| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Genitourinary Imaging |
1 From the Departments of Radiology (W.M.L.L.G.D., G.J.J., J.O.B.), Urology (J.A.W., P.F.M.), and Pathology (C.A.H.v.d.K.), University Medical Center Sint Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands; Departments of Radiology (M.G.H.) and Oncology (D.K.), Massachusetts General Hospital, Boston, Mass; and Department of Radiology, Charité Hospital Berlin, Germany (M.T.). Received July 15, 2003; revision requested September 18; final revision received February 24, 2004; accepted March 16. Address correspondence to W.M.L.L.G.D. (e-mail: w.deserno@rad.umcn.nl).
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
MATERIALS AND METHODS: Fifty-eight patients with proved bladder cancer were enrolled. Results of MR imaging performed before and after injection of ferumoxtran-10 were compared with histopathologic results in surgically removed lymph nodes. High-spatial-resolution three-dimensional T1-weighted magnetization-prepared rapid acquisition gradient-echo (voxel size, 1.4 x 1.4 x 1.4 mm) and T2*-weighted gradient-echo (voxel size, 0.8 x 0.8 x 3.0 mm) sequences were performed before and 24 hours after injection of ferumoxtran-10 (2.6 mg iron per kilogram of body weight). On precontrast images, lymph nodes were defined as malignant by using size and shape criteria (round node, >8 mm; oval, >10 mm axial diameter). On postcontrast images, nodes were considered benign if there was homogeneous decrease in signal intensity and malignant if decrease was absent or heterogeneous. Qualitative evaluation was performed on a node-to-node basis. Sensitivity, specificity, predictive values, and accuracy were evaluated with logistic regression analysis.
RESULTS: In 58 patients, 172 nodes imaged with use of ferumoxtran-10 were matched and correlated with results of node dissection. Of these, 122 were benign and 50 were malignant. With nodal size and shape criteria, accuracy, sensitivity, specificity, and positive and negative predictive values on precontrast images were 92%, 76%, 99%, 97%, and 91%, respectively; corresponding values on postcontrast images were 95%, 96%, 95%, 89%, and 98%. In the depiction of pelvic metastases, sensitivity and negative predictive value improved significantly at postcontrast compared with those at precontrast imaging, from 76% to 96% (P < .001) and from 91% to 98% (P < .01), respectively. At postcontrast imaging, metastases (4–9 mm) were prospectively found in 10 of 12 normal-sized nodes (<10 mm); these metastases were not detected on precontrast images. Postcontrast images also showed lymph nodes that were missed at pelvic node dissection in two patients.
CONCLUSION: Ferumoxtran-10–enhanced MR imaging significantly improves nodal staging in patients with bladder cancer by depicting metastases even in normal-sized lymph nodes.
© RSNA, 2004
Index terms: Bladder neoplasms, metastases, 83.31, 83.33 • Bladder neoplasms, MR, 83.12141 • Iron • Magnetic resonance (MR), contrast media
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
Thus, to detect metastasis in normal-sized lymph nodes it is necessary to obtain differential enhancement between normal lymph node tissue and metastases. Results of previous studies in which ultrasmall superparamagnetic iron oxide (ferumoxtran-10) particles were used have shown that normal nodal tissue shows contrast material uptake and a selective decrease in signal intensity on T2- or T2*-weighed MR images, whereas nodal areas infiltrated with metastases lack ferumoxtran-10 uptake and retain high signal intensity on ferumoxtran 10–enhanced MR images (Fig 1) (5,6). However, authors of these studies did not comment on the role of ferumoxtran-10 in the detection of metastases in nodes smaller than 10 mm (6). In a study of prostate cancer, it was shown that ferumoxtran 10–enhanced MR imaging allowed the detection of small (<10-mm) metastatic lymph nodes (7), which resulted in a significant increase in sensitivity. Metastatic nodes in bladder carcinoma, however, are larger (2); therefore, the results found for prostate cancer cannot be extrapolated to urinary bladder cancer. The purpose of our study was to prospectively evaluate ferumoxtran 10–enhanced MR imaging for nodal staging in patients with urinary bladder cancer.
