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Published online before print November 7, 2006, 10.1148/radiol.2421060093
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(Radiology 2007;242:137-143.)
© RSNA, 2006

Experimental Studies

Lymph Node Metastasis: Ultrasmall Superparamagnetic Iron Oxide–enhanced MR Imaging versus PET/CT in a Rabbit Model1

Seung Hong Choi, MD, Woo Kyung Moon, MD, Ju Hee Hong, MD, Kyu Ri Son, MD, Nariya Cho, MD, Bae Ju Kwon, MD, Jong Jin Lee, MD, June-Key Chung, MD, Hye Sook Min, MD and Seong Ho Park, MD

1 From the Department of Radiology and Clinical Research Institute, Seoul National University Hospital, and Institute of Radiation Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea (S.H.C., W.K.M., K.R.S., N.C., B.J.K.); Department of Radiology, College of Medicine, Chung Buk National University, Cheongju, Korea (J.H.H.); Departments of Nuclear Medicine (J.J.L., J.K.C.) and Pathology (H.S.M.), Seoul National University Hospital, Seoul, Korea; and Department of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (S.H.P.). Received January 16, 2006; revision requested March 22; revision received April 4; accepted May 9; final version accepted July 7. Supported by a grant from the National R & D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (0420080-1). Address correspondence to W.K.M. (e-mail: moonwk{at}radcom.snu.ac.kr).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively compare the diagnostic accuracy of ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging and integrated positron emission tomography–computed tomography (PET/CT) for the depiction of lymph node metastasis in an animal model, with histologic findings as the reference standard.

Materials and Methods: This experiment was approved by the local animal care committee. VX2 carcinoma was implanted into the thighs of 11 rabbits 4 weeks before the imaging study. T2- and T2*-weighted MR examinations were performed 24 hours after USPIO administration, followed by integrated PET/CT. USPIO-enhanced MR imaging and PET/CT analysis for the evaluation of the presence of metastasis in iliac lymph nodes were performed independently by two radiologists and two nuclear medicine physicians, respectively, without histopathologic knowledge. Results were evaluated by using receiver operating characteristic (ROC) analysis, and sensitivities and specificities were compared by using a Z test.

Results: Metastases were histopathologically confirmed in 22 of 62 iliac lymph nodes. USPIO-enhanced MR imaging showed a significantly greater area under the ROC curve than did PET/CT (0.984 vs 0.852; P = .023). The respective sensitivity and specificity for the detection of lymph node metastasis were 91% (20 of 22) and 95% (38 of 40) for USPIO-enhanced MR imaging and 64% (14 of 22) and 98% (39 of 40) for PET/CT. In terms of sensitivity, a significant difference was found between USPIO-enhanced MR imaging and PET/CT, particularly for nodal metastasis of less than 5 mm (86% [six of seven] vs 0% [zero of seven]; P = .031), whereas the specificity of the two imaging modalities was similar (P = .226).

Conclusion: USPIO-enhanced MR imaging results in higher diagnostic accuracy for depicting lymph node metastasis than does PET/CT.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
The coregistration of positron emission tomographic (PET) and computed tomographic (CT) images by using combined PET/CT systems has been shown to be of additional value for image interpretation of both modalities, providing complementary information for both techniques (1,2). The improved accuracy of fluorine 18 fluorodeoxyglucose (FDG) imaging in the evaluation of a malignant lymph node, which results in a clinical effect on patient care, has been described with the use of integrated PET/CT in patients with lung, colon, head and neck, and pelvic tumors (3–7). The reported sensitivity and specificity of PET/CT in the evaluation of malignant lymph nodes range from 78% to 89% and from 84% to 95%, respectively.

