01, G2 vs G3; P < 0.01 – – High-grade: 0.92 ± 0.20, Low-grade: 1.28 ± 0.18, P < 0.01 High-grade: 0.79 (0.69-0.88)†, Low-grade: 0.99 (0.92-1.09)†, P < 0.0001
El-Assymy (2009)23 Watanabe (2009)30 Avcu (2011)21
0, 800 0, 1000 0, 500, 1000
123 18 46
T2W: 79, T2W+DW: 96, T2W+DCE: 88, T2W+DW+DCE: 98 63.6 T2W: 79, DCE: 79, DW: 79 –
Kobayashi (2011)26
0, 500, 1000, 2000
143
DW: 78.8–81.7, T2W: 78.8–82.7
Takeuchi (2009)
0, 1000
No. BC
†Data are expressed as median (range).
found to have lower ADC values compared with the normal bladder wall, prostate, seminal vesicles and urine.19,24,25 These significant differences in the quantitative analyses between bladder cancer and the surrounding tissues are in agreement with the clear contrast of bladder cancer on DW-MRI.
Characterization of bladder cancer The utility of DW-MRI quantitative analysis in defining the grade of bladder cancer has been shown in multiple studies (Table 2).21,26,27 In a prospective study that included 40 patients suspected of having bladder cancer, Takeuchi et al. reported that the ADC values of grade 3 bladder cancers were significantly lower than those of grade 1 or 2 bladder cancers.27 Our group reported the evaluation of 143 bladder cancers, and showed that ADC values of high-grade cancers were significantly lower than those of low-grade cancers.26 Avcu et al. also reported an inverse correlation between ADC value and histological grade.21 These results consistently showed the feasibility of non-invasively defining tumor grade using DW-MRI. However, substantial overlap exists between the histological grades, which limits the clinical application of this technique in individual patients. The underlying mechanism by which the ADC value reflects the tumor histological grade is thought to be associated with tumor cell morphological characteristics, including increased cellularity and large cellular size. Recently, our studies have shown an inverse correlation between the ADC value in bladder cancer and cell proliferative potential, which is assessed using the Ki-67 labeling index (Fig. 2). In the prospective study including 132 bladder cancer patients, the ADC values of bladder cancers reflect the Ki-67 labeling index and the T stage, both of which are established prognostic predictors.28 This correlation between ADC value and the tumor proliferation status was also shown in brain tumors and breast cancer. These data suggest that the ADC value is a potential biomarker reflecting the biological features of malignant cancer cells.
Local staging of bladder cancer As DW-MRI is a functional imaging modality, the spatial resolution is limited. However, at high b-values, the signals from 4
bladder cancer are generally high, whereas submucosal layers show low-signal intensity.8 Tumor stalks that consist of a mixture of edematous submucosa, fibrous tissue and capillaries also showed low-signal intensity.29 The feasibility of using DW-MRI in staging has been shown based on these signal contrast characteristics (Table 2).21,23,26,27,30 Although the muscle layer is depicted as a thin layer showing intermediate signal intensity, it might be difficult to precisely detect muscle invasion in bladder cancer. In a study including 106 patients with known bladder cancer, El-Assmy et al. reported that DW-MRI had a relatively low ability to discriminate MIBC from NMIBC (accuracy, 63.6%), and organ-confined disease from non-organconfined disease (accuracy, 69.6%) when the findings of DW-MRI alone were evaluated.23 In another study, Takeuchi et al. proposed novel bladder cancer staging criteria for DW-MRI to discriminate MIBC from NMIBC based on the presence of a low submucosal signal. This criteria includes a thin, flat, high signal intensity area corresponding to a tumor or a high signal intensity tumor with a low signal intensity submucosal stalk or a thickened submucosa is diagnosed as NMIBC, and the characteristic C-shaped high signal of bladder cancer over a low signal intensity submucosal stalk on DW-MRI is called the “inchworm sign” (Fig. 3).27 A high signal intensity tumor without a submucosal stalk and a smooth tumor margin is diagnosed as stage T2, extension into the perivesical fat with an irregular margin indicates stage T3, and extension into adjacent organs indicates stage T4 (Fig. 4). They reported improved staging accuracy when DW-MRI was added to T2WMRI in a study including 52 bladder cancers in 40 patients. The staging accuracy was improved from 79% to 96% for differentiating NMIBC from MIBC, and from 85% to 92% for differentiating organ-confined disease from non-organ-confined disease. Our group validated this staging criterion, and reported a sensitivity of 65.6–71.1%, a specificity of 83.3–90.9% and an accuracy of 78.8–81.7%.26 As DW-MRI provides quantitative information on the tissue water diffusion and perfusion, ADC measurements have the potential to discriminate invasive cancers from others.10 In the aforementioned study, our group reported that patients with higher T stages showed significantly lower ADC values.26 A © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
ADC values: 0.6 × 10–3 mm2/s, Ki-67 LI: 56.4% T2W-MRI
DW-MRI
ADC map
ADC values: 1.1 × 10–3 mm2/s, Ki-67 LI: 13.6% T2W-MRI
DW-MRI
ADC map
Fig. 2 MRI of bladder cancer with a low and high ADC value. Both bladder cancers show similar signal intensity on T2W-MRI high-signal intensity. These tumors have different DW-MRI signals and proliferative activity.
(a)
(b)
Fig. 3 MRI of a non-muscle-invasive bladder cancer (urothelial cancer, stage pT1, grade 2). (a) T2W-MRI shows a hypointense tumor around the left ureteral orifice. (b) DW-MRI shows a C-shaped highsignal tumor with low signal intensity stalk, which is called an “inchworm sign”.
(a)
(b)
(c)
Fig. 4 MRI of a muscle-invasive bladder cancer (urothelial cancer, stage cT4, grade 3 > 2). (a) T2W-MRI shows a solid hypointense tumor at the trigone extending into prostate. (b) DW-MRI shows the tumor as a homogenous high signal mass. (c) The corresponding ADC map shows restricted diffusion within the tumor.
cut-off ADC value of 0.86 × 10−3 mm2/s differentiated clinically aggressive disease, including MIBC or high-grade T1, from less aggressive disease, including low-grade Ta, highgrade Ta or low-grade T1, with a sensitivity of 88%, a specificity of 85% and an accuracy of 87%. We also suggested that using both the ADC value and visual assessment of DW-MRI has the potential to improve the accuracy of T staging. Incorporating high ADC values (≥0.86 × 10−3 mm2/s) with the © 2014 The Japanese Urological Association
“inchworm sign” improved the specificity of discriminating MIBC from 73–75% to 95.5–96%.
