Clinical Imaging 39 (2015) 72–75
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
The relation between apparent diffusion coefficient and clinical stage of clear-cell renal cell carcinoma☆ Tomonori Nakamura a, Takeshi Yoshizako a,⁎, Hisayoshi Araki a, Mitsunari Maruyama a, Koji Uchida a, Yukihisa Tamaki a, Noriyuki Ishikawa b, Hiroaki Shiina c, Hajime Kitagaki a a b c
Department of Radiology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya, Izumo, Japan Department of Organ Pathology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya, Izumo, Japan Department of Urology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya, Izumo, Japan
a r t i c l e
i n f o
Article history: Received 21 June 2014 Received in revised form 20 August 2014 Accepted 2 September 2014 Keywords: Renal cell carcinoma Apparent diffusion coefficients (ADC) Magnetic resonance (MR) imaging Clinical stage
a b s t r a c t Purpose: The utility of the apparent diffusion coefficient (ADC) in patients with clear-cell renal cell carcinoma (RCC) for distinguishing between the four clinical stages was assessed. Methods: Forty-nine patients with pathologically proven RCCs (I, II, III, IV; 27, 5, 10, 7) were included. The ADC was compared between each stage. Results: The difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant. Conclusions: When ADC in primary tumor site of clear-cell RCC would be higher than the cutoff level, the stage might not be an advanced stage (III or IV).
© 2015 Elsevier Inc. All rights reserved.
1. Introduction Renal cell carcinoma (RCC) is the most common malignant tumor of the kidneys in adults. The three major histological types of RCC are clear-cell, papillary, and chromophobe carcinoma, which account for 75%, 10%–15%, and 5% of all renal cancers, respectively [1]. In addition, previous studies [2] have suggested that patients with clearcell RCC have a worse prognosis than patients with chromophobe or papillary RCC. The apparent diffusion coefficient (ADC) in magnetic resonance imaging (MRI) is a parameter that reflects the random movement of water molecules due to Brownian motion, and it shows a correlation with the histological grade of various malignancies, including tumors of the brain and prostate [3,4]. It has been reported [5–8] that ADC is significantly lower for high-grade clear-cell RCC than low-grade clear-cell RCC. However, the relation between ADC and the clinical stage of clear-cell RCC has not been reported, to our knowledge. Accurate characterization of patients with clear-cell RCC is essential to ensure appropriate clinical management and prognosis. It would be useful if the clinical stage of
☆ Advances in knowledge: In clinical practice, patients with low apparent diffusion coefficient should be examined extensively for the possibility of distant metastasis in clear-cell renal cell carcinoma. ⁎ Corresponding author. Department of Radiology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya Izumo, Japan. Tel.: + 81 853 20 2289; fax: +81 853 20 2285. E-mail address: [email protected] (T. Yoshizako). http://dx.doi.org/10.1016/j.clinimag.2014.09.006 0899-7071/© 2015 Elsevier Inc. All rights reserved.
clear-cell RCC could be predicted by assessing ADC of the primary tumor site. Accordingly, this study was to investigate relations among ADC and clinical stage in patients with clear-cell RCC. 2. Materials and methods 2.1. Patients Our institutional review board approved this retrospective study, and the need to obtain informed consent was waived. A retrospective review was performed of all patients who underwent 1.5-T MRI for evaluation of a renal mass from January 2010 to June 2012 and who had pathologic confirmation of the diagnosis of renal cancer. The pathological diagnosis of clear-cell RCC was made by examining tissues obtained at renal biopsy or radical/partial nephrectomy. 2.2. MRI protocol MRI was performed with the patient in the supine position using a 1.5-T unit (Signa HDx; GE Healthcare, Milwaukee, WI, USA) and a body phased-array coil. For evaluation of the kidneys, transverse T1-weighted dual-echo inphase and out-of-phase sequences, transverse and coronal T2-weighted single-shot fast spin-echo sequences, and three-dimensional fatsaturated (LAVA) T1-weighted dynamic contrast-enhanced sequences were obtained with breath holding.
