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Characterization of Focal Hepatic Lesions with Ferumoxides-Enhanced T2-Weighted MR Imaging

¹ Division of Body Imaging and MRI, Department of Radiology, University of Florida College of Medicine, Box 100374, 1600 S.W. Archer Rd., Gainesville, FL 32610.
² Present address: Department of Radiology, Frimley Park Hospital, Portsmouth Rd., Frimley, Camberley, Surrey, GU16 5UJ, United Kingdom.
³ Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115.

Received September 3, 1999; accepted after revision December 8, 1999.

 
Presented at the annual meeting of the Radiological Society of North America, Chicago, November 1997.

Supported in part by a grant from Advanced Magnetics Inc., Princeton, NJ.

Address correspondence to M. R. Paley.

Abstract

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OBJECTIVE. The purpose of this study was to evaluate whether ferumoxides-enhanced MR imaging of focal hepatic lesions provides distinctive signal intensity and lesion-to-liver contrast changes for benign and malignant lesions, helping to further characterize and differentiate these lesions.

MATERIALS AND METHODS. Data analysis was performed on 70 patients, with previously identified focal hepatic lesions, who underwent MR imaging of the liver before and after IV administration of ferumoxides (10 µmol Fe/kg). Lesions analyzed with pathologically proven diagnoses included metastases (n = 40), hepatocellular carcinoma (n = 11), cholangiocarcinoma (n = 6), hemangioma (n = 4), focal nodular hyperplasia (n = 6), and hepatocellular adenoma (n = 3). Response variables measured and statistically compared included the percentage of signal-intensity change and lesion-to-liver contrast.

RESULTS. Focal nodular hyperplasia showed significant signal intensity loss on ferumoxides-enhanced T2-weighted images (mean, -43% ± 6.7%, p < 0.01). All other lesion groups showed no statistically significant change in signal intensity on ferumoxides-enhanced T2-weighted images, although signal intensity loss was seen in some individual hepatocellular adenomas (mean, -6.6% ± 24.0%) and hepatocellular carcinomas (mean, -3.3% ± 10.3%). All lesions, with the exception of hepatocellular carcinoma, had a marked increase in lesion-to-liver contrast on ferumoxides-enhanced T2-weighted images, which was statistically significant for metastases and hemangioma (p < 0.02).

CONCLUSION. Focal nodular hyperplasia shows significant decrease in signal intensity on ferumoxides-enhanced T2-weighted images, which may aid in the differentiation of focal nodular hyperplasia from other focal hepatic lesions. Other lesions, namely, hepatocellular adenoma and carcinoma, can have reticuloendothelial uptake, but usually to a lesser degree than that of focal nodular hyperplasia.

Introduction

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The use of IV ferumoxides, or super-paramagnetic iron oxides, in MR imaging of the liver has been the focus of numerous investigations. That ferumoxides increase the detection of focal liver lesions on T2-weighted images is now widely accepted [1], resulting in its approval by the Food and Drug Administration for clinical use. This increase in lesion detection is caused by the differential uptake of ferumoxides particles by the normal liver, which contains reticuloendothelial cells, but not by lesions that lack reticuloendothelial cells. The high T2 relaxivity of ferumoxides particles leads to marked reduction in signal intensity of normal liver and a high signal intensity in lesions without contrast uptake, increasing conspicuity. In everyday practice, an important aspect of liver imaging is the ability not only to detect and localize a lesion but also to characterize it, in particular to determine whether it is benign or malignant, which affects the patient's treatment. With the use of widely available extracellular contrast agents, both for CT and MR imaging, characterization of a focal hepatic lesion is based on its vascularity and interstitial composition, with image analysis concentrating on the type of enhancement pattern and contrast washout. MR imaging, with its high contrast sensitivity, is a powerful tool for lesion characterization and, when combined with the use of tissue-specific contrast agents, there is potential for additional lesion characterization based on knowledge of tumor cell composition and function. The purpose of this study is to evaluate signal changes in lesions according to their histology to determine whether this can help further define the clinical role of ferumoxides in liver MR imaging.

Materials and Methods

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Patients
A retrospective analysis was made from data of an open-label multicenter phase 3 clinical trial. Our study group was composed of 70 patients with histologic confirmation of focal hepatic lesions. There were 40 patients (57%) with metastases, 11 (16%) with hepatocellular carcinoma, six (8.6%) with cholangiocarcinoma, six (8.6%) with focal nodular hyperplasia, four (6%) with hemangioma, and three (4%) with hepatocellular adenoma.

Contrast Agent
The physical, pharmacokinetic, and biologic properties of ferumoxides have been previously reported [2, 3]. Feridex (Advanced Magnetics, Princeton, NJ) is an iron oxide preparation coated with low-molecular-weight dextran. This agent was supplied in 5-ml vials containing 11.2 mg of iron and 61.3 mg of mannitol per ml. The dose of 0.56 mg (10 µmol) Fe/kg of body weight was diluted with 100 ml of 5% dextrose solution and infused IV at a rate of 3 ml/min through an in-line 5-µm filter.

