Iron oxide-enhanced MR lymphography: initial experience

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Abstract

The detection of nodal metastases is of utmost importance in oncologic imaging. Ultrasmall superparamagnetic iron oxide particles (USPIO) are novel contrast agents specifically developed for MR lymphography. After intravenous administration, they are taken up by the macrophages of the lymph nodes, where they accumulate. They reduce the signal intensity (SI) of normally functioning nodes on postcontrast T2-and T2*-weighted images through the magnetic susceptibility effects on iron oxide. Metastatic nodes, in which macrophages are replaced by tumor cells, show no significant change in SI on postcontrast T2-and T2*-weighted images. Early clinical experience suggests that USPIO-enhanced MR lymphography improves the sensitivity and specificity for the detection of nodal metastases. It also suggests that micrometastases could be detected in normal-sized nodes. This article reviews the physiochemical properties of USPIO contrast agents, their enhancement patterns, and early clinical experience.

Introduction

Ultrasmall superparamagnetic iron oxide particles (USPIO) are novel magnetic resonance (MR) contrast agents specifically developed for intravenous MR lymphography [1], [2], [3], [4], [5], [6], [7]. They are specific for the reticulo–endothelial-system (RES) and provide information on lymph node morphology and function. They have been used to improve the detection of node metastases, and are still in the experimental stage.

Local-regional lymph node involvement is a key prognostic factor and an important determinant of cancer treatment choices. In particular, it is an important element in choosing the most appropriate treatment modality, planning surgical or radiation treatment, and monitoring the response to therapy. After physical examination, computed tomography (CT) is currently the most frequently used method for assessing lymph node status in cancer staging. Magnetic resonance imaging (MRI) can also be used for this purpose but generally has lower spatial resolution, while ultrasonography (US) provides less contrast. The only CT and MR imaging criterion that is generally accepted in the evaluation of node metastases is the size of the node. However, false-negative findings for normal-size metastatic nodes limit staging capabilities. Another limitation is that US, CT and unenhanced MRI cannot distinguish metastatic nodes from non metastatic reactive nodes. Borderline-sized nodes remain indeterminate in these techniques. Conventional lymphography has virtually been abandoned, as it involves a lengthy delivery technique and its usefulness is limited to pelvic and lumbar nodal chains. Surgical lymph node dissection is efficient but invasive; published data on the accuracy of histologic analysis of intraoperative frozen section of nodes conflict, and rates of false-negative results as high as 33% have been reported in pelvic node analyses [8]. The disadvantages of size discrimination with current cross-sectional imaging techniques, together with the morbidity and length of surgical procedures, have prompted extensive research aimed at developing tissue-specific imaging methods, including USPIO-enhanced MR lymphography. This article reviews the development of superparamagnetic iron oxide compounds, together with their physicochemical features, imaging characteristics, and initial clinical experience.

Section snippets

Physicochemical structure

R. Weissleder and his colleagues at Massachusetts General Hospital and Advanced Magnetics Inc. have played a key role in the development of USPIO contrast agents [1], [2], [9], [10]. Use of these agents for MR lymphography is still in the experimental stage. They are composed of iron oxide crystals coated with polymers to avoid uncontrolled aggregation of the magnetic crystals. USPIO salt solutions are prepared by co-precipitation of magnetite in the presence of a coating material. Electron

Administration and tolerability

Sinerem® and Combidex® are provided as lyophilized powders consisting of biodegradable USPIO particles, Dextran and dihydrated sodium citrate. They are reconstitued by mixing the lyophilized powder with 9.7 ml of 0.9% normal saline solution, yielding a dark reddish-brown aqueous solution. The osmolality of the solution is 365 mosm/kg. The doses used in clinical trials range between 1.7 and 2.6 mg of iron/kg of body weight, i.e. 0.085 and 0.13 ml/kg reconstituted solution. The appropriate volume

Lymph node anatomy and physiology

Lymph nodes are solitary structures (Fig. 1) surrounded by a thick fibrous capsule. Several afferent lymphatic vessels pass through the capsule and drain into marginal sinuses [13]. Lymph nodes contain a stromal network of trabeculae. The node parenchyma is divided into poorly defined cortical (paracortical and follicular) and medullary regions. The cortex is made up of lymph follicles, which consist of a germinal area containing B lymphocytes, reticulum cells and histiocytes, and a peripheral

Nodal uptake of USPIO after injection by different routes

Nodal uptake is highly dependent on the injection route. Weissleder [9] and Bengele [15] have shown distinct percentage uptakes of the injected dose in rats with different routes of administration (Table 1). These results show a symmetrical accumulation of USPIO in the right and left popliteal nodes after intravenous injection, but highly asymmetrical accumulation following subcutaneous and intraarterial injection, with very low uptake by contralateral nodes. As expected, uptake by popliteal

Enhancement of normal nodes following IV administration

After IV infusion, USPIO particles are distributed to the lymph nodes via two distinct pathways, as first suggested by Weissleder et al. [1]. The first is direct transcapillary passage through venules into the medullary sinuses within the lymph node, followed by phagocytosis. The second is non selective endothelial transcytosis into the interstitial space throughout the body, followed by uptake of USPIO particles by draining lymphatic vessels and transport to regional lymph nodes via afferent

Detection of nodal metastases

USPIO particles have been developed in the late 1980s, to improve the detection of nodal metastases, and to enable differentiation of benign from metastatic nodes. Several experimental studies have shown that benign and metastatic lymph nodes have different enhancement patterns after i.v. injection of USPIO [1], [3], [4], [9]. Normal nodes show active uptake, while tumorous nodes do not exhibit any uptake. It was initially assumed that benign nodes showed decreased postcontrast signal on T2-

Enhancement patterns in non nodal structures

After intravenous infusion a small fraction of the injected dose accumulates in the spleen, liver, bone marrow and kidneys and can produce a decrease in the signal intensity of these organs on T2 and T2*-weighted images [7], [17].

USPIO compounds can also be used as blood pool agents for MR angiography [24]. Because of their prolonged half-life (35 h in humans), they enhance both arterial and venous structures through their T1-shortening effects. Preliminary studies of USPIO-enhanced MR

Conclusion

Initial findings of USPIO-enhanced MR imaging show that:

  • 1.

    the internal nodal structure is visible, including in normal-sized nodes

  • 2.

    metastases in normal-sized nodes can be detected prospectively

  • 3.

    the sensitivity and specificity of USPIO-enhanced MR imaging are improved compared to precontrast MR imaging

  • 4.

    the choice of the right imaging parameters is essential for the success of MR lymphography.

However, additional studies are needed to determine the efficiency of USPIO-enhanced MR lymphography and its

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