T. Nakamura et al. / Clinical Imaging 39 (2015) 72–75
Gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals, Tokyo, Japan) (0.1 mmol/kg) was injected intravenously at a rate of 2 ml/s with a power injector (Sonic Shot 50; Nemoto Kyorindo Co. Ltd.), followed by a 20-ml saline flush, and dynamic contrast-enhanced imaging was performed in the transverse plane at baseline (precontrast) as well as at 30, 70, and 180 seconds seconds after injection. Transverse free-breathing diffusion-weighted (DW) images were obtained by using a single-shot spin-echo echo-planar sequence before the contrast medium was administered, with b values of 0 and 800 s/mm2. Spectral spatial radiofrequency pulses were used for the excitation of water. Then ADC maps were generated by using commercially available software (Advanced Workstation; GE Healthcare). The MRI parameters are listed in Table 1. 2.3. Image analysis MRI data for each of the 49 renal masses were assessed by two reviewers (M.M. with 6 years of experience and T.Y. with 23 years of experience in the interpretation of magnetic resonance images at the time of this study), who made consensus decisions about the imaging diagnosis prior to review of the pathological findings. The ADC was calculated manually by placing a region of interest (ROI) in the tumor. The ROI was chosen to include solid components of the tumor and was set as large as possible. Care was taken to avoid necrotic/cystic/hemorrhagic areas within them. ADC values were expressed as mean±standard deviation in the form of a ×10−3 mm2/s up to three decimal places.
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Table 2 The ADC values for each clinical stage of clear-cell RCC ADC (×10−3 mm2/s)
Stage I (n=27)
Stage II (n=5)
Stage III (n=10)
Stage IV (n=7)
Median Interquartile range
1.702 1.557–1.857
1.421 1.348–1.597
1.4215 1.160–1.533
1.289 1.020–1.484
The difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant (stage III and IV; P=.03 and P=.006, respectively). However, the difference of ADC between stage I and II was not significant difference (P=.462), and there was no significant difference between other stages.
The Kolmogorov–Smirnov test was used to determine whether the data on ADC for patients in each clinical stage were normally distributed. Then ADC was compared between each clinical stage by using the Kruskal–Wallis H test and Mann–Whitney U test with Bonferroni correction as post hoc test. If the Kruskal–Wallis H test and Mann–Whitney U test with Bonferroni correction as post hoc test revealed a significant difference between the four clinical stages, receiver operating characteristic (ROC) analysis was performed to determine the area under the ROC curve and the optimal cutoff value for ADC with the sensitivity, specificity, positive predictive value, and negative predictive value for staging clear-cell RCC. A P value less than .05 was considered to indicate statistical significance. All analyses were performed with SPSS software (version 17.0.0 for Windows; SPSS, Chicago, IL, USA). 3. Results
2.4. Histological examination All pathology slides were reviewed by a single uropathologist (N.I. with 15 years of experience) who assigned a nuclear grade for each tumor using the Fuhrman classification [9] while being unaware of the MRI findings. The Fuhrman classification assigns tumors a grade of I–IV, with grade I indicating the best prognosis and grade IV indicating the worst prognosis. 2.5. Clinical staging Ultrasonography and a plain X-ray film of the chest were obtained routinely, and computerized tomography or MRI was also performed preoperatively. A bone scan, brain scan, or other investigations were only performed if indicated. The clinical stage was determined according to the 2010 TNM classification of the American Joint Committee on Cancer (AJCC) [10]. 2.6. Statistical analysis Correlations between the clinical stage and the Fuhrman grade were assessed by Spearman's rank correlation analysis.
