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Indirect magnetic resonance lymphangiography in patients with lymphedema
European Journal of Radiology 59 (2006) 401–406
Technical note
Indirect magnetic resonance lymphangiography in patients with lymphedema Preliminary results in humans Christian Lohrmann a,∗ , Etelka Foeldi b , Mathias Langer a a
Division of Diagnostic Radiology, Department of Radiology, University Hospital of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany b Foeldi Clinic for Lymphology, Hinterzarten, R¨ oßlehofweg 2-6, D-79856 Hinterzarten, Germany Received 19 October 2005; received in revised form 12 February 2006; accepted 17 February 2006
Abstract Purpose: To assess the feasibility of indirect magnetic resonance (MR) lymphangiography with intracutaneous injection of gadodiamide, a commercially available, non-ionic, extracellular paramagnetic contrast agent for the detection of lymphatic vessels in patients with lymphedema. Materials and methods: In 2005, three patients with lymphedema of the lower extremities (1 primary, 2 secondary) were referred by the Foeldi Clinic for Lymphology for indirect magnetic resonance lymphangiography. 4.5 mL of gadodiamide and 0.5 mL of mepivacainhydrochloride 1% were injected intracutaneously into the dorsal aspect of each foot. MR imaging was performed with a 1.5-T system equipped with highperformance gradients. For indirect magnetic resonance lymphangiography, a 3D Fast Low Angle Shot (FLASH) sequence (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s) was used. Results: Indirect magnetic resonance lymphangiography depicted lymphatic vessels of the lower and upper leg, and inguinal lymph nodes in all three patients. After 5 min of contrast material application, concomitant venous enhancement was detected. Collateral vessels with dermal back-flow were seen in two patients. A lymphocele in the inguinal region with the afferent lymphatic vessel was depicted in one patient. Conclusion: In the presented small study group, indirect magnetic resonance lymphangiography was technically feasible, and no complications were observed after intracutaneous injection of gadodiamide. Visualizing the lymphatic vessels and accompanying complications non-invasively and without the use of radiation, the presented method has the capability to become a routine diagnostic imaging tool in patients with primary and secondary lymphedema. The method is not able to characterize lymph node morphology, but could provide additional information about the lymphatic vessels when lymph nodes are examined, e.g. with super-paramagnetic iron oxide particles. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Gadodiamide; Indirect magnetic resonance lymphangiography; Lymphedema
1. Introduction Progress achieved in the understanding of microcirculation and molecular biology has made it possible to understand many aspects of morphologic and functional tissue alterations that occur as a consequence of lymphostasis [1–4]. A major hindrance in understanding the pathophysiology of lym-
∗
Corresponding author. Tel.: +49 761 270 3802; fax: +49 761 270 3838. E-mail address: [email protected] (C. Lohrmann).
0720-048X/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2006.02.012
phedema, to differentiate it from other types of edema, and in creating accurate treatment plans, has been the complexity of visualizing the lymphatic pathways in human beings [1–4]. So far, lymphoscintigraphy is considered to be the primary imaging modality in patients with extremity lymphedema. Despite improvements in this technology, an improved depiction of the lymphatic system with a high resolution is desired [5–9]. Interstitial magnetic resonance lymphangiography (I MRL) has shown promising results in experimental animal models with intracutaneous and subcutaneous administration of various lymphotropic paramagnetic contrast agents. Only
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C. Lohrmann et al. / European Journal of Radiology 59 (2006) 401–406
small amounts of these substances are needed for their rapid appearance in lymph nodes and lymphatic vessels. Anyhow, these lymphotropic contrast agents are still in the preclinical phase with an uncertain safety profile [10–13]. I MRL with administration of a commercially available extracellular paramagnetic contrast agent has been proposed to be safe and effective in imaging lymph nodes and lymphatic vessels in animals and humans [14–19]. The purpose of this study was to evaluate the feasibility of I MRL with intracutaneous injection of gadodiamide (Omniscan, GE Healthcare, Munich, Germany), a commercially available, non-ionic, extracellular paramagnetic contrast agent for the detection of lymphatic vessels in patients lymphedema.
An amount of 4.5 mL of contrast material and 0.5 mL mepivacainhydrochloride 1% were subdivided into five portions and injected intracutaneously into the dorsal aspect of each foot in the region of the four interdigital webs; one portion was injected medial to both first proximal phalanges. Immediately after administration of the contrast agent, the injection sites of each foot were massaged for about 60 s. The massage was repeated between the data acquisitions. All patients were asked to describe the intensity of pain at the time of gadodiamide application. A four-point scale was used: 0: no pain; 1: mild pain; 2: moderate pain; and 3: severe pain. After the examination, the patients were monitored closely in the Foeldi Clinic for Lymphology to observe possible complications such as swelling or infection.
