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Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005: pp. 2813-2821 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.07.166 Diagnostic Performance of Nanoparticle-Enhanced Magnetic Resonance Imaging in the Diagnosis of Lymph Node Metastases in Patients With Endometrial and Cervical CancerFrom the Departments of Radiology, Gyneoncology and Histopathology, St Bartholomew's Hospital; Department of Radiology, Royal Marsden Hospital, London, United Kingdom; and Department of Radiology, Massachusetts General Hospital, Boston, MA Address reprint requests to A.G. Rockall, FRCR, Department of Radiology, Dominion House, St Bartholomew's Hospital, W Smithfield, London EC1A 7ED, United Kingdom; e-mail: a.g.rockall{at}qmul.ac.uk
PURPOSE: Lymph node metastases affect management and prognosis of patients with gynecologic malignancies. Preoperative nodal assessment with computed tomography or magnetic resonance imaging (MRI) is inaccurate. A new lymph node–specific contrast agent, ferumoxtran-10, composed of ultrasmall particles of iron oxide (USPIO), may enhance the detection of lymph node metastases independent of node size. Our aim was to compare the diagnostic performance of MRI with USPIO against standard size criteria. METHODS: Forty-four patients with endometrial (n = 15) or cervical (n = 29) cancer were included. MRI was performed before and after administration of USPIO. Two independent observers viewed the MR images before lymph node sampling. Lymph node metastases were predicted using size criteria and USPIO criteria. Lymph node sampling was performed in all patients.
RESULTS: Lymph node sampling provided 768 pelvic or para-aortic nodes for pathology, of which 335 were correlated on MRI; 17 malignant nodes were found in 11 of 44 patients (25%). On a node-by-node basis, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) by size criteria were 29%*, 99%, 56%, and 96%, and by USPIO criteria (reader 1/reader 2) were 93%/82%* (*P = .008/.004), 97%/97%, 61%/59%, and 100%/99%, respectively (where [*] indicates the statistical difference of P = x/x between the two results marked by the asterisk). On a patient-by-patient basis, sensitivity, specificity, PPV, and NPV by size criteria were 27%*, 94%, 60%, and 79%, and by USPIO criteria (reader 1/reader 2) were 100%/91%* (*P = .031/.06), 94%/87%, 82%/71%, and 100%/96%, respectively. The CONCLUSION: Lymph node characterization with USPIO increases the sensitivity of MRI in the prediction of lymph node metastases, with no loss of specificity. This may greatly improve preoperative treatment planning.
In patients with cervical and endometrial cancer, the presence of lymph node metastases suggests poor prognosis, with a marked decrease in 5-year survival rate.1,2 Lymph node involvement is also an important factor in the choice of adjuvant radiotherapy in both endometrial and cervical cancer.3 Surgical lymph node assessment is the gold standard for the diagnosis of lymph node metastases.4 However, surgical lymphadenectomy is specialized and increases the time and cost of the procedure, with an increased risk of immediate and delayed complications to the patient.5-7 Therefore, a noninvasive technique that accurately identifies lymph node metastases would be beneficial. Computed tomography (CT) and magnetic resonance imaging (MRI) may be used to predict lymph node metastases. However, there are no reliable discernible morphologic criteria to differentiate benign nodes from those containing metastases. Size criteria may predict the likelihood of nodal metastases, using a threshold value above which the node is considered malignant. However, nodes that are smaller than the threshold may harbor metastatic deposits. Conversely, a node that is larger than the threshold value may be benign. This problem is reflected in the diagnostic performance of MRI and CT in lymph node staging, in which sensitivities for lymph node metastases in gynecologic cancers range from 43% to 73%.8-11 A lymph node–specific MR contrast agent has been developed that allows the identification of malignant nodal infiltration independent of the lymph node size. This novel MR contrast agent is classified as a nanoparticle (mean diameter, 30 nm), and is composed of an iron oxide core, coated with low molecular weight dextran. The class of these MR contrast agents is collectively known as ultrasmall particles of iron oxide (USPIO). The particles, which are administered intravenously, are taken up by macrophages in the reticuloendothelial system, predominantly within the lymph nodes.12 Uptake of USPIO results in marked loss of signal intensity (darkening) of the node on T2- and T2*-weighted sequences because of a susceptibility artifact caused by the iron. Metastatic tissue within a node displaces the normal macrophages, thus preventing uptake of contrast agent, and the node continues to remain high in signal intensity. The aim of this study was to assess the diagnostic performance of USPIO-enhanced MRI (USPIO-MRI) in predicting nodal metastases within pelvic and para-aortic lymph nodes in patients with cancer of the endometrium and cervix.