During the study period, 49 patients underwent 1.5-T MRI for the evaluation of 49 renal masses and had pathological confirmation of the diagnosis. They comprised 31 men (mean age: 61.4 years; range: 44–79 years) and 18 women (mean age: 70.9 years; range: 49–93 years). The mean age of all 49 patients was 63.3 years (range: 44–93 years). There were 49 clear-cell RCCs in the 49 patients. Histopathological analysis was obtained from radical nephrectomy (n= 33) and partial nephrectomy (n= 16). The mean interval between MRI and surgery was 17.9 days (range: 4–30 days). Data on ADC for each clinical stage did not show a normal distribution. For all 49 patients, the median ADC of clear-cell RCC was 1.562×10 − 3 mm 2/s (interquartile range, 1.41–1.772×10 −3 mm2/s). The clinical stage was I in 27 patients (55.1%), II in 5 patients (10.2%), III in 10 patients (20.4%), and IV in 7 patients (14.3%). Spearman's rank correlation coefficient for the relation between clinical stage and Fuhrman grade was R2=0.3747 (Pb.01). Table 2 shows the ADC values for patients in each clinical stage. The difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant (stage III and IV; P=.03 and P=.006, respectively). However, the difference of ADC between stage I and II was
Table 1 The MR imaging parameters Parameter
Axial T2-weighted imaging
Coronal T2-weighted imaging
In-phase/opposed-phase imaging
DW imaging
Contrast-enhanced MRI
Repetition time (ms) Echo time (ms) Flip angle (degrees) Section thickness (mm) Intersection gap (mm) Matrix Field of view (cm) No. of signals acquired Parallel imaging acceleration factor
5368.42 89.488 90 5 1 320–224 36–44 2 2
5000 90.6 90 5 1 320–224 36–44 0.5 –
150 2.1/4.2 70 7-8 1 256–192 36–44 1 2
5400 64 90 8 1 128–192 36–42 8 2
4.1 2 12 5 -2.5 256–192 34–48 1 2
74
T. Nakamura et al. / Clinical Imaging 39 (2015) 72–75
4. Discussion
Fig. 1. ROC curve for discrimination between clinical stage I and the more advanced stages (III and IV) of clear-cell RCC based on ADC. The area under the curve was 0.826.
not statistically significant (P=.462). In addition, there was no difference between II and III, between II and IV, and between III and IV. Fig. 1 shows an ROC curve for discrimination between clear-cell RCC in clinical stage I and the more advanced stages (III and IV) based on ADC. The area under the ROC curve was 0.826, and the optimum cutoff value of the ADC for distinguishing between clinical stage I to the more advanced stages (III and IV) was 1.552×10−3 mm2/s. Using this cutoff value, ADC had a sensitivity of 73.9%, a specificity of 82.4%, a positive predictive value of 30.0%, and a negative predictive value of 15.0% for assigning between clinical stage I and the more advanced stages (III and IV) (Figs. 1 and 2).
Fig. 2. Scatterplot of ADC for clinical stage I and the more advanced stages (III and IV) of clear-cell RCC. The horizontal line denotes the cutoff ADC that yields the combination of the highest specificity. The optimal cutoff value was 1.552 (×10−3 mm2/s). This cutoff value had a sensitivity of 73.9%, a specificity of 82.4%, a positive predictive value of 30.0%, and a negative predictive value of 15.0%.
We found that the difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant. Furthermore, the difference of ADC between stages I and II was not significantly different. Moreover, there was no significant difference between other stages. Therefore, when ADC value would be higher than cutoff level, the stage might not be advanced stage (III or IV). Thus, ADC of primary tumor site of clear-cell RCC might be useful to distinguish clinical stage I disease from more advanced disease with lymph node or distant metastasis. Previous studies [5–8] have suggested that the ADC of high-grade clear-cell RCC is significantly lower than that of low-grade clear-cell RCC. Also, Paudyal et al. [8] reported that various types of primary renal carcinoma with metastasis had significantly lower ADC values than that without metastasis. They had not compared ADC for each clinical stage of clear-cell RCC. To our knowledge, a comparison of ADC for each clinical stage of clear-cell RCC has not been reported before. Our findings suggest that the potential clinical role of this technique in determining tumor aggressiveness (for instance in selecting patients who might be suitable for surveillance) may have clinical importance as a noninvasive procedure with which to predict malignant potential, such as distant metastasis in clear-cell RCC. The median ADC of all tumors was 1.562×10−3 mm2/s (interquartile range, 1.41–1.772×10 −3 mm 2/s). The actual values of ADC in clear-cell RCC were a similar range to that found by Rosenkrantz et al. [5–8]. There is a wide range of ADC values for clear-cell RCC reported in the literature [5–8], which may reflect the use of different MR units and sequence parameters [5]. In the 