High-Resolution MR Lymphangiography in Patients with Primary and Secondary Lymphedema

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1 Lohrmann et al. MR Lymphangiog raphy of Patients with Lymphedem a Vascular Imaging Technical Innovation C M E D E N T U R I C L I M G I N G JR 2006; 187: X/06/ merican Roentgen Ray Society Y O Christian Lohrmann 1 Etelka Foeldi 2 Oliver Speck 1 Mathias Langer 1 F Lohrmann C, Foeldi E, Speck O, Langer M Keywords: high-resolution angiography, leg, lymphangiography, MRI DOI: /JR Received October 4, 2005; accepted without revision December 7, Department of Radiology, Division of Diagnostic Radiology, University Hospital of Freiburg, Hugstetter Strasse 55, D-79106, Freiburg, Germany. ddress correspondence to C. Lohrmann (lohrmann@mrs1.ukl.uni-freiburg.de). 2 Foeldi Clinic for Lymphology, Hinterzarten, Germany. High-Resolution MR Lymphangiography in Patients with Primary and Secondary Lymphedema OBJECTIVE. The objective of our study was to evaluate the feasibility of high-resolution MR lymphangiography with intracutaneous injection of gadodiamide, a commercially available, nonionic, extracellular paramagnetic contrast agent, for the visualization of lymphatic vessels in patients with primary and secondary lymphedema. CONCLUSION. High-resolution MR lymphangiography is safe, is technically feasible, and has the potential to become a diagnostic imaging tool for patients with lymphedema. major obstacle in understanding the pathophysiology of lymphedema has been the difficulty of visualizing lymphatic vessels in human beings [1]. Despite recent refinements in lymphoscintigraphy, an improved depiction of the lymphatic system with a high resolution is desired [2]. Interstitial MR lymphography has shown promising results in many experimental animal models with intra- and subcutaneous administration of various lymphotropic paramagnetic contrast agents [3]. Only small amounts of these substances are needed, and their advantage is a rapid appearance in lymph nodes and lymphatic vessels. However, these lymphotropic contrast agents are still in the preclinical phase with an uncertain safety profile. Interstitial MR lymphography with the administration of a commercially available extracellular paramagnetic contrast agent has been proposed as a safe and effective method to image lymph nodes and lymphatic vessels in animals and humans [4 6]. The purpose of this study was to evaluate the feasibility of high-resolution (HR) MR lymphangiography with intracutaneous injection of gadodiamide (Omniscan, GE Healthcare), a commercially available, nonionic, extracellular paramagnetic contrast agent, for the visualization of lymphatic vessels in patients with primary and secondary lymphedema. Subjects and Methods Contrast gent Gadodiamide is a commercially available, extracellular, water-soluble paramagnetic contrast agent with a gadolinium concentration of 0.5 mmol, and it is normally administered IV at a recommended dose of 0.1 mmol per kilogram 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 standard. Experimental animal models have shown merely minor tissue damage after non-iv injection or extravasation [7]. Therefore, the agent offers an acceptable safety profile for intracutaneous administration. Study Design Between March and ugust 2005, 10 patients with lymphedema of the lower extremities (eight primary and two secondary after malignant lymph node extirpation and radiation in the pelvic and inguinal regions; mean age, 42 years; range, years; eight women, two men) were referred by the Foeldi Clinic for Lymphology for HR MR lymphangiography. The diagnosis of lymphedema was established with clinical criteria using the Foeldi and Foeldi classification, as described by Foeldi et al. [8]. The inclusion criteria were lymphedema of one or both lower extremities and a willingness to participate in the study. Patients with contraindications for MRI, renal insufficiency, or a known allergy to a gadolinium contrast agent were excluded. The local ethics committee approved the study, and all participants gave their informed consent before being included. Contrast Material dministration For injection of gadodiamide, a thin needle (24 gauge) was used. contrast material dose of 0.1 mmol per kilogram of body weight, which corresponds to the recommended IV dose, and 2 ml of mepivacaine hydrochloride 1% was subdivided into 10 portions. Four portions were injectedcuta- 556 JR:187, ugust 2006

