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(Radiology. 2001;220:129-134.)
© RSNA, 2001

Experimental Studies

Interstitial T1-weighted MR Lymphography: Lipophilic Perfluorinated Gadolinium Chelates in Pigs1

Gundula Staatz, MD, Claus C. A. Nolte-Ernsting, MD, Gerhard B. Adam, MD, Stefanie Grosskortenhaus, Bernd Misselwitz, PhD, Arno Bücker, MD and Rolf W. Günther, MD

1 From the Department of Diagnostic Radiology, University Hospital of the RWTH Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany (G.S., C.C.A.N.E., G.B.A., S.G., A.B., R.W.G.); and Imaging Technologies and Preclinical Contrast Media Research, MRI, Schering, Berlin, Germany (B.M.). Received September 19, 2000; revision requested November 2; revision received December 11; accepted December 21. Address correspondence to G.S. (e-mail: staatz@rad.rwth-aachen.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the enhancement of the regional lymph nodes, lymphatic vessels, and thoracic duct after interstitial administration of lymphotropic perfluorinated gadolinium chelates at magnetic resonance (MR) imaging.

MATERIALS AND METHODS: Two perfluorinated gadolinium chelates, gadofluoramide and gadofluorine 8, were injected subcutaneously into the hind legs of 10 pigs, respectively. Both contrast media were studied at doses of 10 and 25 µmol per kilogram of body weight. T1-weighted three-dimensional gradient-echo and maximum intensity projection images were obtained at 1.5 T between 1 and 210 minutes and 24 hours after injection. The contrast agents were qualitatively compared regarding enhancement and depiction of the regional lymph nodes, lymphatic vessels, and thoracic duct.

RESULTS: The inguinal and iliac lymph nodes and lymphatic vasculature enhanced substantially within 10 minutes after subcutaneous administration of both lymphotropic contrast agents. Gadofluorine 8 showed a lymphographic effect superior to that of gadofluoramide. The paraaortic lymph nodes and thoracic duct were best visualized 10–50 minutes after injection of 25 µmol/kg of gadofluorine 8. Lymphatic system enhancement diminished after 2 hours, and the liver and bowel tract enhanced within 24 hours.

CONCLUSION: Interstitial administration of perfluorinated gadolinium chelates offers great potential for T1-weighted MR lymphography with positive enhancement of the lymph nodes and lymphatic vasculature.

Index terms: Animals • Gadolinium, 99.12943 • Lymphatic system, MR, 99.129412, 99.12943 • Lymphography, 99.125 • Magnetic resonance (MR), contrast enhancement, 99.129412, 99.12943


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The diagnosis of metastatic lymph node disease is of major concern for the prognosis and treatment of patients with tumor. Computed tomography (CT) and magnetic resonance (MR) imaging have shown only low (50%–70%) sensitivity for the depiction of lymph node metastases (1–3). Because of its excellent soft-tissue contrast resolution, MR imaging has advantages in demonstrating abnormal lymph nodes in the abdomen and pelvis, as compared with CT (4). Unfortunately, the relaxation times in benign and malignant lymph node tissue overlap considerably, so that lymph node size remains the most generally accepted criterion in MR imaging and CT (5,6). Using a threshold of 1.0 cm for the minimal transverse diameter of the pelvic lymph nodes, Kim et al (6) found a sensitivity of 62.2% and a specificity of 97.9% for MR imaging in the detection of pelvic lymph node metastases from uterine cervical carcinoma.

The evaluation of micronodal involvement is still critical, which underscores the need for a potential lymphographic contrast agent. Two groups of contrast agents may be used for MR lymphography. Weissleder et al (7) reported experimental results of MR lymphography with superparamagnetic iron oxides, which cause signal loss in normal lymph nodes in T2-weighted pulse sequences. The results of several studies (8–15) of iron oxide–based contrast agents have been published, but to our knowledge, little experience with new-generation lymphotropic T1-type contrast agents, which are still in an experimental stage, exists (16–19). T1-type contrast agents lead to positive enhancement of lymph nodes on T1-weighted images and therefore offer a higher signal-to-noise ratio and better anatomic resolution than do superparamagnetic iron oxides at T2-weighted MR lymphography (17).