2. Materials and methods
2.4. MR imaging examinations
2.1. Contrast agent
MR imaging was performed with a 1.5-T system (Magnetom Symphony; Siemens Medical Systems, Erlangen, Germany) equipped with high-performance gradients. 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. For I MRL, a 3D Fast Low Angle Shot (FLASH) sequence with the following parameters was used: (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s). The three stations were first imaged without contrast material and subsequently repeated 5, 15, 25, 35, 45, and 55 min after intracutaneous application of the contrast material. To highlight the Gd containing structures, baseline images were subtracted before 3D maximum-intensity-projection (MIP) reconstructions were calculated.
Gadodiamide (Omniscan, GE Healthcare, Munich, Germany), is a commercially available, extracellular, watersoluble paramagnetic contrast agent with a gadolinium (Gd) concentration of 0.5 mmol. This contrast agent is normally administered intravenously at a recommended dose of 0.1 mmol/kg of body weight, which is equivalent to a dose of 0.2 mL/kg. For MR angiography, however, gadodiamide has been approved at doses up to three times the normal dose. It is not subjected to metabolization and is excreted unchanged by passive glomerular filtration. Gd chelates have low molecular masses, and are rapidly cleared from the intravascular space through the capillaries into the interstitial space. Experimental animal models have demonstrated solely minor tissue damage after non-intravenous injection or extravasation [20]. Therefore, the agent offers an acceptable safety profile for intracutaneous application. 2.2. Study design In the year 2005, three patients with lymphedema of the lower extremities (1 primary and 2 secondary); mean age 60 years; range 54–69 years; 1 female, 2 males) were referred by the Foeldi Clinic for Lymphology for I MRL. The diagnosis of lymphedema was established with clinical criteria using the Foeldi & Foeldi classification [21]. The inclusion criteria were lymphedema of one or both lower extremities and willingness to participate in the study. Exclusion criteria were contraindications for MRI, renal insufficiency, or a known gadolinium contrast agent allergy. This study has been approved by the local ethics committee, and all participants had given their informed consent before being included in the study. 2.3. Contrast material administration For injection of gadodiamide, a thin needle (24 gauge) was used.
2.5. Image analysis All authors qualitatively assessed the enhancement of gadodiamide in the lymphatic pathways, and inguinal/iliac lymph nodes using the source images and MIP reconstructions. Lymphatic vessels were regarded as clearly visible, if their beaded appearance could be differentiated from parallel enhancing veins. Furthermore, the lymphatic vessels were evaluated concerning size, collaterals, and lymphoceles. An area of progressive dispersion of the contrast media into the soft tissues was regarded as dermal “back-flow”. A diagnosis was made by consensus. The time courses of enhancement of the lymphatic pathways, inguinal/iliac lymph nodes, and veins were analyzed quantitatively by one experienced radiologist. The size of the regions of interest was adapted to encompass as much as possible of these structures. The postcontrast images facilitated the identification of these structures on the precontrast images.
C. Lohrmann et al. / European Journal of Radiology 59 (2006) 401–406
3. Results All patients described the pain at the time of contrast material administration as mild, and were able to walk well and without discomfort after the examination. The minor swelling in the region of the application sites resolved within 24 h in all patients. No complications were observed after the examination. The lymphedema was bilateral in one and unilateral in two patients. In all patients, the beaded appearance of the lymphatic vessels extending from the injection site was reliably detected and clearly differentiated form parallel enhancing
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veins 15 min after injection (Table 1, Fig. 1). After 5 min of contrast material application, concomitant venous enhancement was detected in the lower and upper leg of each patient (Fig. 1). In the lower leg, the best delineation of the lymphatic vessels was present after 35 min in two patients, and after 45 min in one patient (Fig. 1). In all patients, the lymphatic vessels in the upper leg could reliably be detected at 25 min, with the strongest enhancement at 45 min in one patient, and at 55 min in two patients after contrast material application (Fig. 2). In all patients, the inguinal lymph nodes with external iliac lymphatic pathways were reliably depicted at 35 min, with the highest signal intensity at 45 min in one patient,
Fig. 1. Sixty-nine-year-old man with primary lymphedema. (A) Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 15 min after gadodiamide injection, clearly delineates the enlarged lymphatic vessels in the left lower leg (small arrows). Note the small area of dermal back-flow (arrowhead) indicating lymphatic flow obstruction. The concomitantly enhanced vein shows a lower signal intensity (large arrow). (B) Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 35 min after gadodiamide injection, demonstrates increasing contrast media filling of the enlarged lymphatic vessels in the left lower leg (small arrows) and enlarging areas of dermal back-flow (arrowheads). The concomitantly enhanced vein shows a lower signal intensity (large arrow).
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Table 1 Interstitial magnetic resonance lymphangiography (I MRL) findings in three patients with primary and secondary lymphedema HR MRL findings
Number of patients (%)
Lymphatic vessels lower leg Lymphatic vessels upper leg Inguinal lymph nodes External iliac lymph nodes Collateral vessels Dermal back-flow Lymphocele
3 (100) 3 (100) 3 (100) 1 (33) 2 (66) 2 (66) 1 (33)
and at 55 min in two patients after gadodiamide application (Fig. 3). The external iliac lymph nodes were observed in only two patients, and paraaortic lymph nodes in none of the patients.