2010 TNM classification of the AJCC [10], the T factor accounts for tumor size. Stage I means that the tumor is ≤7 cm in diameter and is confined to the kidney. Stage II means that the tumor is larger than 7 cm, but is still limited to the kidney. In stages III and IV, cancer may be found in the lymph nodes and has spread outside the kidney. Thus, stage I is distinguished from stage II by the size of the primary tumor alone. In the present study, ADC of stages I and II were not significant differences. It might have agreed to the concept of TNM classification which divides stages I and II in a tumor size. However, although the difference of ADC between stage II and the more advanced stages (III and IV) was not significant difference, the difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant. It might have agreed to the concept of TNM classification which divides early stage (still limited to the kidney) and the more advanced stages (III and IV) by presenting lymph node or distant metastasis. In our present study, primary tumor of clear-cell RCC with the advanced clinical stages had significantly lower ADC than that of stage I. The tumors with the advanced clinical stages may be aggressive with high cellularity and have restricted movements of water molecules, resulting in low ADC. Therefore, ADC may be used as a differentiating parameter for characterizing the advanced clinical stages potential of primary renal tumors. ADC may have clinical importance as a noninvasive procedure with which to predict malignant potential, such as distant metastasis in clear-cell RCC. The optimum cutoff value of this ADC for distinguishing between clinical stage I and the more advanced stages (III and IV) was 1.552×10 −3 mm 2/s, since this yielded the combination of the highest sensitivity and specificity. Accordingly, one may be more aggressive in evaluating potential distant metastases when ADC values of a primary tumor are less than 1.552×10 −3 mm2/s. Our study had several limitations. First, our retrospective study included a relatively low number of subjects. Especially, there was very low number of the advanced clinical stages (II–IV, n= 22). Therefore, our imaging findings and conclusions should be interpreted as preliminary and subject to further prospective investigation. Second, we did not assess the reproducibility of the ADC values obtained for renal tumors, so further studies to validate reproducibility are needed. Third, only two b-values (0 and 800 s/mm2) were used for calculation of the
T. Nakamura et al. / Clinical Imaging 39 (2015) 72–75
ADC. It may have been desirable to acquire additional b-values in order to obtain more accurate ADC data. In conclusion, when ADC value in primary tumor site of clear-cell RCC would be higher than cutoff level, the stage might not be advanced stage (III or IV). Therefore, in clinical practice, patients with low ADC should be examined extensively for the possibility of distant metastasis in clear-cell RCC. References [1] Reuter VE. The pathology of renal epithelial neoplasms. Semin Oncol 2006;33:534–43. [2] Beck SD, Patel MI, Snyder ME, Kattan MW, Motzer RJ, Reuter VE, Russo P. Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 2004;11:71–7. [3] Arvinda HR, Kesavadas C, Sarma PS, Thomas B, Radhakrishnan VV, Gupta AK, Kapilamoorthy TR, Nair S. Glioma grading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging. J Neurooncol 2009;94:87–96.
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[4] Tamada T, Sone T, Jo Y, Toshimitsu S, Yamashita T, Yamamoto A, Tanimoto D, Ito K. Apparent diffusion coefficient values in peripheral and transition zones of the prostate: comparison between normal and malignant prostatic tissues and correlation with histologic grade. J Magn Reson Imaging 2008;28:720–6. [5] Rosenkrantz AB, Niver BE, Fitzgerald EF, Babb JS, Chandarana H, Melamed J. Utility of the apparent diffusion coefficient for distinguishing clear cell renal cell carcinoma of low and high nuclear grade. Am J Roentgenol 2010;195:344–51. [6] Yu X, Lin M, Ouyang H, Zhou C, Zhang H. Application of ADC measurement in characterization of renal cell carcinomas with different pathological types and grades by 3.0T diffusion-weighted MRI. Eur J Radiol 2012;81:3061–6. [7] Goyal A, Sharma R, Bhalla AS, Gamanagatti S, Seth A, Iyer VK, Das P. Diffusionweighted MRI in renal cell carcinoma: a surrogate marker for predicting nuclear grade and histological subtype. Acta Radiol 2012;53:349–58. [8] Paudyal B, Paudyal P, Tsushima Y, Oriuchi N, Amanuma M, Miyazaki M, TaketomiTakahashi A, Nakazato Y, Endo K. The role of the ADC value in the characterization of renal carcinoma by diffusion-weighted MRI. Br J Radiol 2010;83:336–43. [9] Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655–63. [10] Kideny. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer–Verlag; 2010. p. 479–89.
