British Journal of Radiology (2007) 80, 569-573
© 2007 British Institute of Radiology
doi: 10.1259/bjr/95414884
Gadoteridol for MR imaging of lymphatic vessels in lymphoedematous patients: initial experience after intracutaneous injection
C Lohrmann, MD1,
E Foeldi, MD2,
J-P Bartholomae, MD1 and
M Langer, MD1
1 Division of Diagnostic Radiology, Department of Radiology, University Hospital of Freiburg, Hugstetter Strasse 55, D-79106, Freiburg, 2 Foeldi Clinic for Lymphology, Hinterzarten, Rößlehofweg 2–6, D-79856, Hinterzarten, Germany
Correspondence: Christian Lohrmann MD, Universitätsklinikum Freiburg, Abteilung Röntgendiagnostik, Hugstetter Strasse 55, 79106 Freiburg i. Br., Germany. E-mail: lohrmann{at}mrs1.ukl.uni-freiburg.de
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Abstract
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The aim of this study was to evaluate the feasibility of gadoteridol in visualizing lymphatic vessels of lymphoedematous patients after intracutaneous injection. 20 lower extremities in 10 lymphoedematous patients were examined. Gadoteridol (9 ml) was subdivided into five portions and injected intracutaneously into the dorsal aspect of each foot. For MRI, a three-dimensional spoiled gradient echo sequence was performed. No complications were observed during or after intracutaneous injection of gadoteridol. The lymphoedema was bilateral in seven and unilateral in three of the examined patients. Contrast enhancement of gadoteridol was detected in lymphatic vessels at the level of the lower leg in 17 lower extremities (85%). Enhancing lymphatic vessels of the upper leg were observed in 11 lower extremities (55%). Furthermore, gadoteridol enhanced 10 out of 20 inguinal lymph node groups (50%). No external iliac lymph nodes were observed in any of the patients. Regions of dermal backflow, indicating proximal lymphatic obstruction, were seen in 13 lower extremities (65%). As soon as 15 min after gadoteridol injection, accompanying venous enhancement was detected in all lower extremities (100%). MRI of lymphatic vessels in lymphoedematous patients is safe and feasible after intracutaneous injection of gadoteridol if the diagnosis of lymphoedema necessitates a better definition for optimal therapeutic planning or an objective, diagnostic baseline is required. The proposed technique represents a minimally invasive imaging method of identifying anatomical and physiological derangements in lymphatic vessels.
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Introduction
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At the level of the lower extremities, lymphoedema develops in a primary or secondary form, e.g. secondary to malignancy, and generally constitutes a chronic disease. Intensive complex decongestive physiotherapy is normally the treatment of choice to prevent secondary complications such as chronic inflammation and irreversible fibrosis. An illustration of the lymphatic vessels is particularly important, e.g. if the diagnosis of lymphoedema necessitates a better definition for optimal therapeutic planning or an objective, diagnostic baseline is required.
Gadoteridol (Prohance®; Bracco-Altana, Konstanz, Germany) is a non-ionic, extracellular, water-soluble contrast material for MRI. It has paramagnetic properties with a gadolinium (Gd) concentration of 0.5 M. Each millilitre of Prohance contains 279.3 mg of gadoteridol. Gadoteridol is usually applied intravenously at a recommended dose of 0.1 mmol kg–1 (0.2 ml kg–1) and cleared from the body by glomerular filtration. The safety and benefit of intravenous gadoteridol injection have been demonstrated in various MRI studies [1–3]. Experimental animal models have demonstrated only minor tissue damage after extravasation of non-ionic, paramagnetic contrast agents [4]. Therefore, gadoteridol offers an acceptable safety profile for intracutaneous administration.
For imaging of the lymphatic vessels in lymphoedematous patients, up to now, lymphoscintigraphy was considered to be the primary imaging modality [5–7]. This imaging tool has, however, the disadvantage of radiation and low spatial resolution. Owing to the risk of damaging the lymphatic vessels, conventional lymphography is contraindicated in patients with lymphoedema. Recently, interstitial magnetic resonance lymphography (MRL) with intracutaneous injection of gadodiamide (Omniscan®; GE Healthcare, Munich, Germany) was shown to be safe and technically practicable in patients with primary and secondary lymphoedema [8, 9].
The purpose of this study was to evaluate the feasibility of intracutaneously applied gadoteridol for the visualization of lymphatic vessels in lymphoedematous patients by MRI.
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Methods and materials
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Patients
Between November 2005 and March 2006, 20 lower extremities in 10 patients (mean age 44 years, range 21–64 years; seven females, three males) with lymphoedema of the lower extremities (eight primary, two secondary after retroperitoneal, pelvic and inguinal lymph node extirpation due to malignancy) were examined with interstitial MRL. The inclusion criteria were lymphoedema of one or both lower extremities. Patients with contraindications for MRI, renal insufficiency or a known gadolinium contrast agent allergy were excluded. This study was approved by the local ethics committee, and all participants gave their informed consent before being included in the study.