Predicting the clinical course of bladder cancer Because the ADC value reflects histological grade and T staging, the ADC value could be a surrogate biomarker to predict the clinical course of bladder cancer patients after 5
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treatment. Rosenkrantz et al. showed the potential role of ADC values in assessing the metastatic potential based on the findings that the ADC values were lower in patients with metastatic disease than in those without metastasis in a small study including 17 localized high-grade bladder cancer patients.31 Funatsu et al. showed the feasibility of using the ADC value as an objective biomarker to predict intravesical recurrence after TURB.32 In a retrospective study including 44 patients with a mean follow-up period of 25 months, the ADC values of tumors in patients with recurrence were significantly lower than in those without recurrence.
DW-MRI in predicting sensitivity and monitoring the therapeutic effect As the DW-MRI signal reflects the biophysical characteristics of the tissue, this functional imaging modality is expected to be used as a biomarker for predicting therapeutic response. Several prospective studies in many types of malignancies, including brain tumors and cervical and rectal cancers, have shown that it is feasible for DW-MRI to predict sensitivity to radiotherapy.33–37 DW-MRI can also be an imaging biomarker in monitoring the therapeutic effect. Successful treatment-induced losses of cell membrane integrity and cell shrinkage lead to increased water diffusion. The usefulness of DW-MRI in monitoring therapeutic treatment effects has been reported in liver cancer, cerebral gliomas and soft-tissue sarcoma.38–40
Potential role of DW-MRI in chemoradiotherapy-based bladder-sparing strategy Bladder-sparing approach incorporating consolidative partial cystectomy with pelvic lymph node dissection At Tokyo Medical and Dental University, a CRT-based selective bladder-sparing protocol incorporating partial cystectomy with pelvic lymph node dissection has been carried out since 1997.41–45 In this treatment protocol, candidates for bladder preservation are selected based on the extent, location and post-CRT status of the tumor, and consolidative partial cystectomy with pelvic lymph node dissection. This selection has taken place after induction CRT with the intent to eradicate any possible remaining residual cancer cells at the original MIBC sites and micrometastases in the pelvic lymph nodes; otherwise, radical cystectomy is carried out after induction CRT. Our group evaluated the feasibility of DW-MRI to predict treatment sensitivity and to monitor therapeutic response from CRT by comparing DW-MRI taken before and after induction CRT.16,46
Predicting sensitivity to CRT in bladder cancer DW-MRI could potentially play a role as a biomarker for predicting the therapeutic response in multimodal organ preservation strategies for MIBC. An inverse correlation between CRT sensitivity and ADC values of the tumor was shown in a study that enrolled 23 MIBC patients (cT2/T3 = 7/16) who underwent induction CRT consisting of radiotherapy to the small 6
pelvis (40 Gy) with two cycles of cisplatin (20 mg/day for 5 days) followed by partial or radical cystectomy.16 The ADC values of CRT-sensitive tumors that showed pathological complete response (median 0.63 × 103 mm2/s; range 0.43– 0.77 mm2/s) were significantly lower than those of CRTresistant tumors (non-pathological complete response: median 0.84 × 103 mm2/s; range, 0.69–1.09 mm2/s; P = 0.0003). With a defined cut-off ADC value of 0.74 × 103 mm2/s, the sensitivity, specificity, and accuracy in predicting CRT sensitivity were 92%, 90% and 91%, respectively. A favorable CRT response in highly proliferating MIBC has been reported.16,47,48 Considering the significant inverse correlation between the ADC value and the Ki-67 labeling index, the association between the ADC value and CRT response is based on a higher proliferative activity of bladder cancer that was reflected in a lower ADC value. Accurate prediction of therapeutic sensitivity using the information would optimize patient selection for bladdersparing protocols.
Monitoring response to chemoradiotherapy In multimodal treatment protocols, accurate monitoring of the therapeutic response is an essential point. However, therapeutic response evaluation measuring the change in size of the tumor is not appropriate for discriminating small remnants of cancerous tissue from secondary changes. TURB and CRT-induced fibrotic and inflammatory changes manifest as bladder wall thickening on T2W-MRI, and false-positive results might persist for many years on DCE-MRI.49–51 We reported the utility of DW-MRI in monitoring the CRT response of MIBC (Fig. 5).46 In 20 patients with MIBC who were treated using CRT based-selective bladder-sparing strategy, DW-MRI had superior specificity and accuracy (92% and 80%, respectively) in detecting pathological complete response of cystectomy specimens carried out after CRT compared with T2W-MRI (45% and 44%, respectively) or DCE-MRI (18% and 33%, respectively). The superiority of DW-MRI over conventional imaging is associated with the high reliability of DW-MRI in differentiating post-therapeutic changes from bladder cancer, as was suggested by El-Assmy et al. and Wang et al.52,53 Therefore, DW-MRI could allow for more accurate and optimal patient selection in bladder-sparing protocols. However, the sensitivity of DW-MRI (57%) was comparable with that of T2W-MRI (43%) and DCE-MRI (57%), primarily resulting from limitations in detecting small or microscopic residual cancers.46
Clinical applications of DW-MRI in upper urinary tract cancer Detecting upper urinary tract cancer A total of 60% of UTUC are initially diagnosed as invasive disease compared with 15–25% of bladder cancers.1,2,54 UTUC are difficult lesions to visualize using conventional morphological imaging, as the difference in the signals between UTUC and the ureteral wall is relatively small, and tiny lesions arising from the wall of a long, tube-shaped organ might be overlooked as a result of partial volume effects. UTUC and bladder cancer share the same characteristic findings on DW-MRI. In 2008, our group first showed the feasibility © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
(a)
(b)
(c)
(d)
(e)
(f)
Fig. 5 MRI of a muscle-invasive bladder cancer (urothelial cancer, stage cT3, grade 3) treated with a bladder-sparing protocol consisting of TURB tumor and induction CRT followed by partial or radical cystectomy. At the diagnosis, (a) T2W-MRI shows a solid hypointense tumor at the trigone, (b) sagittal DCE-MRI shows early intense enhancement, (c) DW-MRI shows a hypersignal lobulated mass. After TURB and CRT, (d) this lesion shows wall thickening on T2WI and (e) enhancement on DCE, whereas (f) the abnormal DW-MRI signal is diminished to a normal signal intensity. Histological examination of the cystectomized specimen reveals no residual bladder cancer, showing the findings of post-CRT T2W-MRI and DCE-MRI to be false-positive findings that reflect post-treatment change.