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
The relation between apparent diffusion coefficient and clinical stage of clear-cell renal cell carcinoma☆ Tomonori Nakamura a, Takeshi Yoshizako a,⁎, Hisayoshi Araki a, Mitsunari Maruyama a, Koji Uchida a, Yukihisa Tamaki a, Noriyuki Ishikawa b, Hiroaki Shiina c, Hajime Kitagaki a a b c
Department of Radiology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya, Izumo, Japan Department of Organ Pathology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya, Izumo, Japan Department of Urology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya, Izumo, Japan
a r t i c l e
i n f o
Article history: Received 21 June 2014 Received in revised form 20 August 2014 Accepted 2 September 2014 Keywords: Renal cell carcinoma Apparent diffusion coefficients (ADC) Magnetic resonance (MR) imaging Clinical stage
a b s t r a c t Purpose: The utility of the apparent diffusion coefficient (ADC) in patients with clear-cell renal cell carcinoma (RCC) for distinguishing between the four clinical stages was assessed. Methods: Forty-nine patients with pathologically proven RCCs (I, II, III, IV; 27, 5, 10, 7) were included. The ADC was compared between each stage. Results: The difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant. Conclusions: When ADC in primary tumor site of clear-cell RCC would be higher than the cutoff level, the stage might not be an advanced stage (III or IV).
© 2015 Elsevier Inc. All rights reserved.
1. Introduction Renal cell carcinoma (RCC) is the most common malignant tumor of the kidneys in adults. The three major histological types of RCC are clear-cell, papillary, and chromophobe carcinoma, which account for 75%, 10%–15%, and 5% of all renal cancers, respectively [1]. In addition, previous studies [2] have suggested that patients with clearcell RCC have a worse prognosis than patients with chromophobe or papillary RCC. The apparent diffusion coefficient (ADC) in magnetic resonance imaging (MRI) is a parameter that reflects the random movement of water molecules due to Brownian motion, and it shows a correlation with the histological grade of various malignancies, including tumors of the brain and prostate [3,4]. It has been reported [5–8] that ADC is significantly lower for high-grade clear-cell RCC than low-grade clear-cell RCC. However, the relation between ADC and the clinical stage of clear-cell RCC has not been reported, to our knowledge. Accurate characterization of patients with clear-cell RCC is essential to ensure appropriate clinical management and prognosis. It would be useful if the clinical stage of
☆ Advances in knowledge: In clinical practice, patients with low apparent diffusion coefficient should be examined extensively for the possibility of distant metastasis in clear-cell renal cell carcinoma. ⁎ Corresponding author. Department of Radiology, Shimane University Faculty of Medicine, P.O. Box 00693-8501, 89-1 Enya Izumo, Japan. Tel.: + 81 853 20 2289; fax: +81 853 20 2285. E-mail address: [email protected] (T. Yoshizako). http://dx.doi.org/10.1016/j.clinimag.2014.09.006 0899-7071/© 2015 Elsevier Inc. All rights reserved.
clear-cell RCC could be predicted by assessing ADC of the primary tumor site. Accordingly, this study was to investigate relations among ADC and clinical stage in patients with clear-cell RCC. 2. Materials and methods 2.1. Patients Our institutional review board approved this retrospective study, and the need to obtain informed consent was waived. A retrospective review was performed of all patients who underwent 1.5-T MRI for evaluation of a renal mass from January 2010 to June 2012 and who had pathologic confirmation of the diagnosis of renal cancer. The pathological diagnosis of clear-cell RCC was made by examining tissues obtained at renal biopsy or radical/partial nephrectomy. 2.2. MRI protocol MRI was performed with the patient in the supine position using a 1.5-T unit (Signa HDx; GE Healthcare, Milwaukee, WI, USA) and a body phased-array coil. For evaluation of the kidneys, transverse T1-weighted dual-echo inphase and out-of-phase sequences, transverse and coronal T2-weighted single-shot fast spin-echo sequences, and three-dimensional fatsaturated (LAVA) T1-weighted dynamic contrast-enhanced sequences were obtained with breath holding.