The purpose of our study was twofold: (a) to investigate the enhancement of regional lymph nodes after subcutaneous administration of two new-generation lymphotropic T1-type contrast agents in MR imaging in an experimental animal model and (b) to investigate the use of those contrast agents to depict the lymphatic vasculature, especially the thoracic duct.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Anesthesia
All animal studies were approved by the institutional review board for animal research. Imaging was conducted with the animals sedated by using intramuscularly administered atropine sulfate 1% (0.5 mL/10 kg, Atropine; Braun, Melsungen, Germany), azaperone (2 mL/10 kg, Stresnil; Jansen-Cilag, Neuss, Germany), and ketamine 10% (1 mL/10 kg, Ketamine; Sanofia-Ceva, Düsseldorf, Germany) and then anesthetized with repeated intravenous injection of 3–4 mL of pentobarbital sodium (Narcoren; Rhone Merieux, Laupheim, Germany) as needed. After endotracheal intubation, all animals received assisted mechanical ventilation throughout the experiments.

The lymphatic system of 20 healthy female domestic pigs (Voets, Heinsberg, Germany) weighing 40–120 kg each was studied before and after interstitial administration of two perfluorinated gadolinium chelates, which were injected subcutaneously into the hind legs. Two groups of animals consisting of 10 pigs each were formed, with each group receiving only one contrast agent. Both lymphotropic contrast agents (50 mmol Gd/L solutions) were studied at a dose of 10 µmol per kilogram of body weight in four pigs and 25 µmol/kg in six pigs, which is equivalent to an injected fluid volume of 8.2–60.0 mL (mean volume, 22.5 mL). Each contrast medium was administered at five injection sites. Three portions, each containing 25% of the contrast agent, were injected at the ventral, medial, and lateral part of the thigh. Two portions, each containing 12.5%, were injected at the knee and the lower leg.

Contrast Agents
Both lymphotropic contrast agents used in our study belong to the same group of lipophilic gadolinium chelates with a perfluorinated side chain. Gadofluorine 8 and gadofluoramide (International Patent Application WO97/26017; Schering, Berlin, Germany) are macrocyclic Gd-DO3A complexes. Gadofluorine 8 has a molecular weight of 1,180 Da; gadofluoramide, 1,078 d. The T1 relaxivities (L x mmol-1 x sec-1) of gadofluorine 8, determined spectroscopically (Minispec PC-20; Bruker Instruments) in water and plasma at 0.47 T and 40°C, are higher than the T1 relaxivities of gadofluoramide (Table 1). The perfluorinated side chain allows both contrast agents to form micelles with a diameter of 3.9 nm, and the critical micelle concentration measured with surface tension is 2.5 µmol gadolinium per liter (20). The toxicity of both contrast agents was investigated by the manufacturer by using a mouse model. The LD50 in mice is 0.5 mmol Gd/kg (50 µmol gadolinium per liter) for gadofluorine 8 and 0.3 mmol gadolinium per kilogram (50 µmol gadolinium per liter) for gadofluoramide.


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  		TABLE 1. Relaxivity of Gadofluorine 8 and Gadofluoramide in Water and Plasma

 
MR Imaging
All MR imaging was performed with the pigs in the supine position inside a 1.5-T superconducting magnet (Gyroscan ACS-NT; Philips, Best, the Netherlands). Data were acquired by using the body coil of the magnet. The conventional gradient system used had an amplitude of 15 mT/m and a slew rate of 50 mT/m/msec (rise time, 0.3 msec).

The MR imaging protocol started with a T1-weighted gradient-echo localizer sequence composed of three section stacks oriented in coronal, sagittal, and transverse planes. Pre- and postcontrast MR lymphograms of the lower abdomen were obtained 1, 10, 20, 40, 60, 80, 120, 180, and 210 minutes and 24 hours following contrast material injection. Eight MR lymphograms of the upper abdomen and thorax were obtained immediately after the MR lymphograms of the lower abdomen at 10, 180, and 210 minutes and 24 hours after contrast material injection and 30, 50, 90, and 150 minutes after injection, respectively.

Imaging was performed with a T1-weighted three-dimensional (3D) gradient-echo sequence in the coronal plane. This sequence was characterized by a repetition time of 15 msec and an echo time of 4.2 msec (15/4.2) and a flip angle of 50°–70°. The field of view was 400–420 mm, and the rectangular field of view was 65%. To image most parts of the abdomen, 80–110 single sections were acquired, with a 2.2-mm thickness and a 1.1-mm overlap. MR lymphography was performed 60 minutes after contrast material administration, with a 1.6-mm section thickness, an 0.8-mm overlap, and a 250-mm field of view. The matrix size was 256 x 256, and two signals were acquired. The scanning time was 6.33–7.34 minutes. From the original data set, maximum intensity projection (MIP) images were postprocessed.