(a)
(b)
(c)
Fig. 6 MRI of a left renal pelvic cancer (urothelial cancer, stage pTa, grade 2). (a) The tumor shows a hypointense signal on T2W-MRI. (b) Gadolinium-enhanced image in nephrographic phase does not show intense enhancement. (c) DW-MRI shows the lesion with high signal intensity. The renal parenchyma signals are well restrained, and good tumor contrast is obtained.
of DW-MRI using a high b-value of 800 s/mm2 for detecting UTUC based on the clear contrast between the high signal intensity of UTUC and the well-restrained signal intensity of the surrounding tissue (Figs 6–8).55 However, applying a high diffusion gradient makes the signals of normal tissue less intense, leading to the loss of anatomical information. The interpretation of DW-MRI should be carried out with morphological imaging. Since that report, several studies have reported on the application of DW-MRI in the management of UTUC, consistently showing excellent diagnostic performance (Table 3).18,55–59 In retrospective studies including patients with known UTUC cancers, the sensitivity of DW-MRI in detecting UTUC was © 2014 The Japanese Urological Association
reported to be 88.9–100%.56 Akita et al. reported that the additional use of DW-MRI with T2W-MRI improved the sensitivity from 88% to 98%. There is only one prospective study that evaluated the diagnostic ability of DW-MRI in detecting UTUC. In that study, which included 76 patients with suspected UTUC, our group reported that DW-MRI, reviewed along with T1Wand T2W-MRI, differentiated 49 patients with UTUC from 27 patients with benign conditions with 92–93% sensitivity, 81–96% specificity and 89–93% accuracy.59 The additional use of DW-MRI to conventional MRI significantly improved the sensitivity and accuracy, whereas the specificity did not change, because the specificities of T1W- and T2W-MRI were already high. The location of the UTUC had little impact on diagnostic 7
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(a)
(b)
Fig. 7 MRI of a right ureteral cancer (urothelial cancer, stage pT3, grade 3). (a) T2W-MRI shows a hypointense tumor at the level of sacroiliac joint. (b) DW-MRI show the tumor as a high-signal mass.
ADC values: 0.8 × 10–3 mm2/s, Ki-67 LI: 46.8% T2W-MRI
DW-MRI
ADC map
ADC values: 1.7 × 10–3 mm2/s, Ki-67 LI: 4.1% T2W-MRI
DW-MRI
ADC map
Fig. 8 MRI of UTUC with low and high ADC value. Both UTUC show similar signal intensity T2W-MRI. These tumors have different DW-MRI signal and proliferative activity.
ability, because of the clear visualization of the UTUC and good contrast to the surrounding tissues on DW-MRI. In that study, benign lesions, including a ureteral inflammatory lesion, ureteral stenosis secondary to urolithiasis and ureteral stenosis from postoperative scarring, showed false-positive findings because DW-MRI contrast reflects molecular diffusion, not the presence of existing cancer cells. We need to take care with these relatively rare benign lesions showing high signal intensity on DW-MRI. The detection of CIS lesions was still limited on DW-MRI and on other conventional imaging techniques, although CISassociated findings, including hematoma and a thickened ureteral wall, could provide a chance to detect the lesion. Considering that the positive predictive value for all UTUC and the negative predictive value for UTUC with negative urinary cytology were greater than 90%, a positive DW-MRI is strongly indicative of UTUC, whereas a negative DW-MRI nearly excludes UTUC in patients with negative urinary cytology.59
Characterizing upper urinary tract cancer The standard treatment for localized UTUC is radical nephroureterectomy with excision of the bladder cuff. Recently, kidney-sparing approaches including segmental ureteral resec8
tion and endoscopic ablation using ureteroscopy have become options for low-risk UTUC or imperative cases (renal insufficiency or a solitary functional kidney) for the preservation of renal function.2 In these conservative treatment approaches, a meticulous evaluation of the UTUC is essential. Advances in flexible fiberoptic instruments have improved the quality of upper tract tumor sampling. Rojas et al. reported the accuracy of biopsy under ureteroscopy in grading to be 90%.60 However, considering the invasiveness of biopsy under ureteroscopy, the role of imaging for characterizing UTUC is emphasized to select an appropriate therapeutic option when conservative treatment is being considered. In a quantitative analysis, the ADC value could be a biomarker of UTUC and reflect its aggressiveness, including histological grading and proliferative potential (Table 3).18,55–59 Our group reported that the ADC value was significantly lower in grade 3 cancers than in grade 1–2 cancers, and the ADC value was inversely correlated with the Ki-67 labeling index in UTUC as well as in bladder cancer (Fig. 8).15,16,28,59 Akita et al. showed that the ADC value of high-grade tumors was significantly lower than that of low-grade tumors in a series of 40 UTUC lesions.56 Contrary to these reports, Nishizawa et al. and © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
Table 3
Studies of DW-MRI reporting detectability and apparent diffusion coefficient value for upper tract urothelial carcinoma
Investigator (year)
Design
b-values, (s/mm2)
Yoshida (2008)55 Takeuchi (2008)58 Nishizawa (2010)57 Yoshida (2011)59
Retrospective 0.800 Retrospective 800 Retrospective 1000 Prospective
0.800
No. No. Pts tumor
Pts with UTUC Pts with UTUC Pts with UTUC Pts with suspicion of UTUC
10
P: 10
1.28 (0.92–1.45)* 2.19 (1.42–2.40)* 0.80 (0.41–0.96)* –
16
20
–
–
1.31 ± 0.27
–
17
P: 9, U: 8 P: 32, U: 17
1.98 ± 0.24
2.94 ± 0.32
1.13 ± 0.22
–
76
Akita (2011)56 Retrospective 0, 800 or Pts with 0, 1000 UTUC
40
Sufana Iancu (2013)18
17
Retrospective 0, 1000
ADC value, ×10−3 mm2/s (mean ± SD)
Inclusion criteria
Pts with UTUC
Kidney
Urine
Cancer
Grade
Sensitivity Specificity (%) (%) 100
–
100
–
94.1
–
92–94 81–96 1.69 (0.96–2.28)* 2.04 (1.18–4.18)* 1.04 (0.50–1.81)* G1–2: 1.22 (0.86–1.65)*, G3: 0.91 (0.50–1.50)*; P = 0.028 T2W+DW: – P: 40 1.96 ± 0.26 – 1.36 ± 0.23 High-grade: 98 1.30 ± 0.18, Low-grade: 1.70 ± 0.13; P < 0.01 88.9 – P: 11, U: 7 1.78 ± 0.25 – 1.08 ± 0.19 No significant difference between grades
*Data are expressed as median (range).