T. Nakamura et al. / Clinical Imaging 39 (2015) 72–75
Gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals, Tokyo, Japan) (0.1 mmol/kg) was injected intravenously at a rate of 2 ml/s with a power injector (Sonic Shot 50; Nemoto Kyorindo Co. Ltd.), followed by a 20-ml saline flush, and dynamic contrast-enhanced imaging was performed in the transverse plane at baseline (precontrast) as well as at 30, 70, and 180 seconds seconds after injection. Transverse free-breathing diffusion-weighted (DW) images were obtained by using a single-shot spin-echo echo-planar sequence before the contrast medium was administered, with b values of 0 and 800 s/mm2. Spectral spatial radiofrequency pulses were used for the excitation of water. Then ADC maps were generated by using commercially available software (Advanced Workstation; GE Healthcare). The MRI parameters are listed in Table 1. 2.3. Image analysis MRI data for each of the 49 renal masses were assessed by two reviewers (M.M. with 6 years of experience and T.Y. with 23 years of experience in the interpretation of magnetic resonance images at the time of this study), who made consensus decisions about the imaging diagnosis prior to review of the pathological findings. The ADC was calculated manually by placing a region of interest (ROI) in the tumor. The ROI was chosen to include solid components of the tumor and was set as large as possible. Care was taken to avoid necrotic/cystic/hemorrhagic areas within them. ADC values were expressed as mean±standard deviation in the form of a ×10−3 mm2/s up to three decimal places.
73
Table 2 The ADC values for each clinical stage of clear-cell RCC ADC (×10−3 mm2/s)
Stage I (n=27)
Stage II (n=5)
Stage III (n=10)
Stage IV (n=7)
Median Interquartile range
1.702 1.557–1.857
1.421 1.348–1.597
1.4215 1.160–1.533
1.289 1.020–1.484
The difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant (stage III and IV; P=.03 and P=.006, respectively). However, the difference of ADC between stage I and II was not significant difference (P=.462), and there was no significant difference between other stages.
The Kolmogorov–Smirnov test was used to determine whether the data on ADC for patients in each clinical stage were normally distributed. Then ADC was compared between each clinical stage by using the Kruskal–Wallis H test and Mann–Whitney U test with Bonferroni correction as post hoc test. If the Kruskal–Wallis H test and Mann–Whitney U test with Bonferroni correction as post hoc test revealed a significant difference between the four clinical stages, receiver operating characteristic (ROC) analysis was performed to determine the area under the ROC curve and the optimal cutoff value for ADC with the sensitivity, specificity, positive predictive value, and negative predictive value for staging clear-cell RCC. A P value less than .05 was considered to indicate statistical significance. All analyses were performed with SPSS software (version 17.0.0 for Windows; SPSS, Chicago, IL, USA). 3. Results
2.4. Histological examination All pathology slides were reviewed by a single uropathologist (N.I. with 15 years of experience) who assigned a nuclear grade for each tumor using the Fuhrman classification [9] while being unaware of the MRI findings. The Fuhrman classification assigns tumors a grade of I–IV, with grade I indicating the best prognosis and grade IV indicating the worst prognosis. 2.5. Clinical staging Ultrasonography and a plain X-ray film of the chest were obtained routinely, and computerized tomography or MRI was also performed preoperatively. A bone scan, brain scan, or other investigations were only performed if indicated. The clinical stage was determined according to the 2010 TNM classification of the American Joint Committee on Cancer (AJCC) [10]. 2.6. Statistical analysis Correlations between the clinical stage and the Fuhrman grade were assessed by Spearman's rank correlation analysis.