|
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
|
Nodal Assessment
A node-to-node analysis was performed by using the pre- and postcontrast images. The MR images were prospectively analyzed by one experienced observer at each of the participating institutions (J.O.B., M.T., or M.G.H., with 16, 13, or 5 years of experience, respectively); observers were unaware of the clinical stage or histologic grade. On precontrast MR images, lymph nodes were rated as malignant on the basis of nodal size and shape criteria as described by Jager et al (2). The distinction between round and oval nodes was made on the basis of the ratio between the short axis and long axis. A node was called round if this ratio was 0.8–1.0. A node was called oval if this ratio was smaller than 0.8. The three-dimensional sequences were evaluated on soft-copy images by using multiplanar reconstruction at a workstation. An oval node was considered metastatic if the minimal axial diameter was greater than 10 mm, and a round node was considered metastatic if the minimal axial diameter was greater than 8 mm. On the ferumoxtran-10–enhanced MR images, a node was considered normal if it showed a homogeneous signal intensity decrease and was considered metastatic if the entire node or a focal area did not show a signal intensity decrease on T2*-weighted images. First, the precontrast images were read with use only of the objective nodal size and shape criteria described by Jager et al. Thereafter, the combined pre- and postcontrast MR images were read, and judgment was based only on changes in signal intensity.
Forty-four patients (76%) underwent pelvic lymph node dissection, 12 patients (21%) underwent image-guided biopsy, and two patients (3%) underwent laparoscopic lymph node dissection. Image-guided biopsy was performed only in nodes larger than 8 mm. To ensure "node-to-node" comparison, the urologists (J.A.W., P.F.M.) were preoperatively provided with a schematic drawing of all visible nodes on MR images in relationship to fixed anatomic landmarks, such as the iliac arteries or ureters. To further ensure correct nodal correlation, the radiologist (W.M.L.L.G.D., J.O.B., M.G.H., or M.T.) was present at the time of surgery and helped the surgeon to identify the nodes with the use of marked grids. In accordance with standard surgical protocols, the urologist removed all lymph nodes in the obturator and the common iliac regions on both sides. All additional nodes, which were removed on the basis of findings on the ferumoxtran-10–enhanced MR images, were noted separately.
After removal, the dissected nodes were placed on a grid to show their former location (Fig 2) and thereafter were sent for pathologic analysis. The pathologist (C.A.H.v.d.K., 11 years of experience in bladder cancer) described nodal size in two dimensions and indicated both normal and metastatic nodes on a schematic drawing that was identical to the one provided to the urologist prior to the operation. The histopathologic examination of the nodes included hematoxylin-eosin staining. Finally, the radiologist and pathologist performed the node-to-node correlation in consensus by comparing the node location and diagnosis determined at MR imaging with the pathologist’s report. All results were independently evaluated by several authors (W.M.L.L.G.D., J.O.B., M.G.H., and M.T.).
|
2 test was used only for descriptive statistics. Statistical analysis was carried out by using a software package (SPSS version 10.1; SPSS, Chicago, Ill). |
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
At pelvic lymph node dissection, an average of nine nodes per patient (range, two to 21 nodes per patient) were removed.
In 172 (43%) of 404 dissected nodes, an accurate match could be made between histologic evaluation and MR images (Tables 2, 3). The remaining 232 nodes that could not be matched were benign at histologic evaluation. Of the 172 matching nodes, 116 of the nodes that were nonmetastatic at histologic evaluation showed a signal intensity decrease on the ferumoxtran-10–enhanced MR images (Fig 3). These were true-negative nodes on ferumoxtran-10–enhanced MR images. Of the 50 nodes that were metastatic at histologic evaluation, 48 showed no signal intensity decrease after ferumoxtran-10 administration (true-positive), and the other two showed a decrease in signal intensity (false-negative).