Contrast material–enhanced magnetic resonance (MR) lymphography is a potential noninvasive method for analysis of the lymphatic system after interstitial or intravenous administration of contrast media (8,9). The most widely evaluated intravenous contrast agent for lymphographic MR imaging are ultrasmall superparamagnetic iron oxide (USPIO) particles, which accumulate slowly in macrophages of the lymph nodes and show maximum lymphographic effect 24 hours after administration (10–12). The nonphagocytic metastatic tissues remain unchanged on USPIO-enhanced MR images. Several studies have demonstrated enhanced sensitivity and specificity for lymph node evaluation after administration of ferumoxtran-10 (Combidex; Advanced Magnetics, Cambridge, Mass), a USPIO agent, for pelvic, head and neck, and chest malignancies (13–15). USPIO-enhanced MR imaging has shown similar results to those of PET/CT for the evaluation of malignant lymph nodes, with sensitivity and specificity of 79%–90.5% and 77%–98%, respectively. To our knowledge, however, there has been no report concerning direct comparison of USPIO-enhanced MR imaging versus PET/CT for the detection of lymph node metastasis. Thus, the purpose of our study was to prospectively compare the diagnostic accuracy of USPIO-enhanced MR imaging and integrated PET/CT for the depiction of lymph node metastasis in an animal model, with histologic findings as the reference standard.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Animal Preparation
The experiments were performed in 11 New Zealand white rabbits that weighed 2.5–3.0 kg. This experiment was approved by the animal care committee at Seoul National University Hospital. The animals were allowed food and water ad libitum.

Tumor implantation was performed with an aseptic technique by two radiologists (S.H.C., K.R.S.) who worked together in performing all animal experiments. VX2 carcinoma was inoculated intramuscularly into either the right or the left thigh with 1 mL of tumor suspension by using an 18-gauge needle to produce metastases in iliac lymph nodes. The right or the left thigh was chosen by using a table of random numbers. The experimental VX2 rabbit carcinoma was prepared in a manner reported previously (16). MR imaging and PET/CT were performed 4 weeks after injection of tumor cells, and the rabbits were sacrificed after MR imaging and PET/CT for imaging and histopathologic comparison (Fig 1).


Figure 1
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  		Figure 1: Flow chart shows the study process of the 11 New Zealand white rabbits.

 
MR Contrast Material
Monocrystalline iron oxide nanoparticle (MION)-47 consists of USPIO particles coated with dextran and has a relaxivity (r1) of about 21.9 L · mmol–1 · sec–1 and a relaxivity (r2) of about 44.6 L · mmol–1 · sec–1 at 0.47 T, 37°C in water (17). The concentration of iron in a USPIO agent is 11.22 mg of iron per milliliter of 20 mmol sodium citrate at pH 8, and the mean particle size is 27.3 nm (17). These USPIO particles accumulate slowly in the macrophages of lymph nodes and show maximum lymphographic effect 24 hours after intravenous administration (10). MION-47 is a laboratory-based agent that has not been tested in human subjects.

MR Imaging and PET/CT
During MR imaging and PET/CT, animals were sedated with an intramuscular injection of 50 mg of ketamine hydrochloride (Ketalar; Yuhan Yanghang, Seoul, Korea) and 20 mg of xylazine hydrochloride (Rompun; Bayer, Seoul, Korea) at 0.5 mL per kilogram of body weight. At day 1, precontrast MR imaging was performed, and USPIO-enhanced MR images were obtained the following day. The animals rested for 4–38 hours (mean, 23.6 hours) after completion of MR imaging, and then PET/CT scanning was performed. In our study, MR imaging was performed first and was followed by PET/CT owing to the availability of the facilities. The imaging range was from the midabdomen through the upper thigh. Animals were imaged in the supine position.

MR imaging.—All examinations were performed with a 1.5-T MR imaging system (Signa; GE Medical Systems, Milwaukee, Wis) and a knee coil to improve the resolution. After routine localization images were obtained, coronal T2-weighted spin-echo (repetition time msec/echo time msec, 5000/85; echo train length, 16; section thickness, 2 mm; field of view, 12 cm; matrix, 256 x 256; number of signals acquired, three), T2*-weighted two-dimensional gradient-echo (400/24; flip angle, 20°; section thickness, 2 mm; field of view, 12 cm; matrix, 256 x 256; number of signals acquired, two), and T1-weighted spin-echo (400/12; section thickness, 2 mm; field of view, 12 cm; matrix, 256 x 256; number of signals acquired, two) images were acquired. After precontrast MR imaging, USPIO (2.6 mg of iron per kilogram in 10 mL of normal saline) was administered to each animal via an ear vein during approximately 10 minutes. Coronal T2-weighted spin-echo and T2*-weighted two-dimensional gradient-echo MR images were acquired 24 hours after USPIO administration. The imaging techniques, including imaging plane, section thickness, and imaging parameters, for MR sequences used in this study were selected to depict the pelvic lymph nodes in rabbits.