Patients The local research ethics committee approved the study. Off-license use of USPIO (Sinerem, Guerbet, France) was approved by the Medical Controls Agency, United Kingdom. All patients were older than 18 years and provided written informed consent. All patients were recruited at two large tertiary care academic centers. Patients were enrolled if they had confirmed cervical or endometrial carcinoma and surgical lymphadenectomy was planned. Exclusion criteria included a history of allergy to iron treatment or a previous allergy to USPIO. Forty-four patients completed the protocol (Table 1). Fourteen additional patients (eight with cervical carcinoma and six with endometrial carcinoma) were recruited but did not complete the protocol: six were treated nonsurgically, five had surgery but no lymphadenectomy, and three did not complete the USPIO infusion (see Administration of Contrast).
Imaging All patients were imaged as part of their standard preoperative assessment. T1-weighted axial images were obtained though the upper abdomen and pelvis (repetition time in msec [TR], 500 to 540; echo time in msec [TE], 8 to 9; slice width, 4 to 8 mm; interslice gap, 0 to 2 mm; number of acquisitions, two; field of view, 30 x 30 to 42 x 42 cm; matrix, 256 x 256); T2-weighted axial, sagittal, and oblique axial images were obtained through the pelvis (TR, 3,333 to 7,058; TE, 80 to 120 effective time; echo train length [ETL], 8; slice width, 3 to 4 mm; interslice gap, 0 to 1 mm; number of acquisitions, two; field of view, 24 x 24 cm; matrix, 256 x 256 to 512 x 512). Additional nodal imaging sequences included T2*-weighted gradient echo images in axial and oblique (aligned along the psoas muscle and external iliac vessels) planes (TR, 500 to 800; TE, 15 to 27; flip angle [FA], 30; slice width, 3.5 to 5 mm; interslice gap, 0 mm; number of acquisitions, two; field of view, 24 x 24 to 42 x 42 cm; matrix, 256 x 256 to 512 x 512). At 24 to 36 hours after the administration of USPIO, the T2- and T2*-weighted sequences used for the interpretation of lymph node status were repeated. Imaging was performed on a Signa 1.5T (GE Medical Systems, Milwaukee, WI) in 31 patients, Gyroscan Intera 1.5T system (Philips, Eindhoven, the Netherlands) in 11 patients, and a Symphony 1.5T (Siemens, Erlangen, Germany) in two patients.
Administration of Contrast
Image Interpretation
Size Criteria Several other threshold values for short-axis diameter were also applied above which the node was considered positive: more than 5, 8, and 9 mm, respectively.16
USPIO Criteria
Surgery Nodal status was discussed with the surgeon before lymphadenectomy. Careful identification of the nodes was made at the time of surgery, using a combination of the MR images and diagrams or with the attendance of the radiologist in the operating room. Resected nodes were anatomically labeled. In three patients, image-guided percutaneous biopsy or fine needle aspirate of a lymph node was performed, in accordance with clinical preference (Table 1).