Image Analysis
The enhancement of the regional lymph nodes, lymphatic vessels, and thoracic duct after the administration of both contrast agents were qualitatively assessed by two authors (G.S., G.B.A.) in consensus. First, the regional lymph node groups enhanced with the contrast agents were evaluated in correlation to the dose used. Second, the enhancement of the lymph nodes, lymphatic vessels, and thoracic duct was classified as (a) poor, if only a few lymph nodes, no lymphatic vessels, and no thoracic duct were visible; (b) moderate, if several lymph nodes showed satisfactory enhancement and only a few lymphatic vessels and the distal part of the thoracic duct were delineated; or (c) excellent, if several lymph nodes, lymphatic vessels, and the thoracic duct showed good enhancement. Furthermore, depiction of the thoracic duct in correlation to time after contrast material injection and enhancement of the liver, spleen, and bowel tract were evaluated qualitatively.

The size of the enhancing lymph nodes (minimal transverse diameter) and the length of distribution of the contrast agent within the lymphatic system were measured on the single sections from the 3D gradient-echo sequence. Time-intensity curves were calculated for gadofluorine 8 at its most potent dose of 25 µmol/kg. The signal intensities of one inguinal and one iliac lymph node were determined on the single sections from the 3D sequence by using the region of interest method. Regions of interest as large as possible were centered within each lymph node medially to the margin of the node. Signal-to-noise ratios were calculated 1, 10, 20, 40, 80, 120, 180, 210 minutes, and 24 hours after contrast material injection by dividing the signal intensity (region of interest) by the SD of the background signal intensity. The region of interest for the background signal intensity was positioned lateral to the lower abdomen of the pig. Enhancement, E, expressed as a percentage, was calculated with the equation: E (%) = (Sipost/noise - Sipre/noise) / (Sipre/noise x 100), where Sipre indicated the precontrast signal intensity of a region of interest, Sipost indicated the postcontrast signal intensity of a region of interest, and noise indicated the SD of the background signal intensity.

Local tolerance for both contrast agents was checked at the injection site for 24 hours after administration.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
After subcutaneous injection, rapid accumulation of both contrast agents was evident in the inguinal and iliac lymph node groups (Fig 1). The diameter of the enhancing lymph nodes was 3.5–10.2 mm. As demonstrated on the single sections of the 3D data sets, the bright enhancing inguinal lymph groups consisted of multiple small lymph nodes that could not be separated from each other on the MIP images. Efferent and afferent lymphatic vessels between regional lymph groups were clearly delineated (Fig 1).



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  		Figure 1. Coronal MIP image from T1-weighted 3D gradient-echo MR sequence (15/4.2; flip angle, 70°; section thickness, 1.6 mm with 0.8-mm overlap) obtained in the pelvis 60 minutes after interstitial administration of 25 µmol/kg gadofluorine 8. Inguinal (straight solid arrows) and pelvic (curved solid arrows) lymph nodes are enhanced. Afferent (curved open arrows) and efferent (straight open arrows) lymphatic vessels are sharply delineated.

 
Gadofluorine 8 showed a lymphographic effect superior to that of gadofluoramide (Fig 2). The inguinal and iliac lymph nodes enhanced after injection of both contrast agents. The enhancement of the regional lymph nodes and lymphatic vessels was classified as good in 10 of 10 cases after gadofluorine 8 injection and in seven of 10 cases after gadofluoramide injection.



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  		Figure 2a. Coronal MIP images from T1-weighted 3D gradient-echo MR sequence (15/4.2; flip angle, 50°; section thickness, 2.2 mm with 1.1-mm overlap) obtained in the abdomen 10 minutes after interstitial administration of 25 µmol/kg (a) gadofluorine 8 and (b) gadofluoramide. Gadofluorine 8 shows a lymphographic effect superior to that of gadofluoramide, with accurate demonstration of successive lymph node groups (solid arrows) and lymphatic vessels (open arrows).

 


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  		Figure 2b. Coronal MIP images from T1-weighted 3D gradient-echo MR sequence (15/4.2; flip angle, 50°; section thickness, 2.2 mm with 1.1-mm overlap) obtained in the abdomen 10 minutes after interstitial administration of 25 µmol/kg (a) gadofluorine 8 and (b) gadofluoramide. Gadofluorine 8 shows a lymphographic effect superior to that of gadofluoramide, with accurate demonstration of successive lymph node groups (solid arrows) and lymphatic vessels (open arrows).