PET/CT scanning.—Rabbits fasted for at least 4 hours before the intravenous injection of 37 MBq (1 mCi) FDG. Before scanning, urinary voiding was performed with a 6-F urinary catheter. Scanning was performed by using a dual-modality PET/CT scanner (Gemini; Philips Medical Systems, Milpitas, Calif). This is an open PET/CT system that consists of the MX8000 dual-section CT scanner and the Allegro PET scanner arranged in a separable configuration. CT was performed first (120 kV, 50 mA, 512 x 512 matrix, 0.5 second per rotation, and pitch of 1.5), and PET was performed immediately after acquisition of the CT images. Emission measurement was conducted in a three-dimensional mode with a 256 x 256 matrix. Emission scan time per bed position was 2.5 minutes; nine bed positions (field of view, 160 mm) were acquired. PET images were reconstructed by using an ordered-set expectation-maximization algorithm. CT data were used for attenuation correction, and helical CT scans were reconstructed with a section thickness of 4 mm to match the parameters of the PET scans.

Isolation of Lymph Nodes and Histopathologic Examination
After MR imaging and PET/CT, the tumor-bearing rabbits were sacrificed with a lethal dose (90 mg/kg) of intravenously administered sodium pentobarbital (Pentothal; Choong Wae Pharmacy, Seoul, Korea). The iliac lymph nodes were isolated by one author (S.H.C.) and were dissected with the surrounding tissue, labeled for orientation and location, and fixed with 10% formalin. The lymph nodes were embedded in paraffin, and the prepared sections (approximately 5 µm thick) in the coronal plane with a 0.5-mm interval were stained with hematoxylin-eosin for microscopic examination by a pathologist (H.S.M., 4 years of experience in interpreting lymph node metastasis) with regard to the presence of a metastasis and its size and the location and presence of necrosis in the metastatic foci. Each lymph node was recorded with regard to long- and short-axes diameter in the largest section, and the maximal diameter of metastasis focus was measured.

Image Analysis
Image analysis was performed before pathologic results were known, and the images were presented in random order. For objectivity and reproducibility of the image analysis in this study, the criteria for a malignant lymph node were provided.

MR imaging.—All images were analyzed by two radiologists (W.K.M., B.J.K., with 15 and 5 years of experience, respectively, interpreting MR imaging studies) in consensus. MR images were reviewed on a picture archiving and communication system (PACS; Marotech, Seoul, Korea) workstation. A lymph node with an area of high signal intensity—encompassing the entire node or a portion of it—on T2- or T2*-weighted MR images after the administration of USPIO was considered malignant, and a node with fatty hilum, a complete signal void, and speckles of granularity without a definite focus of high signal intensity was considered nonmalignant (13,14). In addition, a node with central low signal intensity on T2*-weighted MR images after the administration of USPIO was considered nonmalignant (15).

PET/CT.—All images were interpreted in consensus by two nuclear medicine physicians (J.J.L., J.K.C.) with experience in interpretation of PET/CT images. With regard to reader experience, a PET/CT system was installed in the department in November 2003, and, on average, these two reviewers interpret 12 studies daily in consensus. Images were interpreted at a workstation equipped with fusion software (Syntegra; Philips Medical Systems) that enables display of PET images with and without attenuation correction, CT images, and PET/CT images. When an area of presumed metastatic lymph node showed focally prominent FDG uptake compared with the background activity, the node was considered to be positive for malignancy (3–7).

Confidence level.—The reviewers recorded the presence and location of presumed metastatic lymph nodes and assigned a confidence level for the diagnosis of metastasis in each node. Diagnostic confidence for each node was subjectively scored on a five-point scale (score of 0, no metastasis; 1, metastasis probably absent; 2, metastasis possibly present; 3, metastasis probably present; 4, metastasis definitely present). Before interpreting the images, the reviewers were informed that the categorization of confidence levels of 2 or higher represented a positive diagnosis of lymph node metastasis.