Histopathology
Statistics
In differentiating between benign and malignant nodes, ROC curve analysis was also performed. The confidence scores of the readers 1 and 2 in identifying benign and malignant nodes were compared with the final histologic diagnosis using ROC analysis. ROC curves were also calculated for short-axis diameter in millimeters and the size ratio criteria. The mean areas under the ROC curves were determined. The ROC curve analysis was performed on nodes with complete data sets, thereby excluding the five learning curve cases in which confidence scores were only available from one reader in each sample. Thus 279 nodes were suitable for inclusion in the ROC curve analysis. Interobserver variability for USPIO-MRI was calculated using the  statistic. Interobserver variability for nodal size was measured using the mean coefficient of variability.
A total of 768 lymph nodes sampled from the pelvic side wall and para-aortic regions were available for pathology, 17 of which were malignant (2.2%). A mean of 17.5 nodes were harvested per patient (range, one to 41); 11 of 44 patients (25%) had one or more positive nodes and 335 nodes could be anatomically correlated with the magnetic resonance images. The diagnostic performance of size criteria and USPIO criteria were assessed on a node-by-node basis (Table 3) and on a patient-by-patient basis (where a patient is considered to have nodal involvement if one or more nodes are diagnosed as malignant; Table 2). On a node-by-node basis, the sensitivity for the detection of malignant nodes using the size ratio was 0.29 (95% CI, 0.10 to 0.56); the sensitivity using USPIO criteria for reader 1 was 0.93 (95% CI, 0.66 to 1.00; P = .008), and the sensitivity for reader 2 was 0.82 (95% CI, 0.57 to 0.96; P = .004). On a patient-by-patient basis, the sensitivity using size ratio was 0.27 (95% CI, 0.06 to 0.61); the sensitivity using USPIO criteria for reader 1 was 1.00 (95% CI, 0.66 to 1.00; P = .03), and the sensitivity for reader 2 was 0.91 (95% CI, 0.59 to 1.00; P = .06).
ROC curve analysis (Fig 6) shows the area under the curve for short-axis diameter was 0.832 (95% CI, 0.686 to 0.978); for size ratio, the area under the curve was 0.621 (95% CI, 0.391 to 0.851). For USPIO-MRI reader 1, the area under the curve was 0.981 (95% CI, 0.966 to 0.997) and for reader 2, the area under the curve was 0.991 (95% CI, 0.981 to 1.001). Therefore, overall diagnostic performance of readers 1 and 2 using USPIO-MRI is better than that obtained using size ratio.
In four of the 44 patients, several small parametrial nodes were identified within the tissue block of the resected uterus, separate from lymph node dissection. These four patients had a primary diagnosis of cervical carcinoma. Seven of these nodes contained metastatic deposits. These nodes could not be identified in retrospect on the MR images either before or after USPIO administration. If these nodes are included in the node-by-node analysis, then the sensitivity for size criteria using the size ratio was 0.21 (95% CI, 0.07 to 0.42); sensitivity for reader 1 using USPIO criteria was 0.72 (95% CI, 0.46 to 0.90; P = .008), and sensitivity for reader 2 was 0.58 (95% CI, 0.37 to 0.78; P = .004), with a total of 10 false-negative nodal diagnoses (seven parametrial nodes and three pelvic side-wall nodes containing micrometastases, confirmed on immunostains). On a patient-by-patient analysis, when including the parametrial nodes, the sensitivity using the size ratio was 0.25 (95% CI, 0.05 to 0.57); using USPIO criteria, sensitivity for reader 1 was 0.90 (95% CI, 0.55 to 1.00; P = .03), and sensitivity for reader 2 was 0.83 (95% CI, 0.52 to 0.98; P = .06). Altogether, there were two patients with false-negative results: one patient with a false-negative result had two side-wall nodes containing micrometastases as well as three positive parametrial nodes (this was a learning curve patient for reader 1); the second patient with a false-negative result had a single, 4-mm paracervical/parametrial node that could not be seen in retrospect. The remainder of the 25 nodes dissected in this patient were correctly predicted to be benign on USPIO-MRI. False-positive diagnoses on USPIO-MRI (three patients, reader 1; five patients, reader 2) occurred in the following situations. A false-positive result was obtained for a patient in whom extensive local and distant recurrent disease was diagnosed on follow-up CT scan within 3 months of her