|
|
|
Of the 50 metastatic lymph nodes, 38 were enlarged (mean size, 15.3 mm; range, 10–28 mm) on precontrast MR images and 12 were normal in size (mean, 7.2 mm; range, 6–9 mm). Ten of these 12 normal-sized nodes showed a lack of ferumoxtran-10 uptake and signal intensity decrease in focal areas on postcontrast images, which suggested metastasis (Figs 4, 5). Of the 122 benign nodes, one node was false-positive on precontrast MR images. This node was enlarged according to size criteria but was correctly classified as negative on the basis its low signal intensity on the postcontrast MR images (Fig 6). Six (5%) normal-sized nodes were false-positive on these postcontrast MR images.
|
|
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
Provision of accurate nodal information prior to surgery, by using noninvasive imaging modalities such as CT, MR imaging, or PET, may help to reduce these complications and contribute to a more complete lymph node dissection. Nodal assessment with CT or MR imaging relies on insensitive nodal size criteria and does not have the desired sensitivity for identification of metastases. The rather low sensitivity (76%) of nonenhanced MR imaging, as found in our study, concurs with existing results in the literature (12,13). The reason for this low sensitivity is a reliance on insensitive nodal size criteria and a lack of differences in signal intensity between normal and metastatic lymph nodes (14,15). Although promising in the evaluation of lung cancer, the role of fluorine 18 fluorodeoxyglucose PET in the urinary tract region is limited (4). In a recent study of PET conducted in 64 patients with bladder cancer, Bachor et al (16) found a sensitivity of 67% and a negative predictive value of 84%.
Published results of previous studies have shown that ferumoxtran 10–enhanced MR imaging can improve the accuracy for characterizing lymph nodes (17–22). After intravenous injection, the iron nanoparticles are transported to normal-functioning nodal macrophages and reduce the signal intensity of the nodes in which they accumulate; this is because of the T2* and susceptibility effects of the iron oxide. Normal and benign nodes thus show negative enhancement (reduced signal intensity) after the administration of ferumoxtran-10 (Figs 1, 4). In metastatic nodes, cancer cells replace the normal-functioning macrophages. Because the cancer cells lack reticuloendothelial activity and are unable to retain the iron particles, these nodes retain their high signal intensity after ferumoxtran-10 administration (Figs 4, 5).
Our results confirm the findings of Bellin et al (17), who determined that ferumoxtran-10 aids in differentiating metastatic and benign nodes because of the decreased signal intensity in normal lymph nodes. Bellin et al reported a sensitivity of 82%, a specificity of 83%, and a negative predictive value of 87% for ferumoxtran-10–enhanced imaging. Our study results showed a higher sensitivity (96%), specificity (95%), and negative predictive value (98%); this difference is probably attributed to our use of high-spatial-resolution MR imaging techniques and reduced respiratory and motion artifacts (13). Also, the higher specificity in our study can be explained by our use of a higher dose of contrast agent (2.6 vs 1.7 mg Fe per kilogram of body weight). In a study in which four doses were compared (1.1, 1.7, 2.6, and 3.4 mg Fe per kilogram) in 24 healthy adults, Hudgins et al (23) showed that the decrease in lymph node signal intensity on ferumoxtran-10–enhanced MR images was more pronounced with use of the dose of 2.6 mg Fe per kilogram than with the dose of 1.7 mg Fe per kilogram (as used by Bellin et al).
The high sensitivity and specificity in our study confirm the results of previous studies, in patients with other types of cancer, in which high-spatial-resolution techniques and a dose of 2.6 mg Fe per kilogram were also used (7,24–27). The results are in agreement with the findings of Jager et al (2), who determined that malignant nodes in urinary bladder cancer are larger, on average, than those found in prostate cancer. This explains the higher sensitivity (76%) of nonenhanced MR imaging in the urinary bladder in our study in comparison with the results of Harisinghani et al (7) in the prostate. Nonetheless, in our study, the sensitivity of ferumoxtran-10–enhanced MR imaging was still significantly higher than that of nonenhanced MR imaging because of the detection of metastases in 10 small (<8–10-mm) nodes. Sensitivity of ferumoxtran-10–enhanced MR imaging in these two cancers, however, is comparable: 91% in prostate cancer and 96% in bladder cancer.