2 MR Lymphangiography of Patients with Lymphedema neously 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. Because of patients limited tolerability, the maximum applied volume of gadodiamide was restricted to 1.8 ml per portion. Directly after administration of the contrast material, the injection sites of each foot were massaged for approximately 60 seconds. The massage was repeated during data acquisition. ll patients were asked to describe the intensity of pain at the time of gadodiamide application. 4-point scale was used: 0, no pain; 1, mild pain; Fig. 1 Four cases of lymphedema: two primary and two secondary., 33-year-old man with primary lymphedema. Frontal 3D spoiled gradient-echo highresolution MR lymphangiography image, obtained 45 minutes after gadodiamide injection, clearly delineates slightly enlarged lymphatic vessels in right lower leg (arrows). Note concomitantly enhanced vein (arrowheads) that shows lower signal intensity. B, 46-year-old man with primary lymphedema. Bilateral frontal 3D spoiled gradientecho high-resolution MR lymphangiography sequence, obtained 45 minutes after gadodiamide injection, clearly delineates several slightly enlarged lymphatic vessels in both lower legs. Note concomitantly enhanced veins (arrowheads), which show lower signal intensity. (Fig. 1 continues on next page) 2, moderate pain; and 3, severe pain. fter the examination, the patients were monitored closely in the Foeldi Clinic for Lymphology to observe the patients for possible complications such as swelling or infection. MRI Examinations MRI was performed with a 1.5-T scanner (Magnetom Symphony, Siemens Medical Systems) equipped with high-performance gradients. Three stations were examined: first, the lower leg and the foot region; second, the upper leg and the knee region; and third, the pelvic region and the proximal upper leg. 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. Before HR MR lymphangiography, the extent and distribution of the lymphedema were evaluated using a heavily T2-weighted 3D turbo spin-echo sequence (TR/TE, 2,000/694; flip angle, 180 ; matrix, ; bandwidth, 247 Hz/pixel; 6/8 rectangular field of view, 480 mm; slices, 96; voxel size, mm; acquisition time, 4 minutes 4 seconds). To highlight the edema, 3D maximum-intensity-projection (MIP) reconstructions were performed. B JR:187, ugust

3 Lohrmann et al. C Fig. 1 (continued) Four cases of lymphedema: two primary and two secondary. C, 43-year-old woman with history of cervical cancer and secondary lymphedema related to pelvic and inguinal lymph node extirpation. Frontal 3D spoiled gradient-echo high-resolution MR lymphangiography image of left lower leg, obtained 35 minutes after gadodiamide injection, reveals delayed lymphatic flow with reticular pattern of dilated lymphatic vessels indicating neovascularization related to obstruction. Furthermore, dermal backflow (arrowhead) is detected. Note concomitantly enhanced vein (arrow), which shows lower signal intensity. D, 79-year-old woman with history of malignant melanoma and secondary lymphedema related to inguinal lymph node extirpation and radiation. Frontal 3D spoiled gradient-echo high-resolution MR lymphangiography sequence, obtained 35 minutes after gadodiamide injection, reveals delayed lymphatic flow with extensive reticular pattern of dilated lymphatic vessels, indicating neovascularization related to obstruction. For HR MR lymphangiography a 3D spoiled gradient-echo sequence (volumetric interpolated breathhold examination [VIBE]) with the following parameters was used: TR/TE, 3.4/1.47; flip angle, 25 ; matrix, ; bandwidth, 490 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices, 128; voxel size, mm; acquisition time, 44 seconds). The three stations were first imaged without contrast material and subsequently repeated 5, 15, 25, 35, 45, and 55 minutes after intracutaneous application of the contrast material. To emphasize the gadolinium-containing structures, baseline images were subtracted before 3D MIP reconstructions were calculated. D Fig year-old woman with primary lymphedema. ngled 3D spoiled gradient-echo high-resolution MR lymphangiography image, obtained 55 minutes after gadodiamide injection, clearly delineates multiple large and tortuous lymphatic vessels in left upper leg. Image nalysis Three authors qualitatively assessed the enhancement of gadodiamide in the lymphatic pathways, inguinal and iliac lymph nodes, and veins using the source images and MIP reconstructions. Lymphatic vessels were evaluated regarding their visibility with a beaded appearance, size, and collaterals. n area of progressive dispersion of the contrast medium into the soft tissues was regarded as dermal backflow. diagnosis was made by consensus. One author quantitatively analyzed the time course of enhancement by recording the maximal 558 JR:187, ugust 2006