surgery. This suggests that the positive diagnosis on USPIO-MRI may have been correct but the node suggestive of metastasis was not surgically resected, even though 41 nodes were collected. A false-positive result was obtained in two patients in whom at least one node was histologically positive but in whom USPIO-MRI diagnosed additional nodes. A false-positive result was obtained in four patients in whom no nodal metastasis was present histologically and in whom there was no recurrent nodal disease within 6 months of follow-up. In these latter four patients, misinterpretation was due to a fatty hilum (one patient) heterogeneous signal within a node (two patients); in the fourth patient, all three readers diagnosed metastatic para-aortic nodes with a confidence score of 5, but the patient had concomitant infected pelvic lymphoceles. It is possible that the presence of lymphoceles, secondary to an extensive lymph node dissection in the previous 6 months, may have affected contrast uptake because of disruption of the normal lymph channels. Currently, we do not know what effect previous lymph node dissection of lymphocele has on USPIO uptake. Interobserver variability (Table 4) was good to very good. The mean coefficient of variability for lymph node size measurements between reader 1 and reader 2 was 0.06 (standard deviation, 0.05).
Our results demonstrate a significant increase in the sensitivity, with no loss of specificity, for the noninvasive detection of malignant lymph nodes in patients with cervical and endometrial cancer. This was seen on a node-by-node basis, for which the sensitivity increased from 29% using standard size criteria to 93% using USPIO criteria. This increase in sensitivity was seen to a greater extent on a patient-by-patient basis, for which the sensitivity increased from 27% using standard size criteria to 100% using USPIO criteria. Only one patient with cervical cancer metastatic to lymph nodes along the pelvic side wall had a false-negative result using USPIO criteria by one reader. One patient with a single 4-mm metastatic node within the parametrial tissues also had a false-negative result. All patients with endometrial cancer metastatic to lymph nodes were correctly identified. Nodal size is the current standard criterion for the prediction of metastases to lymph nodes on cross-sectional imaging. There is some variability in the size threshold used by different groups, but the most widely used threshold value for identifying malignant lymph nodes in the literature is 10 mm short-axis diameter.8,19,20 Our results demonstrate a clear improvement when compared with this threshold level. More recently, a size ratio has been used whereby indeterminate-sized nodes (8 to 10 mm) that are round are considered malignant.14 Our results show a clear improvement when compared with this threshold. Setting a lower short-axis diameter threshold value for diagnosis of malignant nodes improves sensitivity but with a corresponding decrease in the specificity. This is reflected in the ROC curve analysis in which the area under the curve for using short-axis diameter as the diagnostic tool was 0.834 compared with 0.991 using USPIO criteria (although close confidence intervals were observed), reflecting the small number of positive nodes in our group of patients. Contrast administration was generally well tolerated; flushing or a rash was the most frequent symptom. Contrast administration was stopped in 5% of patients, as a precaution, but no patient had any significant sequelae as a result of the infusion. The MRI sequences used in our study are widely available on most MR systems independent of vendor platforms, and image analysis does not require any additional software. False-negative diagnoses were predominantly due to our failure to identify nodes in the parametrial tissues, both before and after USPIO administration, as well as in retrospect. This may be due to limitations of our MRI technique, in which we set out specifically to diagnose the pelvic side-wall nodes, which are well seen on MRI and are the traditional focus for radiologists attempting preoperative lymph node diagnosis. Future improvements in technique may help prevent this problem. However, the parametrial tissues frequently contain an extensive plexus of serpiginous veins, and the identification of parametrial nodes is likely to remain challenging. Currently, the parametrial tissues are removed at primary surgery in most patients with cervical