In our study, one enlarged hyperplastic node was correctly classified as nonmetastatic on the basis of its low signal intensity on postcontrast MR images. However, specificity was decreased due to six heterogeneous nodes with small focal areas with lack of signal intensity decrease. In two cases, this decrease could be explained as being caused by focal fibrosis, as follows: The signal intensity of fibrosis was not different enough from that of normal nodal tissue to be visualized on our T1- and T2*-weighted MR images and, therefore, could not be recognized on the precontrast images. Because of the selective strong decreases in signal intensity of normal nodal tissue on postcontrast images, fibrosis became visible. In another case that was false-positive at MR imaging, histologic results showed focal lipomatosis. In the remaining cases, its remains uncertain why the result was false-positive. One possible explanation may be that the misinterpretation of "noise" or heterogeneous hilar fat as small metastastic foci or reactive hyperplasia was the reason for absence of signal intensity decrease (28).
Earlier studies have addressed the limitation of making precise nodal comparisons between surgery and MR imaging (29). To minimize this in our study, we used a stringent nodal localization protocol prior to and during surgery. Nonetheless, despite the special care taken in matching the nodes on MR images with pathologic results, definitely matching pairs were found in only 172 (43%) of 404 nodes. Since all noncomparable nodes were benign, this bias will probably have no negative effect on the outcome.
Our results show a higher sensitivity than specificity at ferumoxtran-10–enhanced MR imaging. This may not be a deterrent in a clinical setting; since a malignant node on ferumoxtran-10–enhanced MR images always needs to be histologically confirmed, the only consequence may be the removal of a few additional nodes by the urologist. The improvement in sensitivity from 76% at precontrast imaging to 96% at postcontrast imaging (P < .001) implies better visualization of metastatic nodes. Therefore, ferumoxtran-10–enhanced MR imaging can better guide the surgeon in dissection, which results in the removal of malignant nodes only. This is clinically important, as some authors claim that removing all possible malignant lymph nodes results in a better prognosis for local lymph node recurrence a better probability of patient survival (11,24,30). Furthermore, it is important to show all potential locations of malignant nodes with a higher sensitivity because if a patient has more than four malignant lymph nodes or has lymph nodes with extracapsular tumor growth, cystectomy is not considered to be the correct option for improved survival (31). In our study, information provided by ferumoxtran-10–enhanced MR imaging in nine patients allowed the surgeon to resect nodes outside the normal surgical dissection field. In addition, extranodal growth was visualized in another patient. To prove that ferumoxtran-10–enhanced MR imaging improves the outcome of lymph node dissection, prospective randomized clinical trials are needed; however, such studies are not ethically feasible.
A practical limitation on the use of ferumoxtran-10 is that it requires a 30-minute administration period with medical supervision and two separate MR examinations performed within 24–36 hours; therefore, use of ferumoxtran-10 is time-consuming and adds expenses. This problem may be solved in the future, since initial reports have shown that ferumoxtran-10–enhanced MR imaging alone may be sufficient for characterizing the nodes (32). Another limitation of our study was that there was a single reading, and, therefore, no information about interobserver variability was obtained. However, the images were read by three independent and experienced readers, which decreases the chance of interobserver bias. Nonetheless, it can be expected that results may differ when inexperienced readers are used. Finally, there are probably some clustering effects on several levels (hospital, physician, and patient levels). But without the correction on clustering, the differences between pre- and postcontrast MR imaging were so great at logistic regression analysis that we did not think it was necessary to correct for clustering effects. We did not distinguish between different hospitals because the nodal numbers did not allow this.