In false-negative cases, USPIO-enhanced MR images or PET/CT images were retrospectively reviewed by the same reviewers who had prospectively assessed the images to investigate the known reasons for the failure (eg, small metastases below the resolution of the scanner, misinterpretation or technical factors) (18,19). Small metastases of less than 2 mm at USPIO-enhanced MR imaging and less than 5 mm at PET/CT were regarded as below the current detection thresholds (1,13,20). In false-positive cases, the findings of USPIO-enhanced MR images or PET/CT images were also retrospectively analyzed by the same reviewers to determine the causes of these misinterpretations.

Statistical Analysis
For all statistical analyses, a two-tailed P value of less than .05 was considered to indicate a statistically significant difference. Statistical analyses were performed by using commercially available software (MedCalc, version 8.0.0.1; MedCalc, Mariakerke, Belgium).

A receiver operating characteristic (ROC) analysis was performed to compare the diagnostic performance of USPIO-enhanced MR imaging and PET/CT for the detection of lymph node metastases, with histologic findings as the reference standard. The diagnostic accuracy of each imaging modality was estimated by calculating the area under the ROC curve. Two paired ROC curves were compared by means of a Z test, as described by Hanley and McNeil (21).

The sensitivity and specificity of the two modalities were calculated, along with 95% confidence intervals. For sensitivity, results were also provided according to the size of lymph node metastasis (< 5 mm and ≥5 mm). Data clustering (ie, more than one lesion per rabbit) was accounted for with the method of Rao and Scott (22). Statistical differences were evaluated with a Z test by comparing the sensitivity and specificity of USPIO-enhanced MR imaging and PET/CT; at Z testing, estimates of variance and covariance were weighted for data clustering in rabbits (23).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Histopathologic Findings
Sixty-two iliac lymph nodes were isolated from 11 rabbits, and metastasis was found in 22 iliac lymph nodes in nine rabbits. The mean long-axis nodal size of malignant and benign lymph nodes was 8.6 mm ± 2.7 (standard deviation) (range, 3.0–16 mm) and 5.3 mm ± 1.3 (range, 3.3–9.2 mm), respectively, and the mean short-axis nodal size was 6.3 mm ± 2.2 (range, 2.0–10 mm) and 3.7 mm ± 0.5 (range, 2.8–5.3 mm), respectively. Maximal diameters of metastatic foci ranged from 1.3 to 15 mm (mean, 7.0 mm ± 3.4) in the 22 metastatic lymph nodes; seven were less than 5 mm and 15 were 5 mm or greater in maximal diameter. Focal necrosis was identified in nine nodal metastatic foci; maximal diameters of metastatic foci having focal necrosis ranged from 8 to 15 mm (mean, 10.2 mm ± 2.0).

ROC Analysis, Sensitivity, and Specificity
USPIO-enhanced MR imaging demonstrated a significantly greater area under the ROC curve than did PET/CT (0.984 vs 0.852; P = .023) (Table). Sensitivity and specificity for the detection of lymph node metastasis were, respectively, 91% (20 of 22; 95% confidence interval: 68%, 100%) and 95% (38 of 40; 95% confidence interval: 76%, 100%) for USPIO-enhanced MR imaging and 64% (14 of 22; 95% confidence interval: 41%, 87%) and 98% (39 of 40; 95% confidence interval: 79%, 100%) for PET/CT. In terms of sensitivity, there was a significant difference between the two modalities (P = .035), particularly for nodal metastasis of less than 5 mm (86% [six of seven] vs 0% [zero of seven]; P = .031), whereas there was no significant difference in specificity between USPIO-enhanced MR imaging and PET/CT (P = .226).


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  		ROC Analysis and Sensitivity and Specificity in Detection of Metastatic Lymph Nodes

 
USPIO-enhanced MR imaging enabled detection of six additional metastatic lymph nodes that were not detected with PET/CT, whereas 14 of 22 metastatic lymph nodes were detected with both modalities (Fig 2) and none were detected with PET/CT only. PET/CT could not depict seven metastatic foci of less than 5 mm. The sizes of eight metastatic foci in lymph nodes, which were not depicted at PET/CT, ranged from 1.3 to 6.0 mm (mean, 3.6 mm ± 1.4). At USPIO-enhanced MR imaging, only two lymph node metastases were not detected, of which the sizes of metastatic foci were 1.3 and 6 mm. In addition, all nine nodal metastases with necrosis were detected with both modalities.