Sufana Iancu et al. did not find any correlation between the ADC value and histological grade in a smaller number of UTUC.18,57 To validate these results, further studies with a larger study population are required. As the ADC value reflects the biophysical characteristics of cancer cells, it might be useful for the preoperative risk stratification of UTUC patients.61 In a prospective study including 34 patients treated with nephroureterectomy, our group reported a significant and inverse correlation of the ADC value with the Ki-67 labeling index in UTUC.15 In the study, cancer-specific survival after nephroureterectomy was clearly stratified according to the ADC value; the 3-year cancer-specific survival rate of patients with low ADC UTUC (
International Journal of Urology (2014)
doi: 10.1111/iju.12587
Review Article
Role of diffusion-weighted magnetic resonance imaging as an imaging biomarker of urothelial carcinoma Soichiro Yoshida,1 Fumitaka Koga,2 Hitoshi Masuda,3 Yasuhisa Fujii1 and Kazunori Kihara1 1
Department of Urology, Tokyo Medical and Dental University Graduate School, 2Department of Urology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, and 3Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
Abbreviations & Acronyms ADC = apparent diffusion coefficient BC = bladder cancer CCRCC = clear cell renal cell carcinoma CRT = chemoradiotherapy DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging DW-MRI = diffusion-weighted magnetic resonance imaging G = grade Ki-67 LI = Ki-67 labeling index MIBC = muscle-invasive bladder cancer MRI = magnetic resonance imaging NMIBC = non-muscle invasive bladder cancer NR = not reported P = pelvis Pts = patients ROI = regions of interest T2W-MRI = T2-weighted magnetic resonance imaging TURB = transurethral resection of the bladder U = ureter U/C = urinary cytology UTUC = upper tract urothelial carcinoma Correspondence: Soichiro Yoshida M.D., Ph.D., Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Email: [email protected] Received 23 May 2014; accepted 4 July 2014. © 2014 The Japanese Urological Association
Abstract: Diffusion-weighted magnetic resonance imaging is a type of functional imaging that is increasingly being applied in the management of upper tract urothelial carcinoma and bladder cancer. The image contrast is derived from differences in the Brownian motion of water molecules in tissues. The homogenous high signal intensity of upper tract urothelial carcinoma and bladder cancer on diffusion-weighted magnetic resonance imaging provides helpful diagnostic information for the presence of cancerous lesions in a non-invasive manner. Recently, growing evidence has emerged showing that diffusion-weighted magnetic resonance imaging can serve as an imaging biomarker for characterizing cancer pathophysiology, because the signal reflects biophysical information about the tissues. Quantitative analysis by evaluating the apparent diffusion coefficient values potentially reflects the histological grade and the biological aggressiveness of urothelial carcinoma. The apparent diffusion coefficient value could be a biomarker predicting the clinical course of upper tract urothelial carcinoma and bladder cancer. In addition, in chemoradiotherapy-based bladdersparing approaches against muscle-invasive bladder cancer, the role of diffusion-weighted magnetic resonance imaging for predicting the chemoradiosensitivity and for monitoring therapeutic response has been shown. Diffusion-weighted magnetic resonance imaging is expected to improve the diagnostic accuracy, and this qualitative information might allow individualized treatment strategies for patients with urothelial carcinoma. Key words: biological marker, carcinoma, diffusion magnetic resonance imaging, transitional cell, ureteral neoplasms, urinary bladder neoplasms.
Introduction Urothelial carcinomas are mainly located in the bladder or upper urinary tract. Bladder cancer and upper urinary tract cancer account for 90–95% and 5–10% of urothelial carcinomas, respectively.1,2 In recent clinical practice, contrast-enhanced computed tomography and MRI have become the most widely-used imaging modalities for radiological evaluation of the upper urinary tract and bladder.3 Generally, MRI is superior to computed tomography in locoregional staging because of its superior soft tissue delineation.4,5 Urothelial carcinoma of the bladder and UTUC share some significant characteristics, and their radiological findings are similar. However, an important point is that the treatment approaches differ significantly between these two diseases because of distinct differences in inherent anatomical locations.1,2,6,7 DW-MRI is a type of functional imaging, which is increasingly being applied in the management of UTUC and bladder cancer, and provides helpful information for the diagnosis of urothelial carcinoma in a non-invasive manner.8,9 Growing evidence has emerged showing that DW-MRI can serve as an imaging biomarker for characterizing the pathophysiology of cancer, which is requested for customizing therapeutic approaches for UTUC and bladder cancer.10 Thus, the present review focuses on the potential role of DW-MRI in detecting and characterizing UTUC and bladder cancer.
DW-MRI: Biophysical basis DW-MRI is a non-invasive functional imaging technique; the image contrast is derived from differences in the Brownian motion of water molecules in tissues.9,10 The imaging signal confers information about the biophysical properties of tissues, such as cell organization and density. A lesion where water molecules can diffuse freely shows low-signal intensity on DW-MRI. Stejskal and Tanner initially devised the DW-MRI technique in 1965. Since Le Bihan reported the first 1
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images of water diffusion in the human brain in 1986, DW-MRI has been applied in the early detection of microstructural and functional changes.11 DW-MRI can detect acute cerebral infarction before secondary morphological changes are observed by conventional imaging. In a similar manner, malignant lesions characteristically show high signal intensity because of the dense cellularity, tissue disorganization and decreased extracellular space that are typical characteristics of cancerous tissue, all of which restrict water diffusion.9,10 As the DW-MRI signal is derived from the inherent tissue contrast, the administration of intravenous contrast media is not required in this imaging technique. Therefore, DW-MRI is applicable in patients with allergies to contrast agents and those with renal insufficiency. The addition of DW-MRI to a routine MRI protocol requires only a few minutes, and it can be acquired using most current clinical MRI scanners.