MR Imaging
The MR imaging systems used in this study were nine different 1.5-T systems (Signa, General Electric Medical Systems, Milwaukee, WI [n = 7]; and Magnetom SP, Siemens Medical, Iselin, NJ [n = 2]) and one 1.0-T system (Magnetom SP; Siemens). At all sites, the entire liver was imaged within 24 hr before and 45 min to 4 hr after the commencement of contrast material administration. Conventional T1-weighted spin-echo (TR/TE, 300/20 msec) and T2-weighted spin-echo images (TR/TE, 500/60) with a section thickness of 10 mm were obtained in the axial plane with at least 128 phase-encoding steps and 12 sections.

Image Analysis
Unenhanced and ferumoxides-enhanced images were assessed quantitatively. The background signal intensity and the signal intensities of the liver, spleen, and hepatic lesions were measured before and after administration of the contrast agent for both T1- and T2-weighted images. Regions of interest were placed on homogeneous structures in regions free of artifacts, avoiding any high-intensity scars. Regions of interest were chosen to be representative of the tissue being evaluated. Measurements were made at the same anatomic level for unenhanced and enhanced images in each patient. Regions of interest for signal intensity of tissues included at least 50 pixels; regions of interest for noise included at least 1000 pixels. For the measurement of organ signal intensity, three separate regions of interest from different areas of the same section were measured, and the results were averaged. Mean background noise was measured for each image ventral to the liver outside the patient along the phase-encoding direction and included any ghosting artifacts that might have been propagated over the image.

For both unenhanced and ferumoxides-enhanced T2-weighted images, the signal intensities and signal-to-noise ratios (signal-to-noise ratio = signal intensity [x] / signal intensity [noise]) were measured for each lesion, where x represents the lesion of interest. The effect of contrast material on lesion signal intensity was calculated as the percentage of signal-intensity change for lesions after contrast administration using the formula: % signal intensity change (x) = 100 x (signal-to-noise ratio [enhanced] - signal-to-noise ratio [unenhanced]) / signal-to-noise ratio [unenhanced]. Lesion-to-liver contrast was also calculated, with normalization to the standard deviation of the noise, using the formula: lesion-to-liver contrast = (signal intensity [lesion] - signal intensity [liver]) / (signal intensity [liver] - signal intensity [nSD]), where nSD represents the standard deviation of the noise. These values are negative for hypointense lesions and positive for hyperintense lesions. Changes in signal intensity and lesion-to-liver contrast between unenhanced and ferumoxides-enhanced images were evaluated statistically using the paired t test.

Results

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The lesion signal-to-noise ratios and relative signal intensity changes on T2-weighted unenhanced and ferumoxides-enhanced images are shown in Table 1. In malignant lesions, no significant loss in mean signal intensity was observed, although signal intensity loss was seen in three individual hepatocellular carcinomas and one hepatocellular adenoma, shown in Table 2. The benign lesions showed some reduction in signal-to-noise ratio on T2-weighted images after ferumoxides administration (Fig. 1), but only focal nodular hyperplasia showed a statistically significant signal intensity reduction of 43% ± 6.7% (p < 0.01) (Figs. 2 and 3A,3B).

View larger version (15K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1. —Graph shows signal-to-noise ratio of lesions on T2-weighted images before and after ferumoxides enhancement. Note that benign lesions show reduction in signal-to-noise ratio as opposed to malignant lesions. White and gray bars indicate unenhanced and ferumoxides-enhanced, respectively. Mets = metastases, HCC = hepatocellular carcinoma, Chol = cholangiocarcinoma, Hem = hemangioma, FNH = focal nodular hyperplasia, HCA = hepatocellular adenoma.

View larger version (8K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —Graph shows lesion signal intensity change on T2-weighted images after ferumoxides enhancement. Note that focal nodular hyperplasia shows significant reduction in signal intensity. Mets = metastases, HCC = hepatocellular carcinoma, Chol = cholangiocarcinoma, Hem = hemangioma, FNH = focal nodular hyperplasia, HCA = hepatocellular adenoma.

View larger version (165K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A. —Focal nodular hyperplasia in 43-year-old woman. Unenhanced T2-weighted spin-echo MR image shows lesion (arrow) as well circumscribed and, in right lobe, mildly hyperintense to liver.

View larger version (153K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B. —Focal nodular hyperplasia in 43-year-old woman. Ferumoxides-enhanced T2-weighted spin-echo MR image shows decrease in signal intensity of lesion, liver, and spleen, and increased conspicuity of hyperintense central scar.

The lesion-to-liver contrast on T2-weighted unenhanced and ferumoxides-enhanced images is shown in Table 3. All lesions, with the exception of hepatocellular carcinoma, showed markedly improved lesion-to-liver contrast after ferumoxides administration, with the difference statistically significant for metastases (Fig. 4A,4B) and hemangiomas (p < 0.02).

View larger version (146K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A. —Sarcoma metastases in 66-year-old woman. Unenhanced T2-weighted spin-echo MR image shows large lobulated hyperintense lesion in left lobe and smaller lesions in right lobe.