Figure 2
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  		Figure 2a: Images of two left iliac lymph nodes (arrow and arrowheads in a–f) in a rabbit 4 weeks after VX2 tumor inoculation in prone position. (a) Coronal T1-weighted spin-echo MR image (400/12) before USPIO injection shows nodes with low signal intensity. T2*-weighted gradient-echo MR images (400/24, flip angle of 20°) obtained (b) before and (c) 24 hours after USPIO injection show nodes with high signal intensity. Node indicated by arrow in c shows less increased signal intensity than that indicated by arrowheads, which is probably due to relatively preserved functional lymphatic tissues in node indicated by arrow. (d) CT, (e) PET, and (f) integrated PET/CT images show intense foci of FDG uptake in nodes. (g) Photomicrograph of histopathologic specimen shows nodes nearly completely replaced by malignant tissue (arrows and arrowheads). (Hematoxylin-eosin stain; original magnification, x5.)

 

Figure 2
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  		Figure 2b: Images of two left iliac lymph nodes (arrow and arrowheads in a–f) in a rabbit 4 weeks after VX2 tumor inoculation in prone position. (a) Coronal T1-weighted spin-echo MR image (400/12) before USPIO injection shows nodes with low signal intensity. T2*-weighted gradient-echo MR images (400/24, flip angle of 20°) obtained (b) before and (c) 24 hours after USPIO injection show nodes with high signal intensity. Node indicated by arrow in c shows less increased signal intensity than that indicated by arrowheads, which is probably due to relatively preserved functional lymphatic tissues in node indicated by arrow. (d) CT, (e) PET, and (f) integrated PET/CT images show intense foci of FDG uptake in nodes. (g) Photomicrograph of histopathologic specimen shows nodes nearly completely replaced by malignant tissue (arrows and arrowheads). (Hematoxylin-eosin stain; original magnification, x5.)

 

Figure 2
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  		Figure 2c: Images of two left iliac lymph nodes (arrow and arrowheads in a–f) in a rabbit 4 weeks after VX2 tumor inoculation in prone position. (a) Coronal T1-weighted spin-echo MR image (400/12) before USPIO injection shows nodes with low signal intensity. T2*-weighted gradient-echo MR images (400/24, flip angle of 20°) obtained (b) before and (c) 24 hours after USPIO injection show nodes with high signal intensity. Node indicated by arrow in c shows less increased signal intensity than that indicated by arrowheads, which is probably due to relatively preserved functional lymphatic tissues in node indicated by arrow. (d) CT, (e) PET, and (f) integrated PET/CT images show intense foci of FDG uptake in nodes. (g) Photomicrograph of histopathologic specimen shows nodes nearly completely replaced by malignant tissue (arrows and arrowheads). (Hematoxylin-eosin stain; original magnification, x5.)

 

Figure 2
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  		Figure 2d: Images of two left iliac lymph nodes (arrow and arrowheads in a–f) in a rabbit 4 weeks after VX2 tumor inoculation in prone position. (a) Coronal T1-weighted spin-echo MR image (400/12) before USPIO injection shows nodes with low signal intensity. T2*-weighted gradient-echo MR images (400/24, flip angle of 20°) obtained (b) before and (c) 24 hours after USPIO injection show nodes with high signal intensity. Node indicated by arrow in c shows less increased signal intensity than that indicated by arrowheads, which is probably due to relatively preserved functional lymphatic tissues in node indicated by arrow. (d) CT, (e) PET, and (f) integrated PET/CT images show intense foci of FDG uptake in nodes. (g) Photomicrograph of histopathologic specimen shows nodes nearly completely replaced by malignant tissue (arrows and arrowheads). (Hematoxylin-eosin stain; original magnification, x5.)