Applications of DW-MRI in the abdominal and pelvic organs The application of DW-MRI to the abdominal organs is challenging because of physiological motion artifacts, such as respiratory movements, pulsation and bowel motion. However, a single-shot echo planar sequence with parallel imaging techniques, high-gradient amplitudes and multichannel coils allows for rapid data acquisition with improved image quality.12 Takahara et al. reported a procedure for body DW-MRI under free breathing conditions.13 Such approaches enable longer scan times and more thin-slice images with multiple signal averaging, and provide a high-quality multiplanar display. These technological improvements have allowed DW-MRI to be increasingly applied in abdominal and pelvic examinations, and it was quickly introduced as an important diagnostic imaging tool for detecting various types of tumors, including UTUC and bladder cancer.9
Degree of water diffusion as an imaging biomarker DW-MRI offers unique information reflecting the physiological characteristics of tissues by quantifying the diffusion of water molecules. The degree of water molecule diffusion is represented by the ADC value. The sensitivity of the diffusion is changed by using various “b-values,” which are proportional to the gradient amplitude, the duration of the applied gradient and the time interval between the paired gradients.9,10 The ADC value is calculated by evaluating the signal attenuation on DW-MRI with increasing b-values. Although a visual assessment of DW-MRI is carried out qualitatively, restriction of diffusion can be quantitatively assessed by evaluating the ADC values of a lesion. As DW-MRI provides biophysical information about cell organization, density and microstructure, tumor ADC values are expected to reflect the characteristics of the lesion.9,10 Various researchers have pointed out that ADC values could be a useful adjunct to characterize tumors in different regions, including the genitourinary organs. On an ADC map, the ADC values are calculated automatically for each pixel of the image and displayed. By setting ROI on the ADC map, profiles of the ADC values within the delineated regions are obtained. 2
However, the reproducibility of the ADC value is an intrinsic limitation of ADC measurements. Because the ADC value depends on the MRI system and imaging protocol, standardization of ADC assessment is essential to use ADC values as biomarkers to characterize cancerous lesions.10
Features of urothelial carcinoma on DW-MRI On DW-MRI with high b-values of 800–1000 s/mm2, urothelial carcinomas in the upper urinary tract and bladder generally show a homogenous, hyperintense signal reflecting homogenous histological characteristics, whereas the signals from the surrounding tissues, including the urine, renal parenchyma and surrounding tissues, are well-restrained.14 In most UTUC and bladder cancer patients, the intratumoral distribution of ADC values are homogenous on the ADC map. Homogenous diffusion environments within UTUC and bladder cancer lesions has been shown by a histogram analysis within a ROI positioned to maximally cover the tumor. Histogram analyses of intratumoral ADC values showed a single prominent peak in 82% of UTUC and 83% of bladder cancer lesions (Fig. 1).15,16 Compared with renal cell carcinoma that shows a heterogeneous signal on DW-MRI and on the ADC map, a ROI is relatively easy to set within a UTUC or bladder cancer lesion.17 The method of positioning a ROI for measuring ADC values of urothelial carcinoma is not standardized. However, Sufana Iancu et al. reported that there was no significant difference between the ADC values of UTUC obtained by drawing a large ROI covering the greatest part of the tumor and those measured from a small ROI in the most restricted part of the tumor.18 Because of the clear contrast between tumors and normal lesions, and the homogenous diffusion environment within the tumor, interobserver variability of measuring ADC values of UTUC and bladder cancers can be relatively small, although no study has evaluated this point.
Clinical applications of DW-MRI in bladder cancer Detection of bladder cancer The usefulness of DW-MRI in the diagnosis of bladder cancer has been shown in recent studies.8 On DW-MRI with a high b-value, bladder cancers generally show a hyperintense signal, whereas the signals of the surrounding tissue, including the urine and normal tissues, are well-restrained. Matsuki et al. first reported the feasibility of DW-MRI in detecting bladder cancer.19 In that study, all 15 known bladder cancers were clearly shown to have a high signal intensity compared with the surrounding tissue. A clear contrast was obtained between bladder cancer and the surrounding tissue. The same findings were reported in the following studies using a cohort composed of patients with known bladder cancer, showing the high sensitivity of DW-MRI in terms of detecting cancer. Details of the published studies are shown in Table 1.19–26 In a study of 123 cystoscopy-identified bladder cancers in 106 patients, El-Assmy et al. reported that 98% of the cancers were correctly identified, whereas two polypoid lesions less than 4 mm in diameter could not be identified, even when viewed © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
Bladder cancer
UTUC DW-MRI
DW-MRI
DW-MRI
ADC map
ADC map
ADC map
Histogram
Histogram 10
Table 1
Histogram
1.1
1.7
Pixel number
21
Pixel number
11
Pixel number
Fig. 1 DW-MRI, ADC map, and the ADC value histogram of a representative case of bladder cancer, UTUC and CCRCC. On DW-MRI with a b-value of 800 s/mm2, bladder cancer and UTUC show a homogenously high signal intensity, whereas CCRCC shows a heterogeneous signal intensity. A ROI was positioned to contain the whole part of the tumor on the ADC map. Histograms for ADC value distribution in bladder cancer and UTUC show a single prominent peak, whereas the histogram of CCRCC shows several peaks.
CCRCC
0.6
ADC values (10–3 mm2/s)
1.3
0.9
ADC values (10–3 mm2/s)
2.0 ADC values (10–3 mm2/s)
Studies of DW-MRI reporting detectability and apparent diffusion coefficient value for bladder cancer
Investigator (year)
19
b-values, (s/mm2)
Matsuki (2007) El-Assymy (2008)24 Kılıckesmez (2009)25 El-Assymy (2009)23 Abou-El-Ghar (2009)20 Kobayashi (2011)526
0, 800 0, 800 0, 500, 1000 0, 800 0. 800 0, 500, 1000, 2000
Avcu (2011)21 Dag˘gülli (2011)22
0, 500, 1000 100, 600, 1000
Inclusion criteria
Pts with known BC Pts with known BC Pts with known BC Pts with known BC Pts with gross hematuria Pts with known BC and/or positive U/C Pts with known BC Pts with hematuria
No. controls
No. BC
– – 50 – – –
17 43 14 123 130 121
20 30
46 35
ADC value, ×10−3 mm2/s (mean ± SD)
Sensitivity (%)
Specificity (%)
BC
Bladder wall
Urine
1.18 ± 0.19 1.40 ± 0.51 0.94 ± 0.18 – – 0.86 (0.39–2.07)†
2.27 ± 0.24 2.29 ± 0.78 2.08 ± 0.22 – – –
3.28 ± 0.20 3.50 ± 0.43 – – – –
NR NR NR 98.4 98.1 91.3–92.3
NR NR NR NR 92.3 NR
1.07 ± 0.26 –
– –
2.02 ± 0.11 –
100 94.2
76.5 85
†Data are expressed as median (range).
retrospectively.23 In another study carried out by our group on 143 patients with bladder cancer, a sensitivity level of 99% was reported in detecting bladder cancers larger than 7 mm.26 This level of bladder cancer detectability was equivalent to that of T2W-MRI, whereas the interobserver agreement using DW-MRI (κ score, 0.88) in detecting bladder cancer was superior to that of T2W-MRI (κ score, 0.67). Other studies have also reported high specificities in discriminating bladder cancers from benign conditions. In a prospective study includ© 2014 The Japanese Urological Association
ing 130 consecutive patients with gross hematuria, Abou-ElGhar et al. reported that DW-MRI had a 98.1% sensitivity and 92.3% specificity to discriminate bladder cancers from benign conditions.20 In a smaller study including 45 patients presenting with hematuria, Dag˘gülli et al. reported the sensitivity and specificity of DW-MRI for detecting bladder cancer to be 94.2% and 85.0%, respectively.22 Several studies showed restricted diffusion in bladder cancer by analyzing ADC values. Bladder cancers were consistently 3
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Table 2
Studies of DW-MRI for staging and characterizing bladder cancer
Investigator (year)
27
b-values, (s/mm2)
52
ADC value, ×10−3 mm2/s (mean ± SD)
Staging accuracy (%)
pTa-1 vs pT2-4
pTa-2 vs pT3-4
Grade
T2W: 85, T2W+DW: 92, T2W+DCE: 90, T2W+DW+DCE: 94 69.6 – –
–
G1: 1.29 ± 0.27, G2: 1.13 ± 0.24, G3: 0.81 ± 0.11; G1 vs G3; P < 0.01, G2 vs G3; P < 0.01 – – High-grade: 0.92 ± 0.20, Low-grade: 1.28 ± 0.18, P < 0.01 High-grade: 0.79 (0.69-0.88)†, Low-grade: 0.99 (0.92-1.09)†, P < 0.0001
El-Assymy (2009)23 Watanabe (2009)30 Avcu (2011)21
0, 800 0, 1000 0, 500, 1000
123 18 46
T2W: 79, T2W+DW: 96, T2W+DCE: 88, T2W+DW+DCE: 98 63.6 T2W: 79, DCE: 79, DW: 79 –
Kobayashi (2011)26
0, 500, 1000, 2000
143
DW: 78.8–81.7, T2W: 78.8–82.7
Takeuchi (2009)
0, 1000
No. BC
†Data are expressed as median (range).