4 MR Lymphangiography of Patients with Lymphedema signal intensities on the consecutive images. The size of the regions of interest was adapted to encompass as much as possible of these structures. Noise was defined as the SD from a measurement of signal intensity outside the patient. Signal-tonoise ratios were calculated by dividing the signal intensity by noise. Results The pain at the time of gadodiamide application was described as mild by eight patients and as moderate by two patients. ll patients were able to walk well and without discomfort after the examination. The minor swelling in the region of the interdigital web after gadodiamide application resolved within 24 hours in all patients. No complications were observed after the examination. The lymphedema was unilateral in six and bilateral in four patients. In all patients the lymphedema showed an epifascial distribution with a high signal intensity on T2-weighted Fig year-old woman with primary lymphedema (not same patient as in Fig. 2). ngled 3D spoiled gradient-echo highresolution MR lymphangiography sequence, obtained 55 minutes after contrast material injection, clearly delineates dilated lymphatic external iliac pathway (arrowhead), originating from inguinal lymph nodes, indicating obstruction. Furthermore, dermal backflow (arrows) is detected. Note enhancement of bladder (asterisk), showing venous uptake and renal clearance of contrast medium after intracutaneous injection. images. In one patient with primary lymphedema, T2-weighted images were able clearly to delineate multiple large and tortuous lymphatic vessels in the upper and lower leg. In all patients, the beaded appearance of the lymphatic vessels extending from the injection site was reliably detected 15 minutes after injection (Figs. 1 1D). fter 5 minutes of contrast material application, concomitant venous enhancement was detected in the lower and upper leg of each patient (Figs. 1 1C). In the lower leg, the best delineation of the lymphatic vessels was present after 45 minutes in six patients and after 35 minutes in four patients. In eight patients, the lymphatic vessels in the upper leg could be detected, with the strongest enhancement at 55 minutes in six patients and at 45 minutes 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 minutes, with the highest signal intensity at 55 minutes after gadodiamide application (Fig. 3). The external iliac lymph nodes were merely observed in four patients and paraaortic lymph nodes in none of the patients. Collateral vessels with dermal backflow between lymph vessels, indicating proximal lymph flow obstruction with alternate pathways of transport, were seen in seven patients (Figs. 1C and 3). The maximum diameter of a dilated lymphatic vessel was 5 mm. Discussion Where the diagnosis of lymphedema is unclear or needs a better definition for optimal therapeutic planning, an excellent noninvasive imaging technique to visualize the lymphatic system and the lymphedema with a high resolution is crucial. To date, no imaging procedure has fulfilled these criteria. The proposed HR MR lymphangiography strategy with a three-station protocol provided a safe, noninvasive, HR display of the lymphatic vessels up to the external iliac pathways. Conventional indirect lymphography, however, enabled only the imaging of 40- to 60-cm-long sections of lymph vessels in the lower extremities. Furthermore, the lack of radiation exposure in HR MR lymphangiography is a great advantage in the management of the large number of patients affected by lymphedema. Until now, lymphoscintigraphy has been the primary imaging technique in diagnosing patients with suspected extremity lymphedema [2]. However, this method has the disadvantage of ionizing radiation exposure and poor spatial and temporal resolution, limiting its value for accurate assessment of the lymphatic anatomy and function. Direct lymphography provides the highest accumulation of the contrast agent in lymph vessels and nodes. Invasiveness, long examination times, radiation exposure, and potential side effects such as pulmonary embolism and local wound infection have limited its clinical applicability, however. We injected the contrast material intracutaneously because the contrast medium depots are in the vicinity of the lymphatic capillaries and in precollector sections capable of absorption [1]. fter absorption, the contrast material is transported through a set of precollectors, which are connected with deeper layers of lymphatics in the dermis, where lymph fluid is transported centrally through collectors. In subcutaneous applications, the injection material must diffuse upward through the intercellular space system of the cutis until it gets through to vessels capable of absorption [1]. JR:187, ugust