Contrast material application
Gadoteridol (9 ml) and 1 ml of mepivacainhydrochloride 1% were divided into five portions and injected intracutaneously into the dorsal aspect of each foot in the region of the four interdigital webs; one portion was applied medial to both first proximal phalanges. Mepivacainhydrochloride 1% was used to alleviate the pain for patients at the time of contrast material injection. A thin needle (24 gauge) was used for the injection of the contrast material.
MRI examinations
MRI was performed with a 1.5 T system (Avanto; Siemens Medical Systems, Erlangen, Germany). Three stations were examined: first, the lower leg and foot region; second, the upper leg and the knee region; and third, the pelvic region and the proximal upper leg. A phased array body coil was used to image the pelvic region, and a dedicated peripheral surface coil was used to examine the upper and lower leg. To describe the lymphoedema, a heavily T2 weighted three-dimensional (3D) turbo spin echo (TSE) sequence (TR/TE: 2000/694; flip angle: 180°; matrix: 256 x 256, bandwidth: 247 Hz/pixel; 6/8 rectangular field of view 480 mm; slices: 96; voxel size: 2.0 x 1.9 x 1.7 mm; acquisition time: 4 min 48 s) was conducted before MRL was performed. For MRL, a 3D spoiled gradient echo sequence (volumetric interpolated breath-hold examination, VIBE) was used with the following parameters (TR/TE: 3.58/1.47; flip angle: 35°; matrix: 448 x 448, bandwidth: 490 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 128; voxel size: 1.2 x 1.1 x 1.2 mm; acquisition time: 1 min 40 s). The three stations were first imaged without contrast material and subsequently repeated 15, 25, 35, 45 and 55 min after intracutaneous application of the contrast material for image subtraction.
Image analysis
Two authors have quantitatively and qualitatively analysed the enhancement of gadoteridol in the lymphatic pathways, inguinal lymph nodes and veins using the source images and maximum intensity projection (MIP) reconstructions. The size of the regions of interest was adapted to encompass as much as possible of these structures. Noise was defined as the standard deviation from a measurement of signal intensity outside the patient. Signal-to-noise ratios were calculated by dividing the signal intensity by noise. Lymphatic vessels were evaluated regarding their visibility with a beaded appearance and size. An area of progressive dispersion of the contrast media into the soft tissues was regarded as "dermal backflow". A diagnosis was made by consensus.
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Results
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Intracutaneous injection of gadoteridol was tolerated by all patients; eight patients described the pain at contrast media application as mild, and two as moderate. The dorsal aspect of the feet was swollen for a maximum of 3 days in the examined patients. During the clinical observation period after the examination, which lasted between 4 and 13 days, no complications, e.g. infection or skin necrosis, were observed. Additionally, no later damage was reported by the patients after discharge. The lymphoedema was bilateral in seven and unilateral in three patients (Figure 1a
). Lymphatic vessels were detected by gadoteridol in 17 lower legs (85%) (Figures 1b and 2; Table 1). The highest contrast enhancement of the lymphatic vessels in the lower leg was present after 45 min in one lower extremity, after 35 min in three lower extremities and after 55 min in 13 lower extremities. In 11 lower extremities (55%), lymphatic vessels of the upper leg could be visualized (Table 1). The strongest signal of gadoteridol in the lymphatic vessels of the upper leg was present after 35 min in one lower extremity, after 45 min in three lower extremities and after 55 min in seven lower extremities. A contrast material uptake was seen in 10 out of 20 inguinal lymph node groups (50%) (Figure 1c; Table 1) with the highest signal intensities measured in two lower extremities after 35 min and in eight lower extremities after 55 min.
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Figure 1. 70-year-old woman with bilateral primary lymphoedema. (a) Coronal heavily T2 weighted three-dimensional (3D) turbo spin echo (TSE) source image demonstrates extensive epifascial lymphoedema of both upper legs (arrows). (b) Frontal 3D spoiled gradient echo magnetic resonance lymphography (MRL) maximum intensity projection (MIP) image, obtained 35 min after Prohance injection, clearly depicts one enlarged lymphatic vessel with a beaded appearance in both lower legs (small arrows). Note the concomitantly enhancing vein at the level of the right lower leg, which shows a lower signal intensity (arrowheads). Additionally, extensive areas of dermal backflow are revealed at the dorsal aspect of both feet, indicating delayed lymphatic flow with neovascularization due to obstruction (large arrows). (c) 3D spoiled gradient echo MRL source image reveals left inguinal lymph nodes (arrows) with afferent and efferent lymphatic vessels (arrowheads). Note enhancement of the bladder (asterisk), indicating venous uptake and renal clearance of the contrast media after intracutaneous injection.