found to have lower ADC values compared with the normal bladder wall, prostate, seminal vesicles and urine.19,24,25 These significant differences in the quantitative analyses between bladder cancer and the surrounding tissues are in agreement with the clear contrast of bladder cancer on DW-MRI.
Characterization of bladder cancer The utility of DW-MRI quantitative analysis in defining the grade of bladder cancer has been shown in multiple studies (Table 2).21,26,27 In a prospective study that included 40 patients suspected of having bladder cancer, Takeuchi et al. reported that the ADC values of grade 3 bladder cancers were significantly lower than those of grade 1 or 2 bladder cancers.27 Our group reported the evaluation of 143 bladder cancers, and showed that ADC values of high-grade cancers were significantly lower than those of low-grade cancers.26 Avcu et al. also reported an inverse correlation between ADC value and histological grade.21 These results consistently showed the feasibility of non-invasively defining tumor grade using DW-MRI. However, substantial overlap exists between the histological grades, which limits the clinical application of this technique in individual patients. The underlying mechanism by which the ADC value reflects the tumor histological grade is thought to be associated with tumor cell morphological characteristics, including increased cellularity and large cellular size. Recently, our studies have shown an inverse correlation between the ADC value in bladder cancer and cell proliferative potential, which is assessed using the Ki-67 labeling index (Fig. 2). In the prospective study including 132 bladder cancer patients, the ADC values of bladder cancers reflect the Ki-67 labeling index and the T stage, both of which are established prognostic predictors.28 This correlation between ADC value and the tumor proliferation status was also shown in brain tumors and breast cancer. These data suggest that the ADC value is a potential biomarker reflecting the biological features of malignant cancer cells.
Local staging of bladder cancer As DW-MRI is a functional imaging modality, the spatial resolution is limited. However, at high b-values, the signals from 4
bladder cancer are generally high, whereas submucosal layers show low-signal intensity.8 Tumor stalks that consist of a mixture of edematous submucosa, fibrous tissue and capillaries also showed low-signal intensity.29 The feasibility of using DW-MRI in staging has been shown based on these signal contrast characteristics (Table 2).21,23,26,27,30 Although the muscle layer is depicted as a thin layer showing intermediate signal intensity, it might be difficult to precisely detect muscle invasion in bladder cancer. In a study including 106 patients with known bladder cancer, El-Assmy et al. reported that DW-MRI had a relatively low ability to discriminate MIBC from NMIBC (accuracy, 63.6%), and organ-confined disease from non-organconfined disease (accuracy, 69.6%) when the findings of DW-MRI alone were evaluated.23 In another study, Takeuchi et al. proposed novel bladder cancer staging criteria for DW-MRI to discriminate MIBC from NMIBC based on the presence of a low submucosal signal. This criteria includes a thin, flat, high signal intensity area corresponding to a tumor or a high signal intensity tumor with a low signal intensity submucosal stalk or a thickened submucosa is diagnosed as NMIBC, and the characteristic C-shaped high signal of bladder cancer over a low signal intensity submucosal stalk on DW-MRI is called the “inchworm sign” (Fig. 3).27 A high signal intensity tumor without a submucosal stalk and a smooth tumor margin is diagnosed as stage T2, extension into the perivesical fat with an irregular margin indicates stage T3, and extension into adjacent organs indicates stage T4 (Fig. 4). They reported improved staging accuracy when DW-MRI was added to T2WMRI in a study including 52 bladder cancers in 40 patients. The staging accuracy was improved from 79% to 96% for differentiating NMIBC from MIBC, and from 85% to 92% for differentiating organ-confined disease from non-organ-confined disease. Our group validated this staging criterion, and reported a sensitivity of 65.6–71.1%, a specificity of 83.3–90.9% and an accuracy of 78.8–81.7%.26 As DW-MRI provides quantitative information on the tissue water diffusion and perfusion, ADC measurements have the potential to discriminate invasive cancers from others.10 In the aforementioned study, our group reported that patients with higher T stages showed significantly lower ADC values.26 A © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
ADC values: 0.6 × 10–3 mm2/s, Ki-67 LI: 56.4% T2W-MRI
DW-MRI
ADC map
ADC values: 1.1 × 10–3 mm2/s, Ki-67 LI: 13.6% T2W-MRI
DW-MRI
ADC map
Fig. 2 MRI of bladder cancer with a low and high ADC value. Both bladder cancers show similar signal intensity on T2W-MRI high-signal intensity. These tumors have different DW-MRI signals and proliferative activity.
(a)
(b)
Fig. 3 MRI of a non-muscle-invasive bladder cancer (urothelial cancer, stage pT1, grade 2). (a) T2W-MRI shows a hypointense tumor around the left ureteral orifice. (b) DW-MRI shows a C-shaped highsignal tumor with low signal intensity stalk, which is called an “inchworm sign”.
(a)
(b)
(c)
Fig. 4 MRI of a muscle-invasive bladder cancer (urothelial cancer, stage cT4, grade 3 > 2). (a) T2W-MRI shows a solid hypointense tumor at the trigone extending into prostate. (b) DW-MRI shows the tumor as a homogenous high signal mass. (c) The corresponding ADC map shows restricted diffusion within the tumor.
cut-off ADC value of 0.86 × 10−3 mm2/s differentiated clinically aggressive disease, including MIBC or high-grade T1, from less aggressive disease, including low-grade Ta, highgrade Ta or low-grade T1, with a sensitivity of 88%, a specificity of 85% and an accuracy of 87%. We also suggested that using both the ADC value and visual assessment of DW-MRI has the potential to improve the accuracy of T staging. Incorporating high ADC values (≥0.86 × 10−3 mm2/s) with the © 2014 The Japanese Urological Association
“inchworm sign” improved the specificity of discriminating MIBC from 73–75% to 95.5–96%.