 

Figure 2
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  		Figure 2e: Images of two left iliac lymph nodes (arrow and arrowheads in a–f) in a rabbit 4 weeks after VX2 tumor inoculation in prone position. (a) Coronal T1-weighted spin-echo MR image (400/12) before USPIO injection shows nodes with low signal intensity. T2*-weighted gradient-echo MR images (400/24, flip angle of 20°) obtained (b) before and (c) 24 hours after USPIO injection show nodes with high signal intensity. Node indicated by arrow in c shows less increased signal intensity than that indicated by arrowheads, which is probably due to relatively preserved functional lymphatic tissues in node indicated by arrow. (d) CT, (e) PET, and (f) integrated PET/CT images show intense foci of FDG uptake in nodes. (g) Photomicrograph of histopathologic specimen shows nodes nearly completely replaced by malignant tissue (arrows and arrowheads). (Hematoxylin-eosin stain; original magnification, x5.)

 

Figure 2
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  		Figure 2f: Images of two left iliac lymph nodes (arrow and arrowheads in a–f) in a rabbit 4 weeks after VX2 tumor inoculation in prone position. (a) Coronal T1-weighted spin-echo MR image (400/12) before USPIO injection shows nodes with low signal intensity. T2*-weighted gradient-echo MR images (400/24, flip angle of 20°) obtained (b) before and (c) 24 hours after USPIO injection show nodes with high signal intensity. Node indicated by arrow in c shows less increased signal intensity than that indicated by arrowheads, which is probably due to relatively preserved functional lymphatic tissues in node indicated by arrow. (d) CT, (e) PET, and (f) integrated PET/CT images show intense foci of FDG uptake in nodes. (g) Photomicrograph of histopathologic specimen shows nodes nearly completely replaced by malignant tissue (arrows and arrowheads). (Hematoxylin-eosin stain; original magnification, x5.)

 

Figure 2
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  		Figure 2g: Images of two left iliac lymph nodes (arrow and arrowheads in a–f) in a rabbit 4 weeks after VX2 tumor inoculation in prone position. (a) Coronal T1-weighted spin-echo MR image (400/12) before USPIO injection shows nodes with low signal intensity. T2*-weighted gradient-echo MR images (400/24, flip angle of 20°) obtained (b) before and (c) 24 hours after USPIO injection show nodes with high signal intensity. Node indicated by arrow in c shows less increased signal intensity than that indicated by arrowheads, which is probably due to relatively preserved functional lymphatic tissues in node indicated by arrow. (d) CT, (e) PET, and (f) integrated PET/CT images show intense foci of FDG uptake in nodes. (g) Photomicrograph of histopathologic specimen shows nodes nearly completely replaced by malignant tissue (arrows and arrowheads). (Hematoxylin-eosin stain; original magnification, x5.)

 
False-Negative and False-Positive Nodes
A single false-negative case of USPIO-enhanced MR imaging and all false-negative cases of PET/CT were attributed to small metastases below the resolution of the scanner. The 6-mm metastasis not detected at USPIO-enhanced MR imaging was attributed to motion artifact due to the small bowel. The two false-positive cases of USPIO-enhanced MR imaging showed an uneven signal intensity decrease of peripheral functional tissue; these were reactive lymph nodes at histopathologic examination. The one false-positive PET/CT case was due to misinterpretation of focal physiologic uptake in the bowel.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Our ROC analysis results show that USPIO-enhanced MR imaging had a significantly higher diagnostic accuracy for depicting metastatic lymph nodes than did PET/CT (area under the ROC curve, 0.984 vs 0.852; P = .023). USPIO-enhanced MR imaging depicted six additional metastatic lymph nodes smaller than 5 mm that were not detected at PET/CT. As a result, USPIO-enhanced MR imaging had a higher sensitivity (91% [20 of 22]) than PET/CT (64% [14 of 22]) and there was a significant difference (P = .035). However, there was no significant difference in specificity between USPIO-enhanced MR imaging and PET/CT (95% [38 of 40] vs 98% [39 of 40], P = .226).