View larger version (163K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B. —Sarcoma metastases in 66-year-old woman. Ferumoxides-enhanced T2-weighted spin-echo MR image shows decrease in signal intensity of background liver, increasing liver-to-lesion contrast for both large and small lesions.

Discussion

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The characterization of focal hepatic lesions is an important aspect of liver imaging that has implications for patient treatment and prognosis. MR imaging has excellent soft-tissue contrast and, in combination with the selective use of extracellular contrast agents such as gadopentetate dimeglumine, has improved our capability for liver lesion characterization [4]. However, the development of tissue-specific contrast agents provides new possibilities for lesion characterization on the basis of its cellular composition and function rather than its vascularity and diffusion within its extracellular space. In terms of its ultimate target, the macrophage-monocytic phagocytes within the reticuloendothelial system, ferumoxides may be seen as analagous to ^99mTc sulfur colloid used in nuclear medicine. The reticuloendothelial system component in the liver is the Kupffer's cells, which are known to occur in a number of primary liver lesions, such as focal nodular hyperplasia, hepatocellular adenoma, and some early hepatocellular carcinomas [5,6,7]. The observation in this series of signal intensity reduction after ferumoxides administration in some hepatocellular carcinomas and hepatocellular adenomas has been previously described [8, 9]; hence, signal intensity reduction alone cannot be relied on to provide a definitive diagnosis of focal nodular hyperplasia. Therefore, in everyday clinical practice it is necessary to use this objective finding in conjunction with subjective assessment of morphologic features, such as scar, capsule, hemorrhage, background cirrhosis, and relevant demographic and clinical findings to achieve a diagnosis.

The reduction in signal intensity seen with hemangiomas, a feature that has been observed in previous studies, cannot be explained by the presence of Kupffer's cells; and other mechanisms have been invoked, such as trapping or pooling of contrast material in vascular lakes, to account for this [8]. Despite the relatively short blood half-life (10 min in the rat) [3], a small blood pool effect has been observed with ferumoxides [9, 10]; therefore, lesion vascularity is likely to have an influence on signal intensity changes. This has been observed to a greater degree with ultrasmall superparamagnetic iron oxides [11]. In addition to the presence of and uptake into Kupffer's cells, the signal changes after ferumoxides administration depend on the dose, the rate of administration, and the timing of the scan after administration of contrast material. A concentration-dependent effect, with T1 shortening at low concentrations, has been observed, with T2 shortening becoming predominant at higher concentrations [12]; therefore, it is clear that a number of different mechanisms may interact to influence the signal intensity changes. We chose to restrict our study to T2-weighted images because of significantly greater T2 relaxivity of ferumoxides [13] and the proven superiority of T2-weighted spin echo over T1-weighted spin echo in detection of focal liver lesions [1].

Although the use of ferumoxides may have benefit in terms of characterization of lesions such as focal nodular hyperplasia, it may on occasion be detrimental in terms of lesion detection, depending on the baseline lesion-to-liver contrast. Signal intensity loss in focal nodular hyperplasia may vary, presumably reflecting variations in cell composition of the lesion. Signal intensity can be greater than that of the adjacent liver [14], which can result in a lesion that is hyperintense to liver on unenhanced T2-weighted images becoming isointense and harder to detect. The established characteristic imaging appearances of other lesions may also be modified by ferumoxides. For instance, in hemangiomas the typically hyperintense signal on T2-weighted images may be reduced. For this reason, it would seem prudent to retain the use of unenhanced scanning.

A number of limitations are recognized in this study. First, although the study group is large, the relative number of benign lesions is small, reflecting the prevalence of some rarer lesions. In any multicenter study, variations in technique are inevitable as a result of using different MR platforms. In addition, the imaging protocols used in the original study are not the protocols that are typically being used in liver MR imaging today, when fast spin echo is more frequently being used for T2 weighting. Fast spin echo has intrinsically different contrast characteristics compared with those of conventional spin echo; however, studies have shown that this does not have adverse consequences for characterization of focal hepatic lesions [15]. As yet, no firm consensus exists on the most appropriate sequences for use with ferumoxides. Finally, the absolute statistical changes need to be related to clinical practicality, which requires qualitative assessment via a multiinterpreter study and receiver operating characteristics analysis.

In conclusion, although a signal intensity loss after ferumoxides administration suggests a benign cause, Kupffer's cells may be found in early hepatocellular carcinoma, and ferumoxides uptake with resulting signal intensity reduction in these lesions has been described [5, 14]. The contrast effects of ferumoxides are complex; both T1 and T2 shortening are described, with the T2 effect being more dominant. A significant reduction in signal intensity so that it is comparable to or greater than the surrounding liver should suggest the diagnosis of focal nodular hyperplasia. Just as the use of dynamic gadopentetate dimeglumine-enhanced MR imaging has improved the ability to characterize hemanangiomas, so may the use of ferumoxides to characterize focal nodular hyperplasia. The importance of improved diagnostic confidence for the characterization of such benign lesions, which are typically treated nonsurgically, using this noninvasive method, is the obviation of tissue biopsy.

References

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