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Figure 2. 21-year-old woman with bilateral primary lymphoedema. Angled three-dimensional (3D) spoiled gradient echo magnetic resonance lymphography (MRL) maximum intensity projection (MIP) image, obtained 45 min after Gadoteridol injection, clearly depicts a reticular network of enlarged lymphatic vessels in both lower legs (small arrows). Furthermore, areas of dermal backflow are revealed bilaterally, indicating delayed lymphatic flow with neovascularization due to obstruction (asterisks). Note the concomitantly enhanced veins in both lower legs (arrowheads).
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After 15 min of contrast material application, accompanying venous enhancement was detected in the lower and upper leg of all 20 lower extremities (100%) (
Figures 1b and 2; Table 1). The highest gadoteridol uptake in the veins of the lower leg was present after 15, 35 and 45 min in four lower extremities and after 25 min in eight lower extremities. The highest signal intensities of veins in the upper leg were measured after 55 min in one lower extremity, after 15 min in two lower extremities, after 35 min in six lower extremities and after 25 min in 11 lower extremities. External iliac lymph nodes were not observed in any of the patients. Areas of dermal backflow, indicating proximal lymphatic obstruction, were seen in 13 lower extremities (65%). The maximum diameter of a dilated lymphatic vessel was 6 mm.
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Discussion
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Interstitial MRL has demonstrated promising results in animal studies with intra- and subcutaneous administration of various lymphotropic paramagnetic contrast agents [10, 11]. Only small amounts of these agents are needed in order to be visible in lymph nodes and lymphatic vessels. However, these lymphotropic contrast agents are in the preclinical phase with a contingent safety profile. In 2001, Ruehm et al proposed interstitial MRL with the administration of a commercially available extracellular paramagnetic contrast agent to be safe and effective in imaging lymph nodes and lymphatic vessels in both animals and humans [12, 13].
Owing to the increasing number of patients suffering from lymphoedema, the importance of clinical lymphology is increasing worldwide [14, 15]. Up to now, in lymphoedematous patients, no imaging modality has been able to create high-resolution images of the lymphatic vessels non-invasively and without radiation exposure. Currently, interstitial MRL with intracutaneous injection of gadodiamide, a commercially available, non-ionic, extracellular paramagnetic contrast agent, represents a first step towards imaging pathologically changed lymphatic pathways in humans [8, 9].
The primary objective of the present study was to evaluate the feasibility of intracutaneously applied gadoteridol in visualizing lymphatic vessels of lymphoedematous patients. In agreement with previous MRL studies using paramagnetic, extracellular contrast agents, no complications occurred during or after gadoteridol injection [8, 9, 12].
According to previous reports using gadodiamide, gadoteridol has enabled the delineation of a high number of lymphatic vessels extending from the injection site [8, 9]. Owing to the low molecular masses of the Gd chelates, gadoteridol is rapidly taken up by the interstitial space through the capillaries into the lymphatic and venous systems. In the cutis, the initial lymphatic vessels form a polygonal capillary network, whereas the initial lymphatics are closely interconnected in a hexagonal shaped pattern and have blind endings. The diameter ranges from 10 to 60 µm and is thus significantly larger than the diameter of arteriovenous capillaries at a size of approximately 8 µm [14, 15]. Depending on the degree of distension, extracellular fluids and proteins enter the initial lymphatics through interendothelial openings or by vesicular transport. Both mechanisms are of equal importance [14–16].
Because of dysfunctional lymphatic drainage at the level of the lower leg, no enhancement of lymphatic collectors in the upper leg and inguinal lymph nodes was seen in seven extremities. Presumably because of dysplasia of the lymphatic system, no lymphatic collectors and inguinal lymph nodes could be enhanced in one extremity. As a result of surgery with lymph node extirpation, two inguinal lymph node groups were not seen by MRL. In two lower legs and one upper leg, it was not entirely possible to differentiate lymphatic vessels from veins on the basis of their beaded appearance. We assumed, however, that the lymphatic vessels were present, as the inguinal lymph node groups had shown contrast enhancement during the examination.
On account of gadoteridol uptake of the venous system and excretion via the kidneys, enhancement of the bladder was noted in all subjects, as described in previous reports [8, 9, 12, 13]. In the examined patients, lymphatic vessels in the lower/upper leg and inguinal lymph nodes showed a tendency to have the highest contrast material uptake in the later acquisitions, compared with the veins. This phenomenon is probably due to the slower flow velocity in lymphatic vessels, in comparison with the venous system. As in interstitial MR lymphangiography studies using gadodiamide, gadoteridol was not able to enhance the inguinal lymph nodes sufficiently to allow analysis of nodal morphology in the presented series [8, 9].
In conclusion, interstitial MRL with gadoteridol is safe and feasible for the visualization of lymphatic vessels in lymphoedematous patients. Should the diagnosis of lymphoedema necessitate a better definition for optimal therapeutic planning or an objective, diagnostic baseline is required, the proposed technique represents a minimally invasive imaging method of identifying the anatomical and physiological derangements of lymphatic vessels.
Received for publication May 15, 2006.
Revision received September 17, 2006.
Accepted for publication October 8, 2006.
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Abstract
Introduction