In our study, the lower disease detection thresholds at USPIO-enhanced MR imaging and PET/CT were 2 and 6 mm, respectively, which are very similar to the results obtained in various clinical trials (3–7,13–15,20). USPIO-enhanced MR imaging allows identification of metastatic foci within the lymph nodes independently of the lymph node size. In our study, USPIO-enhanced MR imaging depicted all but one nodal metastasis smaller than 5 mm in size. A small lesion, however, can be undetected at USPIO-enhanced MR imaging because T2*-weighted imaging is extremely sensitive to magnetic susceptibility effects (14). It has also been suggested that micrometastases in the germinal center may not be seen at USPIO-enhanced MR imaging owing to the scarcity of macrophages in that area (24). Although integrated PET/CT had improved the accuracy for detection of lymph node metastasis, the spatial resolution of PET is insufficient for detection of microscopic metastases to lymph nodes (20). If radionuclide uptake is not increased at PET, integrated PET/CT cannot provide further information.

Both USPIO-enhanced MR imaging and PET/CT had high specificity (95% and 98%, respectively). It is well known that an insufficient dose of contrast agent or delivery problems can cause false-positive findings at USPIO-enhanced MR imaging (18). In addition, when lymph nodes undergo reactive enlargement, the macrophages remain predominantly within the medullary sinus and the susceptibility effects of USPIO in a reactive lymph node can appear confined to the center of the node; thus, reactive change of a lymph node is also a potential cause of a false-positive finding at USPIO-enhanced MR imaging (16). Timing of USPIO-enhanced MR imaging, section thickness, and optimal echo time for a T2*-weighted sequence are also important to provide adequate contrast in a benign lymph node. Physiologic uptake can cause false-positive findings at PET/CT (19), although integrated PET/CT could potentially reduce the number of false-positive PET results by allowing physiologic variations in the uptake in a specific organ or structure to be adequately accounted for.

USPIO-enhanced MR imaging has limitations with regard to its further clinical applications. Evaluations require two MR examinations to be performed 24 hours apart. The first examination is used to evaluate the existence and location of the lymph nodes. Twenty-four hours after the injection of a USPIO, the second MR examination is performed to evaluate contrast enhancement of these identified lymph nodes. Moreover, since a USPIO cannot be used to evaluate primary tumor staging, another MR contrast agent is often needed for primary tumor evaluation. Therefore, further cost-effectiveness analysis in various conditions may be necessary to determine the appropriate clinical use of this technique (25,26).

Our study had some limitations. First, we imaged a relatively small focused area from the midabdomen through the upper thigh for the evaluation of iliac lymph nodes, which might have increased the sensitivity of USPIO-enhanced MR imaging, but the sensitivity of PET/CT was limited by its spatial resolution. The detection of nodal metastases with the two imaging modalities may have been overestimated because of the limited lymph node dissection in our study. Second, only coronal MR images were acquired to minimize image acquisition times, which might have decreased detection performance for lymph node metastasis at USPIO-enhanced MR imaging. Third, sequential imaging was performed in the same group of rabbits rather than separating the animals into two groups to minimize the number of animals in accord with our institution guidelines. This raises the issue of a potential interaction between USPIO and FDG; however, no data are available in the literature on this topic, to our knowledge. In the present study, FDG was injected at approximately 48 hours after USPIO administration. Fourth, the PET/CT protocol of the present study did not include contrast-enhanced CT scans, which might be a limitation for PET/CT evaluation.

In conclusion, in our animal studies USPIO-enhanced MR imaging had a higher sensitivity for the detection of lymph node metastasis than did PET/CT, which is ascribed to its improved detection of small metastases (<5 mm).

Practical application: In the field of oncologic imaging, the differentiation between malignant and benign lymph nodes is of major interest when determining the therapeutic plan. USPIO-enhanced MR imaging and PET/CT are known to be the most advanced imaging tools to improve the nodal staging accuracy in noninvasive manner. Our results with the described VX2 rabbit model indicate that USPIO-enhanced MR imaging is more sensitive at depicting lymph node metastasis than PET/CT, and future experimental and clinical investigations seem warranted.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: FDG = fluorine 18 fluorodeoxyglucose • ROC = receiver operating characteristic • USPIO = ultrasmall superparamagnetic iron oxide

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, S.H.C., W.K.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, S.H.C., W.K.M., J.H.H.; experimental studies, S.H.C., W.K.M., K.R.S., B.J.K., J.J.L., J.K.C., H.S.M.; statistical analysis, S.H.C., W.K.M., B.J.K., S.H.P.; and manuscript editing, S.H.C., W.K.M., J.H.H., N.C., B.J.K., J.K.C., H.S.M.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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