Predicting the clinical course of bladder cancer Because the ADC value reflects histological grade and T staging, the ADC value could be a surrogate biomarker to predict the clinical course of bladder cancer patients after 5
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treatment. Rosenkrantz et al. showed the potential role of ADC values in assessing the metastatic potential based on the findings that the ADC values were lower in patients with metastatic disease than in those without metastasis in a small study including 17 localized high-grade bladder cancer patients.31 Funatsu et al. showed the feasibility of using the ADC value as an objective biomarker to predict intravesical recurrence after TURB.32 In a retrospective study including 44 patients with a mean follow-up period of 25 months, the ADC values of tumors in patients with recurrence were significantly lower than in those without recurrence.
DW-MRI in predicting sensitivity and monitoring the therapeutic effect As the DW-MRI signal reflects the biophysical characteristics of the tissue, this functional imaging modality is expected to be used as a biomarker for predicting therapeutic response. Several prospective studies in many types of malignancies, including brain tumors and cervical and rectal cancers, have shown that it is feasible for DW-MRI to predict sensitivity to radiotherapy.33–37 DW-MRI can also be an imaging biomarker in monitoring the therapeutic effect. Successful treatment-induced losses of cell membrane integrity and cell shrinkage lead to increased water diffusion. The usefulness of DW-MRI in monitoring therapeutic treatment effects has been reported in liver cancer, cerebral gliomas and soft-tissue sarcoma.38–40
Potential role of DW-MRI in chemoradiotherapy-based bladder-sparing strategy Bladder-sparing approach incorporating consolidative partial cystectomy with pelvic lymph node dissection At Tokyo Medical and Dental University, a CRT-based selective bladder-sparing protocol incorporating partial cystectomy with pelvic lymph node dissection has been carried out since 1997.41–45 In this treatment protocol, candidates for bladder preservation are selected based on the extent, location and post-CRT status of the tumor, and consolidative partial cystectomy with pelvic lymph node dissection. This selection has taken place after induction CRT with the intent to eradicate any possible remaining residual cancer cells at the original MIBC sites and micrometastases in the pelvic lymph nodes; otherwise, radical cystectomy is carried out after induction CRT. Our group evaluated the feasibility of DW-MRI to predict treatment sensitivity and to monitor therapeutic response from CRT by comparing DW-MRI taken before and after induction CRT.16,46
Predicting sensitivity to CRT in bladder cancer DW-MRI could potentially play a role as a biomarker for predicting the therapeutic response in multimodal organ preservation strategies for MIBC. An inverse correlation between CRT sensitivity and ADC values of the tumor was shown in a study that enrolled 23 MIBC patients (cT2/T3 = 7/16) who underwent induction CRT consisting of radiotherapy to the small 6
pelvis (40 Gy) with two cycles of cisplatin (20 mg/day for 5 days) followed by partial or radical cystectomy.16 The ADC values of CRT-sensitive tumors that showed pathological complete response (median 0.63 × 103 mm2/s; range 0.43– 0.77 mm2/s) were significantly lower than those of CRTresistant tumors (non-pathological complete response: median 0.84 × 103 mm2/s; range, 0.69–1.09 mm2/s; P = 0.0003). With a defined cut-off ADC value of 0.74 × 103 mm2/s, the sensitivity, specificity, and accuracy in predicting CRT sensitivity were 92%, 90% and 91%, respectively. A favorable CRT response in highly proliferating MIBC has been reported.16,47,48 Considering the significant inverse correlation between the ADC value and the Ki-67 labeling index, the association between the ADC value and CRT response is based on a higher proliferative activity of bladder cancer that was reflected in a lower ADC value. Accurate prediction of therapeutic sensitivity using the information would optimize patient selection for bladdersparing protocols.
Monitoring response to chemoradiotherapy In multimodal treatment protocols, accurate monitoring of the therapeutic response is an essential point. However, therapeutic response evaluation measuring the change in size of the tumor is not appropriate for discriminating small remnants of cancerous tissue from secondary changes. TURB and CRT-induced fibrotic and inflammatory changes manifest as bladder wall thickening on T2W-MRI, and false-positive results might persist for many years on DCE-MRI.49–51 We reported the utility of DW-MRI in monitoring the CRT response of MIBC (Fig. 5).46 In 20 patients with MIBC who were treated using CRT based-selective bladder-sparing strategy, DW-MRI had superior specificity and accuracy (92% and 80%, respectively) in detecting pathological complete response of cystectomy specimens carried out after CRT compared with T2W-MRI (45% and 44%, respectively) or DCE-MRI (18% and 33%, respectively). The superiority of DW-MRI over conventional imaging is associated with the high reliability of DW-MRI in differentiating post-therapeutic changes from bladder cancer, as was suggested by El-Assmy et al. and Wang et al.52,53 Therefore, DW-MRI could allow for more accurate and optimal patient selection in bladder-sparing protocols. However, the sensitivity of DW-MRI (57%) was comparable with that of T2W-MRI (43%) and DCE-MRI (57%), primarily resulting from limitations in detecting small or microscopic residual cancers.46
Clinical applications of DW-MRI in upper urinary tract cancer Detecting upper urinary tract cancer A total of 60% of UTUC are initially diagnosed as invasive disease compared with 15–25% of bladder cancers.1,2,54 UTUC are difficult lesions to visualize using conventional morphological imaging, as the difference in the signals between UTUC and the ureteral wall is relatively small, and tiny lesions arising from the wall of a long, tube-shaped organ might be overlooked as a result of partial volume effects. UTUC and bladder cancer share the same characteristic findings on DW-MRI. In 2008, our group first showed the feasibility © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
(a)
(b)
(c)
(d)
(e)
(f)
Fig. 5 MRI of a muscle-invasive bladder cancer (urothelial cancer, stage cT3, grade 3) treated with a bladder-sparing protocol consisting of TURB tumor and induction CRT followed by partial or radical cystectomy. At the diagnosis, (a) T2W-MRI shows a solid hypointense tumor at the trigone, (b) sagittal DCE-MRI shows early intense enhancement, (c) DW-MRI shows a hypersignal lobulated mass. After TURB and CRT, (d) this lesion shows wall thickening on T2WI and (e) enhancement on DCE, whereas (f) the abnormal DW-MRI signal is diminished to a normal signal intensity. Histological examination of the cystectomized specimen reveals no residual bladder cancer, showing the findings of post-CRT T2W-MRI and DCE-MRI to be false-positive findings that reflect post-treatment change.