Fig. 3. Fifty-three-year-old man with a history of malignant melanoma and lymphedema of the right leg due to inguinal lymph node extirpation and radiation. Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 55 min after gadodiamide injection, demonstrates inguinal lymph nodes (arrowheads) with afferent and efferent lymphatic vessels (arrows) on the left side. No inguinal lymph nodes were detected on the right side.
Collateral vessels with dermal back-flow, indicative of proximal lymph flow obstruction with alternate pathways of transport, were seen in two patients (Figs. 1 and 2). The maximum diameter of a dilated lymphatic vessel was 5 mm. In one patient, enhancement of a lymphocele in the left groin with the afferent lymphatic vessel was detected (Fig. 4).
4. Discussion
Fig. 2. Sixty-nine-year-old man with primary lymphedema. Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 45 min after gadodiamide injection, demonstrates enlarged lymphatic vessels in the left lower and upper leg (arrowheads). Areas of dermal back-flow are seen (large arrows) indicating lymphatic flow obstruction. The concomitantly enhanced vein shows a lower signal intensity (small arrow).
To date, lymphoscintigraphy has been the primary imaging tool in diagnosing patients with lower leg lymphedema [5–9]. This method, though, has the disadvantage of ionizing radiation, and low spatial and temporal resolution, which limits its worth for exact assessment of the lymphatic anatomy and function [5–9]. Direct lymphography achieves the highest concentration of the contrast media in the lymph vessels and nodes [22]. Long examination times, radiation exposure, invasiveness, and potential side effects like local wound infection and pulmonary embolism have, although, limited its clinical applicability [23]. If the underlying reason of lymphedema is unclear or needs an improved definition for ideal therapeutic planning, a non-invasive imaging modality to visualize the lymphatic system with a high resolution is crucial. I MRL with a three station protocol provided a noninvasive, high-resolution display of the lymphatic vessels and accompanying complications in patients with lower extremity lymphedema. As seen in conventional indirect lymphography with suitable water-soluble contrast media, the presented method allowed evaluation of several lymphatic vessels after intracutaneous contrast material injection [22]. Conventional indirect lymphography, however, enabled only the imaging of
C. Lohrmann et al. / European Journal of Radiology 59 (2006) 401–406
Fig. 4. Fifty-seven-year-old obese woman with lymphedema of the left leg and a lymphocele in the left groin due lymph collector damage during liposuction. (A) Frontal 3D Fast Low Angle Shot sequence (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 55 min after contrast material injection, clearly delineates the feeding lymphatic vessel (arrowhead) of the lymphocele (large arrows) in the left groin. Note the epifascial lymphedema of the left upper leg (small arrows). The subcutaneous tissue on the right side is unremarkable. (B) Frontal 3D Fast Low Angle Shot sequence (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 55 min after contrast material injection, demonstrates contrast media filling (arrowheads) of the the lymphocele (large arrows). Note the epifascial lymphedema of the left upper leg (small arrows). The subcutaneous tissue on the right side is unremarkable.
40–60 cm-long sections of lymph vessels in the lower extremities. It was rarely possible to image the lymph vessels as far as the inguinal region [24]. The presented I MRL protocol enabled enhancement of the inguinal lymph nodes and of the lymphatic vessels up to the external iliac region in all three patients. Compared to conventional indirect lymphography, it was consequently possible to examine the lymphatic system of the entire leg with one I
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MRL examination. Due to the high resolution of the presented protocol with a voxel size of 2.0 mm × 1.0 mm × 1.0 mm, even small collateral lymphatic vessels could be visualized in two patients. I MRL localized areas of dysfunctional lymphatic drainage with adjacent areas of dermal back-flow in two patients. Accurate localizing of the pathology by I MRL thereby supports the clinician to choose the appropriate treatment modality, e.g. manual lymphatic drainage and compression therapy. In one patient, I MRL was successful in identifying a lymphocele in the left groin with the afferent lymphatic vessel. The important differentiation to other fluid collections, e.g. hematoma and seroma, could thus be made. In accordance with a report by Ruehm et al. [14], we observed concomitant enhancement of veins in all patients. 