During the study period, 49 patients underwent 1.5-T MRI for the evaluation of 49 renal masses and had pathological confirmation of the diagnosis. They comprised 31 men (mean age: 61.4 years; range: 44–79 years) and 18 women (mean age: 70.9 years; range: 49–93 years). The mean age of all 49 patients was 63.3 years (range: 44–93 years). There were 49 clear-cell RCCs in the 49 patients. Histopathological analysis was obtained from radical nephrectomy (n= 33) and partial nephrectomy (n= 16). The mean interval between MRI and surgery was 17.9 days (range: 4–30 days). Data on ADC for each clinical stage did not show a normal distribution. For all 49 patients, the median ADC of clear-cell RCC was 1.562×10 − 3 mm 2/s (interquartile range, 1.41–1.772×10 −3 mm2/s). The clinical stage was I in 27 patients (55.1%), II in 5 patients (10.2%), III in 10 patients (20.4%), and IV in 7 patients (14.3%). Spearman's rank correlation coefficient for the relation between clinical stage and Fuhrman grade was R2=0.3747 (Pb.01). Table 2 shows the ADC values for patients in each clinical stage. The difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant (stage III and IV; P=.03 and P=.006, respectively). However, the difference of ADC between stage I and II was
Table 1 The MR imaging parameters Parameter
Axial T2-weighted imaging
Coronal T2-weighted imaging
In-phase/opposed-phase imaging
DW imaging
Contrast-enhanced MRI
Repetition time (ms) Echo time (ms) Flip angle (degrees) Section thickness (mm) Intersection gap (mm) Matrix Field of view (cm) No. of signals acquired Parallel imaging acceleration factor
5368.42 89.488 90 5 1 320–224 36–44 2 2
5000 90.6 90 5 1 320–224 36–44 0.5 –
150 2.1/4.2 70 7-8 1 256–192 36–44 1 2
5400 64 90 8 1 128–192 36–42 8 2
4.1 2 12 5 -2.5 256–192 34–48 1 2
74
T. Nakamura et al. / Clinical Imaging 39 (2015) 72–75
4. Discussion
Fig. 1. ROC curve for discrimination between clinical stage I and the more advanced stages (III and IV) of clear-cell RCC based on ADC. The area under the curve was 0.826.
not statistically significant (P=.462). In addition, there was no difference between II and III, between II and IV, and between III and IV. Fig. 1 shows an ROC curve for discrimination between clear-cell RCC in clinical stage I and the more advanced stages (III and IV) based on ADC. The area under the ROC curve was 0.826, and the optimum cutoff value of the ADC for distinguishing between clinical stage I to the more advanced stages (III and IV) was 1.552×10−3 mm2/s. Using this cutoff value, ADC had a sensitivity of 73.9%, a specificity of 82.4%, a positive predictive value of 30.0%, and a negative predictive value of 15.0% for assigning between clinical stage I and the more advanced stages (III and IV) (Figs. 1 and 2).
Fig. 2. Scatterplot of ADC for clinical stage I and the more advanced stages (III and IV) of clear-cell RCC. The horizontal line denotes the cutoff ADC that yields the combination of the highest specificity. The optimal cutoff value was 1.552 (×10−3 mm2/s). This cutoff value had a sensitivity of 73.9%, a specificity of 82.4%, a positive predictive value of 30.0%, and a negative predictive value of 15.0%.
We found that the difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant. Furthermore, the difference of ADC between stages I and II was not significantly different. Moreover, there was no significant difference between other stages. Therefore, when ADC value would be higher than cutoff level, the stage might not be advanced stage (III or IV). Thus, ADC of primary tumor site of clear-cell RCC might be useful to distinguish clinical stage I disease from more advanced disease with lymph node or distant metastasis. Previous studies [5–8] have suggested that the ADC of high-grade clear-cell RCC is significantly lower than that of low-grade clear-cell RCC. Also, Paudyal et al. [8] reported that various types of primary renal carcinoma with metastasis had significantly lower ADC values than that without metastasis. They had not compared ADC for each clinical stage of clear-cell RCC. To our knowledge, a comparison of ADC for each clinical stage of clear-cell RCC has not been reported before. Our findings suggest that the potential clinical role of this technique in determining tumor aggressiveness (for instance in selecting patients who might be suitable for surveillance) may have clinical importance as a noninvasive procedure with which to predict malignant potential, such as distant metastasis in clear-cell RCC. The median ADC of all tumors was 1.562×10−3 mm2/s (interquartile range, 1.41–1.772×10 −3 mm 2/s). The actual values of ADC in clear-cell RCC were a similar range to that found by Rosenkrantz et al. [5–8]. There is a wide range of ADC values for clear-cell RCC reported in the literature [5–8], which may reflect the use of different MR units and sequence parameters [5]. In the 