(a)
(b)
(c)
Fig. 6 MRI of a left renal pelvic cancer (urothelial cancer, stage pTa, grade 2). (a) The tumor shows a hypointense signal on T2W-MRI. (b) Gadolinium-enhanced image in nephrographic phase does not show intense enhancement. (c) DW-MRI shows the lesion with high signal intensity. The renal parenchyma signals are well restrained, and good tumor contrast is obtained.
of DW-MRI using a high b-value of 800 s/mm2 for detecting UTUC based on the clear contrast between the high signal intensity of UTUC and the well-restrained signal intensity of the surrounding tissue (Figs 6–8).55 However, applying a high diffusion gradient makes the signals of normal tissue less intense, leading to the loss of anatomical information. The interpretation of DW-MRI should be carried out with morphological imaging. Since that report, several studies have reported on the application of DW-MRI in the management of UTUC, consistently showing excellent diagnostic performance (Table 3).18,55–59 In retrospective studies including patients with known UTUC cancers, the sensitivity of DW-MRI in detecting UTUC was © 2014 The Japanese Urological Association
reported to be 88.9–100%.56 Akita et al. reported that the additional use of DW-MRI with T2W-MRI improved the sensitivity from 88% to 98%. There is only one prospective study that evaluated the diagnostic ability of DW-MRI in detecting UTUC. In that study, which included 76 patients with suspected UTUC, our group reported that DW-MRI, reviewed along with T1Wand T2W-MRI, differentiated 49 patients with UTUC from 27 patients with benign conditions with 92–93% sensitivity, 81–96% specificity and 89–93% accuracy.59 The additional use of DW-MRI to conventional MRI significantly improved the sensitivity and accuracy, whereas the specificity did not change, because the specificities of T1W- and T2W-MRI were already high. The location of the UTUC had little impact on diagnostic 7
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(a)
(b)
Fig. 7 MRI of a right ureteral cancer (urothelial cancer, stage pT3, grade 3). (a) T2W-MRI shows a hypointense tumor at the level of sacroiliac joint. (b) DW-MRI show the tumor as a high-signal mass.
ADC values: 0.8 × 10–3 mm2/s, Ki-67 LI: 46.8% T2W-MRI
DW-MRI
ADC map
ADC values: 1.7 × 10–3 mm2/s, Ki-67 LI: 4.1% T2W-MRI
DW-MRI
ADC map
Fig. 8 MRI of UTUC with low and high ADC value. Both UTUC show similar signal intensity T2W-MRI. These tumors have different DW-MRI signal and proliferative activity.
ability, because of the clear visualization of the UTUC and good contrast to the surrounding tissues on DW-MRI. In that study, benign lesions, including a ureteral inflammatory lesion, ureteral stenosis secondary to urolithiasis and ureteral stenosis from postoperative scarring, showed false-positive findings because DW-MRI contrast reflects molecular diffusion, not the presence of existing cancer cells. We need to take care with these relatively rare benign lesions showing high signal intensity on DW-MRI. The detection of CIS lesions was still limited on DW-MRI and on other conventional imaging techniques, although CISassociated findings, including hematoma and a thickened ureteral wall, could provide a chance to detect the lesion. Considering that the positive predictive value for all UTUC and the negative predictive value for UTUC with negative urinary cytology were greater than 90%, a positive DW-MRI is strongly indicative of UTUC, whereas a negative DW-MRI nearly excludes UTUC in patients with negative urinary cytology.59
Characterizing upper urinary tract cancer The standard treatment for localized UTUC is radical nephroureterectomy with excision of the bladder cuff. Recently, kidney-sparing approaches including segmental ureteral resec8
tion and endoscopic ablation using ureteroscopy have become options for low-risk UTUC or imperative cases (renal insufficiency or a solitary functional kidney) for the preservation of renal function.2 In these conservative treatment approaches, a meticulous evaluation of the UTUC is essential. Advances in flexible fiberoptic instruments have improved the quality of upper tract tumor sampling. Rojas et al. reported the accuracy of biopsy under ureteroscopy in grading to be 90%.60 However, considering the invasiveness of biopsy under ureteroscopy, the role of imaging for characterizing UTUC is emphasized to select an appropriate therapeutic option when conservative treatment is being considered. In a quantitative analysis, the ADC value could be a biomarker of UTUC and reflect its aggressiveness, including histological grading and proliferative potential (Table 3).18,55–59 Our group reported that the ADC value was significantly lower in grade 3 cancers than in grade 1–2 cancers, and the ADC value was inversely correlated with the Ki-67 labeling index in UTUC as well as in bladder cancer (Fig. 8).15,16,28,59 Akita et al. showed that the ADC value of high-grade tumors was significantly lower than that of low-grade tumors in a series of 40 UTUC lesions.56 Contrary to these reports, Nishizawa et al. and © 2014 The Japanese Urological Association
Imaging biomarker of urothelial carcinoma
Table 3
Studies of DW-MRI reporting detectability and apparent diffusion coefficient value for upper tract urothelial carcinoma
Investigator (year)
Design
b-values, (s/mm2)
Yoshida (2008)55 Takeuchi (2008)58 Nishizawa (2010)57 Yoshida (2011)59
Retrospective 0.800 Retrospective 800 Retrospective 1000 Prospective
0.800
No. No. Pts tumor
Pts with UTUC Pts with UTUC Pts with UTUC Pts with suspicion of UTUC
10
P: 10
1.28 (0.92–1.45)* 2.19 (1.42–2.40)* 0.80 (0.41–0.96)* –
16
20
–
–
1.31 ± 0.27
–
17
P: 9, U: 8 P: 32, U: 17
1.98 ± 0.24
2.94 ± 0.32
1.13 ± 0.22
–
76
Akita (2011)56 Retrospective 0, 800 or Pts with 0, 1000 UTUC
40
Sufana Iancu (2013)18
17
Retrospective 0, 1000
ADC value, ×10−3 mm2/s (mean ± SD)
Inclusion criteria
Pts with UTUC
Kidney
Urine
Cancer
Grade
Sensitivity Specificity (%) (%) 100
–
100
–
94.1
–
92–94 81–96 1.69 (0.96–2.28)* 2.04 (1.18–4.18)* 1.04 (0.50–1.81)* G1–2: 1.22 (0.86–1.65)*, G3: 0.91 (0.50–1.50)*; P = 0.028 T2W+DW: – P: 40 1.96 ± 0.26 – 1.36 ± 0.23 High-grade: 98 1.30 ± 0.18, Low-grade: 1.70 ± 0.13; P < 0.01 88.9 – P: 11, U: 7 1.78 ± 0.25 – 1.08 ± 0.19 No significant difference between grades
*Data are expressed as median (range).
Sufana Iancu et al. did not find any correlation between the ADC value and histological grade in a smaller number of UTUC.18,57 To validate these results, further studies with a larger study population are required. As the ADC value reflects the biophysical characteristics of cancer cells, it might be useful for the preoperative risk stratification of UTUC patients.61 In a prospective study including 34 patients treated with nephroureterectomy, our group reported a significant and inverse correlation of the ADC value with the Ki-67 labeling index in UTUC.15 In the study, cancer-specific survival after nephroureterectomy was clearly stratified according to the ADC value; the 3-year cancer-specific survival rate of patients with low ADC UTUC (