3D MIP reconstruction, however, permitted identification of the lymphatic vessels and differentiation from veins. All three patients graded the pain at the time of contrast media injection as mild. However, to further increase patient acceptance, a reduction of the injected contrast media volume would be worthwhile. One option could be the use of a more concentrated Gd formulation (1.0 instead of 0.5 mol/L), such as gadobutrol (Gadovist; Schering, Berlin, Germany), which has proven to be feasible for I MRL in rats [19]. Furthermore, the lack of radiation in I MRL is a great advantage in managing the large number of patients affected by lymphedema. For the detection of lymph nodes, intravenous injection of super-paramagnetic iron oxide particles of various sizes has been evaluated. The advantage is that, theoretically, all lymph nodes in the body can be accessed. Major drawbacks are an inhomogeneous uptake and slow accumulation in different lymph node groups. Furthermore, susceptibility artefacts are seen on MR images [25–27]. Due to the negative contrast, enhancement of iron oxides particles and the low spatial resolution, lymphatic vessels can, however, not be demonstrated with T2-weighted MR lymphography [25–27]. Gd-enhanced T1-weighted MR images exhibit higher spatial resolution, higher signal-to-noise ratio, and fewer artefacts than do MR images with negative contrast, such as iron oxide particles [10–13]. Gd-based, lymphotropic contrast agents are, however, still in the preclinical phase and cannot be used in humans [10–13]. Due to a short repetition time, the FLASH sequence renders all tissues dark, except those containing a considerable amount of T1-shortening contrast agent. Even though susceptibility effects as a result of the highly concentrated gadodiamide were seen at the injection sites, the signal distortions due to T2-shortening effects were insignificant. In routine lymphoscintigraphic [5–9] and MR lymphography studies [10–19], the injection technique, e.g. subcutaneous or intracutaneous injections, has shown to have an influence on the transport and distribution of the contrast media. We injected the contrast material intracutaneously, because the contrast material is close to the lymphatic capillaries and pre-collector sections capable of absorption [2]. In
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lymphoscintigraphic examinations, intracutaneous contrast media administration was shown to be associated with rapid lymphatic transport, facilitating fast evaluation and better quantification of lymphatic flow [8]. The individual initial lymphatics are closely interconnected in the shape of a hexagonal pattern and have blind endings, ranging in diameter from 10 to 60 m, significantly larger than the diameter of arteriovenous capillaries with a size of about 8 m [2,28]. Depending on the degree of distension, extracellular fluids and proteins enter the initial lymphatics through interendothelial openings and by vesicular transport through the endothelial cells, both ways being of equal importance [2,28]. The injection sites were massaged in the presented patients, because reports have demonstrated the advantage for contrast material lymphatic uptake [15]. I MRL depicted inguinal lymph nodes in two patients and iliac lymph nodes in one patient. In comparison to MR lymphography studies using lymphotropic contrast agents, although, the lymph node enhancement was not enough for analysis of nodal morphology.
5. Conclusion In the presented small study group, I MRL was technically feasible, and no complications were observed after intracutaneous injection of gadodiamide. Visualizing the lymphatic vessels and accompanying complications non-invasively and without the use of radiation, the presented method has the capability to become a routine diagnostic imaging tool in patients with primary and secondary lymphedema. The method is not directed at the characterization of lymph node morphology, but could provide additional information about the lymphatic vessels when lymph nodes are examined, e.g. with super-paramagnetic iron oxide particles. Clearly, the clinical utility of I MRL requires further validation in a larger patient population.
References [1] Foeldi E. The treatment of lymphedema. Cancer 1998;83:2833–4. [2] Foeldi M, Foeldi E, Kubik S. Textbook of lymphology. 1st ed. Munich, Germany: Elsevier; 2003. [3] International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema. Consensus document of the International Society of Lymphology. Lymphology 2003;36:84–91. [4] Rockson SG, Miller LT, Senie R, et al. American Cancer Society Lymphedema Workshop. Workgroup III: diagnosis and management of lymphedema. Cancer 1998;83:2882–5. [5] Weissleder H, Weissleder R. Lymphedema: evaluation of qualitative and quantitative lymphoscintigraphy in 238 patients. Radiology 1988;167:729–35. [6] Williams WH, Witte CL, Witte MH, McNeill GC. Radionuclide lymphangioscintigraphy in the evaluation of peripheral lymphedema. Clin Nucl Med 2000;25:451–64. [7] McNeill GC, Witte MH, Witte CL, et al. Whole-body lymphangioscintigraphy: preferred method for initial assessment of the peripheral lymphatic system. Radiology 1989;172:495–502.