At ferumoxtran-10–enhanced MR imaging, normal nodal tissue and metastasis have different signal intensities; this difference allows detection of metastases even in normal-sized nodes, which results in increased sensitivity, from 76% to 96%, and negative predictive value, from 91% to 98%, in comparison with the sensitivity of nonenhanced MR imaging. The use of this technique thus provides a better detection of metastatic nodes, which can improve the accuracy of surgical nodal resection.
|
FOOTNOTES |
|---|
Author contributions: Guarantors of integrity of entire study, W.M.L.L.G.D., M.G.H., M.T., G.J.J., J.A.W., P.F.M., C.A.H.v.d.K., J.O.B.; study concepts, W.M.L.L.G.D., M.G.H., M.T., J.O.B.; study design, W.M.L.L.G.D., M.G.H., J.O.B.; literature research, W.M.L.L.G.D., M.G.H., G.J.J., J.A.W., J.O.B.; clinical studies, W.M.L.L.G.D., M.G.H., M.T., J.A.W., P.F.M., C.A.H.v.d.K., D.K., J.O.B.; data acquisition, W.M.L.L.G.D., M.G.H., M.T., J.A.W., P.F.M., C.A.H.v.d.K., D.K., J.O.B.; data analysis/interpretation, all authors; statistical analysis, W.M.L.L.G.D., G.J.J.; manuscript preparation, W.M.L.L.G.D., J.O.B.; manuscript definition of intellectual content, W.M.L.L.G.D., M.G.H., M.T., G.J.J., J.A.W., P.F.M., C.A.H.v.d.K., J.O.B.; manuscript editing, M.G.H., G.J.J., J.A.W., C.A.H.v.d.K., J.O.B.; manuscript revision/review, M.G.H., M.T., G.J.J., J.A.W., P.F.M., C.A.H.v.d.K., J.O.B.; manuscript final version approval, W.M.L.L.G.D., M.G.H., J.O.B.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  H. S. Park, J. M. Lee, J.-Y. Choi, M. W. Lee, H. J. Kim, J. K. Han, and B. I. Choi Preoperative Evaluation of Bile Duct Cancer: MRI Combined with MR Cholangiopancreatography Versus MDCT with Direct Cholangiography Am. J. Roentgenol., February 1, 2008; 190(2): 396 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Purcell, F. V. Coakley, B. L. Franc, R. A. Hawkins, S. E. Boddington, and B. M. Yeh Anterior Layering of Excreted 18F-FDG in the Bladder on PET/CT: Frequency and Cause Am. J. Roentgenol., August 1, 2007; 189(2): W96 - W99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Torigian, S. S. Huang, M. Houseni, and A. Alavi Functional Imaging of Cancer with Emphasis on Molecular Techniques CA Cancer J Clin, July 1, 2007; 57(4): 206 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rubaltelli, S. Corradin, A. Dorigo, A. Tregnaghi, F. Adami, C. R. Rossi, and R. Stramare Automated Quantitative Evaluation of Lymph Node Perfusion on Contrast-Enhanced Sonography Am. J. Roentgenol., April 1, 2007; 188(4): 977 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Memarsadeghi, C. C. Riedl, A. Kaneider, A. Galid, M. Rudas, W. Matzek, and T. H. Helbich Axillary Lymph Node Metastases in Patients with Breast Carcinomas: Assessment with Nonenhanced versus USPIO-enhanced MR Imaging. Radiology, November 1, 2006; 241(2): 367 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schnall and M. Rosen Primer on Imaging Technologies for Cancer J. Clin. Oncol., July 10, 2006; 24(20): 3225 - 3233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. M. Heesakkers, J. J. Futterer, A. M. Hovels, H. C. M. van den Bosch, T. W. J. Scheenen, Y. L. Hoogeveen, and J. O. Barentsz Prostate Cancer Evaluated with Ferumoxtran-10-enhanced T2*-weighted MR Imaging at 1.5 and 3.0 T: Early Experience. Radiology, May 1, 2006; 239(2): 481 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Wong-You-Cheong, P. J. Woodward, M. A. Manning, and I. A. Sesterhenn From the Archives of the AFIP: Neoplasms of the Urinary Bladder: Radiologic-Pathologic Correlation RadioGraphics, March 1, 2006; 26(2): 553 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Singh, A. Saokar, P. F. Hahn, and M. G. Harisinghani Imaging of Penile Neoplasms RadioGraphics, November 1, 2005; 25(6): 1629 - 1638. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| RADIOLOGY | RADIOGRAPHICS | RSNA JOURNALS ONLINE |