2010 TNM classification of the AJCC [10], the T factor accounts for tumor size. Stage I means that the tumor is ≤7 cm in diameter and is confined to the kidney. Stage II means that the tumor is larger than 7 cm, but is still limited to the kidney. In stages III and IV, cancer may be found in the lymph nodes and has spread outside the kidney. Thus, stage I is distinguished from stage II by the size of the primary tumor alone. In the present study, ADC of stages I and II were not significant differences. It might have agreed to the concept of TNM classification which divides stages I and II in a tumor size. However, although the difference of ADC between stage II and the more advanced stages (III and IV) was not significant difference, the difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant. It might have agreed to the concept of TNM classification which divides early stage (still limited to the kidney) and the more advanced stages (III and IV) by presenting lymph node or distant metastasis. In our present study, primary tumor of clear-cell RCC with the advanced clinical stages had significantly lower ADC than that of stage I. The tumors with the advanced clinical stages may be aggressive with high cellularity and have restricted movements of water molecules, resulting in low ADC. Therefore, ADC may be used as a differentiating parameter for characterizing the advanced clinical stages potential of primary renal tumors. ADC may have clinical importance as a noninvasive procedure with which to predict malignant potential, such as distant metastasis in clear-cell RCC. The optimum cutoff value of this ADC for distinguishing between clinical stage I and the more advanced stages (III and IV) was 1.552×10 −3 mm 2/s, since this yielded the combination of the highest sensitivity and specificity. Accordingly, one may be more aggressive in evaluating potential distant metastases when ADC values of a primary tumor are less than 1.552×10 −3 mm2/s. Our study had several limitations. First, our retrospective study included a relatively low number of subjects. Especially, there was very low number of the advanced clinical stages (II–IV, n= 22). Therefore, our imaging findings and conclusions should be interpreted as preliminary and subject to further prospective investigation. Second, we did not assess the reproducibility of the ADC values obtained for renal tumors, so further studies to validate reproducibility are needed. Third, only two b-values (0 and 800 s/mm2) were used for calculation of the
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ADC. It may have been desirable to acquire additional b-values in order to obtain more accurate ADC data. In conclusion, when ADC value in primary tumor site of clear-cell RCC would be higher than cutoff level, the stage might not be advanced stage (III or IV). Therefore, in clinical practice, patients with low ADC should be examined extensively for the possibility of distant metastasis in clear-cell RCC. References [1] Reuter VE. The pathology of renal epithelial neoplasms. Semin Oncol 2006;33:534–43. [2] Beck SD, Patel MI, Snyder ME, Kattan MW, Motzer RJ, Reuter VE, Russo P. Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 2004;11:71–7. [3] Arvinda HR, Kesavadas C, Sarma PS, Thomas B, Radhakrishnan VV, Gupta AK, Kapilamoorthy TR, Nair S. Glioma grading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging. J Neurooncol 2009;94:87–96.
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[4] Tamada T, Sone T, Jo Y, Toshimitsu S, Yamashita T, Yamamoto A, Tanimoto D, Ito K. Apparent diffusion coefficient values in peripheral and transition zones of the prostate: comparison between normal and malignant prostatic tissues and correlation with histologic grade. J Magn Reson Imaging 2008;28:720–6. [5] Rosenkrantz AB, Niver BE, Fitzgerald EF, Babb JS, Chandarana H, Melamed J. Utility of the apparent diffusion coefficient for distinguishing clear cell renal cell carcinoma of low and high nuclear grade. Am J Roentgenol 2010;195:344–51. [6] Yu X, Lin M, Ouyang H, Zhou C, Zhang H. Application of ADC measurement in characterization of renal cell carcinomas with different pathological types and grades by 3.0T diffusion-weighted MRI. Eur J Radiol 2012;81:3061–6. [7] Goyal A, Sharma R, Bhalla AS, Gamanagatti S, Seth A, Iyer VK, Das P. Diffusionweighted MRI in renal cell carcinoma: a surrogate marker for predicting nuclear grade and histological subtype. Acta Radiol 2012;53:349–58. [8] Paudyal B, Paudyal P, Tsushima Y, Oriuchi N, Amanuma M, Miyazaki M, TaketomiTakahashi A, Nakazato Y, Endo K. The role of the ADC value in the characterization of renal carcinoma by diffusion-weighted MRI. Br J Radiol 2010;83:336–43. [9] Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655–63. [10] Kideny. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer–Verlag; 2010. p. 479–89.