[8] Suga K, Uchisako H, Nakanishi T, et al. Lymphoscintigraphic assessment of leg oedema following arterial reconstruction using a load produced by standing. Nucl Med Commun 1991;12:907–17. [9] Ohtake E, Matsui K. Lymphoscintigraphy in patients with lymphedema. A new approach using intradermal injections of technetium-99m human serum albumin. Clin Nucl Med 1986;11: 474–8. [10] Harika L, Weissleder R, Poss K, Zimmer C, Papisov MI, Brady TJ. MR lymphography with a lymphotropic T1-type MR contrast agent: Gd-DTPA-PGM. Magn Reson Med 1995;33:88–92. [11] Staatz G, Nolte-Ernsting CC, Adam GB, et al. Interstitial T1-weighted MR lymphography: lipophilic perfluorinated gadolinium chelates in pigs. Radiology 2001;220:129–34. [12] Misselwitz B, Platzek J, Weinmann HJ. Early MR lymphography with gadofluorine M in rabbits. Radiology 2004;231: 682–8. [13] Herborn CU, Lauenstein TC, Vogt FM, Lauffer RB, Debatin JF, Ruehm SG. Interstitial MR lymphography with MS-325: characterization of normal and tumor-invaded lymph nodes in a rabbit model. AJR Am J Roentgenol 2002;179:1567–72. [14] Ruehm SG, Schroeder T, Debatin JF. Interstitial MR lymphography with gadoterate meglumine: initial experience in humans. Radiology 2001;220:816–21. [15] Ruehm SG, Corot C, Debatin JF. Interstitial MR lymphography with a conventional extracellular gadolinium-based agent: assessment in rabbits. Radiology 2001;218:664–9. [16] Suga K, Yuan Y, Nobuhiko O, Okada M, Kawakami Y, Matsunaga N. Potential of magnetic resonance lymphography with intrapulmonary injection of gadopentetate dimeglumine for visualization of the pulmonary lymphatic basin in dogs: preliminary results. Invest Radiol 2003;38:679–89. [17] Suga K, Yuan Y, Ogasawara N, Okada M, Matsunaga N. Visualization of normal and interrupted lymphatic drainage in dog legs with interstitial MR lymphography using an extracellular MR contrast agent, gadopentetate dimeglumine. Invest Radiol 2003;38: 349–57. [18] Suga K, Yuan Y, Ogasawara N, Okada M, Matsunaga N. Localization of breast sentinel lymph nodes by MR lymphography with a conventional gadolinium contrast agent. Preliminary observations in dogs and humans. Acta Radiol 2003;44:35–42. [19] Fink C, Bock M, Kiessling F, Delorme S. Interstitial magnetic resonance lymphography with gadobutrol in rats: evaluation of contrast kinetics. Invest Radiol 2002;37:655–62. [20] Cohan RH, Leder RA, Herzberg AJ, et al. Extravascular toxicity of two magnetic resonance contrast agents. Preliminary experience in the rat. Invest Radiol 1991;26:224–6. [21] Foeldi E, Foeldi M, Weissleder H. Conservative treatment of lymphoedema of the limbs. Angiology 1985;36:171–80. [22] Kinmonth JB. Lymphangiography in man; a method of outlining lymphatic trunks at operation. Clin Sci 1952;11:13–20. [23] Koehler PR. Complications of lymphography. Lymphology 1968;1:116–20. [24] Weissleder R, Elizondo G, Josephson L, et al. Experimental lymph node metastases: enhanced detection with MR lymphography. Radiology 1989;171:835–9. [25] Bellin MF, Beigelman C, Precetti-Morel S. Iron oxide-enhanced MR lymphography: initial experience. Eur J Radiol 2000;34:257– 64. [26] Bellin MF, Roy C, Kinkel K, et al. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles—initial clinical experience. Radiology 1998;207:799–808. [27] Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348:2491–9. [28] Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol Rev 1990;70:987–1028.
Technical note
Indirect magnetic resonance lymphangiography in patients with lymphedema Preliminary results in humans Christian Lohrmann a,∗ , Etelka Foeldi b , Mathias Langer a a
Division of Diagnostic Radiology, Department of Radiology, University Hospital of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany b Foeldi Clinic for Lymphology, Hinterzarten, R¨ oßlehofweg 2-6, D-79856 Hinterzarten, Germany Received 19 October 2005; received in revised form 12 February 2006; accepted 17 February 2006
Abstract Purpose: To assess the feasibility of indirect magnetic resonance (MR) lymphangiography with intracutaneous injection of gadodiamide, a commercially available, non-ionic, extracellular paramagnetic contrast agent for the detection of lymphatic vessels in patients with lymphedema. Materials and methods: In 2005, three patients with lymphedema of the lower extremities (1 primary, 2 secondary) were referred by the Foeldi Clinic for Lymphology for indirect magnetic resonance lymphangiography. 4.5 mL of gadodiamide and 0.5 mL of mepivacainhydrochloride 1% were injected intracutaneously into the dorsal aspect of each foot. MR imaging was performed with a 1.5-T system equipped with highperformance gradients. For indirect magnetic resonance lymphangiography, a 3D Fast Low Angle Shot (FLASH) sequence (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s) was used. Results: Indirect magnetic resonance lymphangiography depicted lymphatic vessels of the lower and upper leg, and inguinal lymph nodes in all three patients. After 5 min of contrast material application, concomitant venous enhancement was detected. Collateral vessels with dermal back-flow were seen in two patients. A lymphocele in the inguinal region with the afferent lymphatic vessel was depicted in one patient. Conclusion: In the presented small study group, indirect magnetic resonance lymphangiography was technically feasible, and no complications were observed after intracutaneous injection of gadodiamide. Visualizing the lymphatic vessels and accompanying complications non-invasively and without the use of radiation, the presented method has the capability to become a routine diagnostic imaging tool in patients with primary and secondary lymphedema. The method is not able to characterize lymph node morphology, but could provide additional information about the lymphatic vessels when lymph nodes are examined, e.g. with super-paramagnetic iron oxide particles. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Gadodiamide; Indirect magnetic resonance lymphangiography; Lymphedema
1. Introduction Progress achieved in the understanding of microcirculation and molecular biology has made it possible to understand many aspects of morphologic and functional tissue alterations that occur as a consequence of lymphostasis [1–4]. A major hindrance in understanding the pathophysiology of lym-
∗
Corresponding author. Tel.: +49 761 270 3802; fax: +49 761 270 3838. E-mail address: [email protected] (C. Lohrmann).