carcinoma; thus, preoperative diagnosis at this site may not have an impact on decision making. No positive parametrial nodes were diagnosed at histology in patients with endometrial carcinoma. This may be due to a difference in surgical technique: endometrial carcinoma is not commonly treated by radical hysterectomy; it is usually treated by simple hysterectomy, and thus the parametrial tissues are not available for histologic assessment. Micrometastases are also likely to remain a challenge because of limitations in the spatial resolution of MRI systems. False-positive diagnoses may reflect incomplete nodal dissection, in which a node may have been inaccessible to or not seen by the surgeon. In these patients, it may be postulated that USPIO-MRI provides a more complete anatomic map of the lymph node involvement. However, false-positive interpretation also occurred where a node seemed heterogeneous or where a fatty hilum was misinterpreted as a deposit. In addition, the presence of bilateral infected pelvic lymphoceles in one patient may have altered the contrast uptake into the nodes. These misinterpretations may be related to learning curves or possibly due to technical factors. Our findings support earlier published results of USPIO-MRI in other tumors, either in head and neck or breast, or in patients with a tumor in the abdomen or pelvis.21-24 A recently published study restricted to patients with prostate cancer showed the sensitivity for nodal staging using USPIO criteria was 90.5%—significantly greater than that achieved using size criteria, which had a sensitivity of 35.4%.15 On a patient-by-patient basis, the same study had a sensitivity of 100% for detecting patients with one or more positive nodes. USPIO-MRI has the potential to improve the surgical and nonsurgical management of patients with cervical and endometrial carcinoma in several ways. First, the preoperative localization of malignant nodes may allow tailoring of the surgical lymphadenectomy, allowing rapid collection of any node suggestive of metastasis for frozen section, and by directing the surgeon to a node suggestive of metastasis at a site not usually accessed. This tailored approach may reduce both surgical time and morbidity without a reduction in diagnostic yield. Second, when USPIO-MRI is negative, surgical lymph node sampling could be avoided altogether, with a high degree of confidence. This could be of particular value when surgical risks such as obesity and diabetes are present. Third, USPIO-MRI could accurately map the extent of lymph node involvement in both the pelvis and para-aortic regions to define the radiotherapy fields. This is particularly relevant with the development of intensity-modulated radiotherapy, in which the shape of the field may be closely tailored to the individual patient. In conclusion, USPIO-MRI improves the preoperative characterization of lymph node metastases compared with standard MRI. This information may provide the clinician with important information in planning the optimal surgical or radiotherapy treatment.
Andrea Rockall obtained ethics approval, Medical Control Agency approval, and BUPA Foundation Grant (London, UK); recruited patients; interpreted images, analyzed data, and was the primary author of the manuscript. S. Aslam Sohaib recruited patients at the Royal Marsden Hospital, interpreted images, prepared the manuscript, and analyzed data. M. Harisinghani provided advice on MRI sequences, interpreted images, and provided advice on the manuscript. S. Babar recruited patients and assisted with data collection. N. Singh performed node histopathology. I. Jacobs, D. Oram, A. Jeyarajah, and J. Shepherd sampled surgical lymph nodes and provided advice on the manuscript. R. Reznek acted as the senior supervisor and performed data interpretation.
The authors indicated no potential conflicts of interest.
We thank Peter A. Armstrong for reading and commenting on the manuscript and Roger A'Hern for statistical advice.
Supported by the BUPA Foundation, London, United Kingdom. Presented in abstract form at the 2nd Annual Meeting of the International Cancer Imaging Society, Paris, France, October 2002, 15th Annual European Congress of Radiology, Vienna, Austria, March 7-11, 2003, and the 89th Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, IL, November 30-December 5, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
Pelvic Side Wall and Para-Aortic Lymph Nodes, Patient-by-Patient Analysis