5 Lohrmann et al. Signal Intensity (rbitrary Units) veins lymphatic vessels Time fter Injection (min) 55 Fig. 4 Primary lymphedema., Graph shows typical time course of signal enhancement in lymphatic and venous vessels of lower leg. B and C, MR lymphangiography images show signal enhancement in lymphatic vessels (B) and veins (C) of 49-year-old woman with primary lymphedema. B C 560 JR:187, ugust 2006

6 MR Lymphangiography of Patients with Lymphedema In agreement with a study by Ruehm et al. [4], we observed concomitant enhancement of veins in all patients. Three-dimensional MIP images of different angles of view provided detailed outlining of the lymphatic pathways and allowed differentiation from veins based on their beaded appearance. If the beaded appearance of the lymphatic vessels was not recognized definitively, the time course of enhancement provided additional information. Because of the higher flow velocity in veins compared with lymphatic vessels, the enhancement diminished faster in veins, whereas lymphatic vessels remained enhanced for a longer time (Fig. 4). dditional measurements for example, venous time-of-flight MR angiograms can determine flow velocities quantitatively and may help to further differentiate abnormal lymphatic vessels from veins in the future. Characterized by a short TR, the VIBE sequence renders all tissues dark, except those containing a considerable amount of T1- shortening contrast agent. lthough the susceptibility effect caused by the presence of highly concentrated gadodiamide was seen at the injection sites, the signal distortions related to T2-shortening effects were negligible in the lymphatic system. HR MR lymphangiography depicted inguinal lymph nodes in all patients and external iliac lymph nodes in four patients in the present study. However, compared with MR lymphography studies using lymphotropic contrast agents, the lymph node enhancement was not sufficient for analysis of nodal morphology. To further increase patient acceptance, a reduction of the injected contrast material volume is desirable. One option would be using a more concentrated gadolinium formulation (1.0 instead of 0.5 mol/l), such as gadobutrol (Gadovist, Schering), which has proven to be suitable for interstitial MR lymphangiography in rats [6]. In conclusion, HR MR lymphangiography is feasible in the noninvasive visualization of the lymphatic vessels in patients with primary and secondary lymphedema. The method is not aimed at the depiction of lymph node morphology but could provide complementary information about the lymphatic vessels when lymph nodes are examined with superparamagnetic iron oxide particles in cancer patients. Clearly, the clinical usefulness of the proposed MR protocol will require further validation in larger patient cohorts. References 1. Foeldi M, Foeldi E, Kubik S. Textbook of lymphology. Munich, Germany: Elsevier, Weissleder H, Weissleder R. Lymphedema: evaluation of qualitative and quantitative lymphoscintigraphy in 238 patients. Radiology 1988; 167: 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. JR 2002; 179: Ruehm SG, Schroeder T, Debatin JF. Interstitial MR lymphography with gadoterate meglumine: initial experience in humans. Radiology 2001; 220: Ruehm SG, Corot C, Debatin JF. Interstitial MR lymphography with a conventional extracellular gadolinium-based agent: assessment in rabbits. Radiology 2001; 218: Fink C, Bock M, Kiessling F, Delorme S. Interstitial magnetic resonance lymphography with gadobutrol in rats: evaluation of contrast kinetics. Invest Radiol 2002; 37: Cohan RH, Leder R, Herzberg J, et al. Extravascular toxicity of two magnetic resonance contrast agents: preliminary experience in the rat. Invest Radiol 1991; 26: Foeldi E, Foeldi M, Weissleder H. Conservative treatment of lymphoedema of the limbs. ngiology 1985; 36: JR:187, ugust