0720-048X/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2006.02.012
phedema, to differentiate it from other types of edema, and in creating accurate treatment plans, has been the complexity of visualizing the lymphatic pathways in human beings [1–4]. So far, lymphoscintigraphy is considered to be the primary imaging modality in patients with extremity lymphedema. Despite improvements in this technology, an improved depiction of the lymphatic system with a high resolution is desired [5–9]. Interstitial magnetic resonance lymphangiography (I MRL) has shown promising results in experimental animal models with intracutaneous and subcutaneous administration of various lymphotropic paramagnetic contrast agents. Only
402
C. Lohrmann et al. / European Journal of Radiology 59 (2006) 401–406
small amounts of these substances are needed for their rapid appearance in lymph nodes and lymphatic vessels. Anyhow, these lymphotropic contrast agents are still in the preclinical phase with an uncertain safety profile [10–13]. I MRL with administration of a commercially available extracellular paramagnetic contrast agent has been proposed to be safe and effective in imaging lymph nodes and lymphatic vessels in animals and humans [14–19]. The purpose of this study was to evaluate the feasibility of I MRL with intracutaneous injection of gadodiamide (Omniscan, GE Healthcare, Munich, Germany), a commercially available, non-ionic, extracellular paramagnetic contrast agent for the detection of lymphatic vessels in patients lymphedema.
An amount of 4.5 mL of contrast material and 0.5 mL mepivacainhydrochloride 1% were subdivided into five portions and injected intracutaneously into the dorsal aspect of each foot in the region of the four interdigital webs; one portion was injected medial to both first proximal phalanges. Immediately after administration of the contrast agent, the injection sites of each foot were massaged for about 60 s. The massage was repeated between the data acquisitions. All patients were asked to describe the intensity of pain at the time of gadodiamide application. A four-point scale was used: 0: no pain; 1: mild pain; 2: moderate pain; and 3: severe pain. After the examination, the patients were monitored closely in the Foeldi Clinic for Lymphology to observe possible complications such as swelling or infection.
2. Materials and methods
2.4. MR imaging examinations
2.1. Contrast agent
MR imaging was performed with a 1.5-T system (Magnetom Symphony; Siemens Medical Systems, Erlangen, Germany) equipped with high-performance gradients. 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. For I MRL, a 3D Fast Low Angle Shot (FLASH) sequence with the following parameters was used: (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s). The three stations were first imaged without contrast material and subsequently repeated 5, 15, 25, 35, 45, and 55 min after intracutaneous application of the contrast material. To highlight the Gd containing structures, baseline images were subtracted before 3D maximum-intensity-projection (MIP) reconstructions were calculated.
Gadodiamide (Omniscan, GE Healthcare, Munich, Germany), is a commercially available, extracellular, watersoluble paramagnetic contrast agent with a gadolinium (Gd) concentration of 0.5 mmol. This contrast agent is normally administered intravenously at a recommended dose of 0.1 mmol/kg of body weight, which is equivalent to a dose of 0.2 mL/kg. For MR angiography, however, gadodiamide has been approved at doses up to three times the normal dose. It is not subjected to metabolization and is excreted unchanged by passive glomerular filtration. Gd chelates have low molecular masses, and are rapidly cleared from the intravascular space through the capillaries into the interstitial space. Experimental animal models have demonstrated solely minor tissue damage after non-intravenous injection or extravasation [20]. Therefore, the agent offers an acceptable safety profile for intracutaneous application. 2.2. Study design In the year 2005, three patients with lymphedema of the lower extremities (1 primary and 2 secondary); mean age 60 years; range 54–69 years; 1 female, 2 males) were referred by the Foeldi Clinic for Lymphology for I MRL. The diagnosis of lymphedema was established with clinical criteria using the Foeldi & Foeldi classification [21]. The inclusion criteria were lymphedema of one or both lower extremities and willingness to participate in the study. Exclusion criteria were contraindications for MRI, renal insufficiency, or a known gadolinium contrast agent allergy. This study has been approved by the local ethics committee, and all participants had given their informed consent before being included in the study. 2.3. Contrast material administration For injection of gadodiamide, a thin needle (24 gauge) was used.
2.5. Image analysis All authors qualitatively assessed the enhancement of gadodiamide in the lymphatic pathways, and inguinal/iliac lymph nodes using the source images and MIP reconstructions. Lymphatic vessels were regarded as clearly visible, if their beaded appearance could be differentiated from parallel enhancing veins. Furthermore, the lymphatic vessels were evaluated concerning size, collaterals, and lymphoceles. An area of progressive dispersion of the contrast media into the soft tissues was regarded as dermal “back-flow”. A diagnosis was made by consensus. The time courses of enhancement of the lymphatic pathways, inguinal/iliac lymph nodes, and veins were analyzed quantitatively by one experienced radiologist. The size of the regions of interest was adapted to encompass as much as possible of these structures. The postcontrast images facilitated the identification of these structures on the precontrast images.
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3. Results All patients described the pain at the time of contrast material administration as mild, and were able to walk well and without discomfort after the examination. The minor swelling in the region of the application sites resolved within 24 h in all patients. No complications were observed after the examination. The lymphedema was bilateral in one and unilateral in two patients. In all patients, the beaded appearance of the lymphatic vessels extending from the injection site was reliably detected and clearly differentiated form parallel enhancing
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veins 15 min after injection (Table 1, Fig. 1). After 5 min of contrast material application, concomitant venous enhancement was detected in the lower and upper leg of each patient (Fig. 1). In the lower leg, the best delineation of the lymphatic vessels was present after 35 min in two patients, and after 45 min in one patient (Fig. 1). In all patients, the lymphatic vessels in the upper leg could reliably be detected at 25 min, with the strongest enhancement at 45 min in one patient, and at 55 min in two patients after contrast material application (Fig. 2). In all patients, the inguinal lymph nodes with external iliac lymphatic pathways were reliably depicted at 35 min, with the highest signal intensity at 45 min in one patient,
Fig. 1. Sixty-nine-year-old man with primary lymphedema. (A) Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 15 min after gadodiamide injection, clearly delineates the enlarged lymphatic vessels in the left lower leg (small arrows). Note the small area of dermal back-flow (arrowhead) indicating lymphatic flow obstruction. The concomitantly enhanced vein shows a lower signal intensity (large arrow). (B) Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 35 min after gadodiamide injection, demonstrates increasing contrast media filling of the enlarged lymphatic vessels in the left lower leg (small arrows) and enlarging areas of dermal back-flow (arrowheads). The concomitantly enhanced vein shows a lower signal intensity (large arrow).
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Table 1 Interstitial magnetic resonance lymphangiography (I MRL) findings in three patients with primary and secondary lymphedema HR MRL findings
Number of patients (%)
Lymphatic vessels lower leg Lymphatic vessels upper leg Inguinal lymph nodes External iliac lymph nodes Collateral vessels Dermal back-flow Lymphocele
3 (100) 3 (100) 3 (100) 1 (33) 2 (66) 2 (66) 1 (33)
and at 55 min in two patients after gadodiamide application (Fig. 3). The external iliac lymph nodes were observed in only two patients, and paraaortic lymph nodes in none of the patients.
Fig. 3. Fifty-three-year-old man with a history of malignant melanoma and lymphedema of the right leg due to inguinal lymph node extirpation and radiation. Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 55 min after gadodiamide injection, demonstrates inguinal lymph nodes (arrowheads) with afferent and efferent lymphatic vessels (arrows) on the left side. No inguinal lymph nodes were detected on the right side.
Collateral vessels with dermal back-flow, indicative of proximal lymph flow obstruction with alternate pathways of transport, were seen in two patients (Figs. 1 and 2). The maximum diameter of a dilated lymphatic vessel was 5 mm. In one patient, enhancement of a lymphocele in the left groin with the afferent lymphatic vessel was detected (Fig. 4).
4. Discussion
Fig. 2. Sixty-nine-year-old man with primary lymphedema. Frontal 3D Fast Low Angle Shot MIP image (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 45 min after gadodiamide injection, demonstrates enlarged lymphatic vessels in the left lower and upper leg (arrowheads). Areas of dermal back-flow are seen (large arrows) indicating lymphatic flow obstruction. The concomitantly enhanced vein shows a lower signal intensity (small arrow).
To date, lymphoscintigraphy has been the primary imaging tool in diagnosing patients with lower leg lymphedema [5–9]. This method, though, has the disadvantage of ionizing radiation, and low spatial and temporal resolution, which limits its worth for exact assessment of the lymphatic anatomy and function [5–9]. Direct lymphography achieves the highest concentration of the contrast media in the lymph vessels and nodes [22]. Long examination times, radiation exposure, invasiveness, and potential side effects like local wound infection and pulmonary embolism have, although, limited its clinical applicability [23]. If the underlying reason of lymphedema is unclear or needs an improved definition for ideal therapeutic planning, a non-invasive imaging modality to visualize the lymphatic system with a high resolution is crucial. I MRL with a three station protocol provided a noninvasive, high-resolution display of the lymphatic vessels and accompanying complications in patients with lower extremity lymphedema. As seen in conventional indirect lymphography with suitable water-soluble contrast media, the presented method allowed evaluation of several lymphatic vessels after intracutaneous contrast material injection [22]. Conventional indirect lymphography, however, enabled only the imaging of
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Fig. 4. Fifty-seven-year-old obese woman with lymphedema of the left leg and a lymphocele in the left groin due lymph collector damage during liposuction. (A) Frontal 3D Fast Low Angle Shot sequence (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 55 min after contrast material injection, clearly delineates the feeding lymphatic vessel (arrowhead) of the lymphocele (large arrows) in the left groin. Note the epifascial lymphedema of the left upper leg (small arrows). The subcutaneous tissue on the right side is unremarkable. (B) Frontal 3D Fast Low Angle Shot sequence (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 × 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm × 1.0 mm × 1.0 mm; acquisition time: 0 min 31 s), obtained 55 min after contrast material injection, demonstrates contrast media filling (arrowheads) of the the lymphocele (large arrows). Note the epifascial lymphedema of the left upper leg (small arrows). The subcutaneous tissue on the right side is unremarkable.
40–60 cm-long sections of lymph vessels in the lower extremities. It was rarely possible to image the lymph vessels as far as the inguinal region [24]. The presented I MRL protocol enabled enhancement of the inguinal lymph nodes and of the lymphatic vessels up to the external iliac region in all three patients. Compared to conventional indirect lymphography, it was consequently possible to examine the lymphatic system of the entire leg with one I
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MRL examination. Due to the high resolution of the presented protocol with a voxel size of 2.0 mm × 1.0 mm × 1.0 mm, even small collateral lymphatic vessels could be visualized in two patients. I MRL localized areas of dysfunctional lymphatic drainage with adjacent areas of dermal back-flow in two patients. Accurate localizing of the pathology by I MRL thereby supports the clinician to choose the appropriate treatment modality, e.g. manual lymphatic drainage and compression therapy. In one patient, I MRL was successful in identifying a lymphocele in the left groin with the afferent lymphatic vessel. The important differentiation to other fluid collections, e.g. hematoma and seroma, could thus be made. In accordance with a report by Ruehm et al. [14], we observed concomitant enhancement of veins in all patients. 3D MIP reconstruction, however, permitted identification of the lymphatic vessels and differentiation from veins. All three patients graded the pain at the time of contrast media injection as mild. However, to further increase patient acceptance, a reduction of the injected contrast media volume would be worthwhile. One option could be the use of a more concentrated Gd formulation (1.0 instead of 0.5 mol/L), such as gadobutrol (Gadovist; Schering, Berlin, Germany), which has proven to be feasible for I MRL in rats [19]. Furthermore, the lack of radiation in I MRL is a great advantage in managing the large number of patients affected by lymphedema. For the detection of lymph nodes, intravenous injection of super-paramagnetic iron oxide particles of various sizes has been evaluated. The advantage is that, theoretically, all lymph nodes in the body can be accessed. Major drawbacks are an inhomogeneous uptake and slow accumulation in different lymph node groups. Furthermore, susceptibility artefacts are seen on MR images [25–27]. Due to the negative contrast, enhancement of iron oxides particles and the low spatial resolution, lymphatic vessels can, however, not be demonstrated with T2-weighted MR lymphography [25–27]. Gd-enhanced T1-weighted MR images exhibit higher spatial resolution, higher signal-to-noise ratio, and fewer artefacts than do MR images with negative contrast, such as iron oxide particles [10–13]. Gd-based, lymphotropic contrast agents are, however, still in the preclinical phase and cannot be used in humans [10–13]. Due to a short repetition time, the FLASH sequence renders all tissues dark, except those containing a considerable amount of T1-shortening contrast agent. Even though susceptibility effects as a result of the highly concentrated gadodiamide were seen at the injection sites, the signal distortions due to T2-shortening effects were insignificant. In routine lymphoscintigraphic [5–9] and MR lymphography studies [10–19], the injection technique, e.g. subcutaneous or intracutaneous injections, has shown to have an influence on the transport and distribution of the contrast media. We injected the contrast material intracutaneously, because the contrast material is close to the lymphatic capillaries and pre-collector sections capable of absorption [2]. In
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lymphoscintigraphic examinations, intracutaneous contrast media administration was shown to be associated with rapid lymphatic transport, facilitating fast evaluation and better quantification of lymphatic flow [8]. The individual initial lymphatics are closely interconnected in the shape of a hexagonal pattern and have blind endings, ranging in diameter from 10 to 60 m, significantly larger than the diameter of arteriovenous capillaries with a size of about 8 m [2,28]. Depending on the degree of distension, extracellular fluids and proteins enter the initial lymphatics through interendothelial openings and by vesicular transport through the endothelial cells, both ways being of equal importance [2,28]. The injection sites were massaged in the presented patients, because reports have demonstrated the advantage for contrast material lymphatic uptake [15]. I MRL depicted inguinal lymph nodes in two patients and iliac lymph nodes in one patient. In comparison to MR lymphography studies using lymphotropic contrast agents, although, the lymph node enhancement was not enough for analysis of nodal morphology.
5. Conclusion In the presented small study group, I MRL was technically feasible, and no complications were observed after intracutaneous injection of gadodiamide. Visualizing the lymphatic vessels and accompanying complications non-invasively and without the use of radiation, the presented method has the capability to become a routine diagnostic imaging tool in patients with primary and secondary lymphedema. The method is not directed at the characterization of lymph node morphology, but could provide additional information about the lymphatic vessels when lymph nodes are examined, e.g. with super-paramagnetic iron oxide particles. Clearly, the clinical utility of I MRL requires further validation in a larger patient population.
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