 
The paraaortic lymph nodes (Fig 3) were visible with gadofluorine 8 in five of six cases (three times with good and two times with moderate enhancement) at a dose of 25 µmol/kg and in three of four cases with moderate enhancement at a dose of 10 µmol/kg. Gadofluoramide injection resulted in poor enhancement of the paraaortic lymph nodes in three of six cases at a dose of 25 µmol/kg and in one of four cases at a dose of 10 µmol/kg (Table 2).



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  		Figure 3. Coronal T1-weighted 3D gradient-echo MR image (15/4.2; flip angle, 50°; section thickness, 2.2 mm with 1.1-mm overlap) obtained in the upper abdomen 50 minutes after interstitial administration of 25 µmol/kg gadofluorine 8. The aorta is seen as a signal void (curved solid arrows). The iliac (open arrows) and paraaortic (straight solid arrows) lymph nodes also are visible.

 

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  		TABLE 2. Enhancement of Regional Lymph Nodes after Interstitial Administration of Gadofluorine 8 and Gadofluoramide in 20 Pigs

 
The thoracic duct was completely depicted in four of six cases with 25 µmol/kg gadofluorine 8 and in one of four cases with 10 µmol/kg. The paraaortic lymph nodes and thoracic duct were best depicted 10–50 minutes after injection (Figs 3, 4). The contrast agent was distributed within the lymphatic system over a maximum distance of approximately 60 cm. After gadofluoramide injection, the thoracic duct could not be delineated in any of the animals.



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  		Figure 4. Coronal MIP image from T1-weighted 3D gradient-echo MR sequence (15/4.2; flip angle, 50°; section thickness, 2.2 mm with 1.1-mm overlap) obtained in the abdomen and lower thorax 50 minutes after interstitial administration of 25 µmol/kg gadofluoramide. The thoracic lymphatic duct (arrows) is depicted completely.

 
Signal-to-noise ratios as a function of time demonstrated peak enhancement of the inguinal and iliac lymph nodes within 10 minutes after interstitial administration of the lymphotropic contrast agents (Fig 5). Enhancement of the lymphatic system decreased 20 minutes after injection over a 2-hour period (Fig 6). Because of the hepatobiliary elimination of both contrast agents, the liver and the bowel tract demonstrated persistent enhancement up to 24 hours after injection. With the exception of minor swelling and reddening at the injection site, which disappeared within 24 hours, the local tolerance of both contrast agents was good.



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  		Figure 5a. Graphs show time-intensity curves (S/N = signal-to-noise ratio, time is in minutes) obtained after interstitial administration of 25 µmol/kg gadofluorine 8 in six pigs. (a) Iliac and (b) inguinal lymph nodes show rapid accumulation of the contrast agent and a plateaulike washout phase 20-210 minutes after injection. Error bars = SD.

 


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  		Figure 5b. Graphs show time-intensity curves (S/N = signal-to-noise ratio, time is in minutes) obtained after interstitial administration of 25 µmol/kg gadofluorine 8 in six pigs. (a) Iliac and (b) inguinal lymph nodes show rapid accumulation of the contrast agent and a plateaulike washout phase 20-210 minutes after injection. Error bars = SD.

 


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  		Figure 6. Graph shows enhancement (E)-time curve for inguinal and iliac lymph nodes after interstitial administration of 25 µmol/kg gadofluorine 8 in correlation with time (minutes). Both successive lymph node groups are substantially enhanced 10-20 minutes after injection of the gadolinium chelate.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
The knowledge of contrast material uptake and transportation mechanisms within the normal and metastatically involved lymphatic system is essential for the development of new contrast agents for MR lymphography.

MR lymphography can be performed after endolymphatic, intravenous, and interstitial administration of contrast material. Cannulation of a lymphatic vessel, described by Kinmonth et al (21), allows delivery of defined doses of contrast material to the lymph nodes (10,21). However, the invasiveness of this procedure and the coverage of a limited number of lymph nodes prevented routine clinical use of this method.

Intravenously injected contrast agents like ultrasmall or superparamagnetic iron oxide nanoparticles pass the endothelium of blood capillaries through transcytosis and are distributed in the interstitium (8,9,22,23). Similar to interstitially administered contrast material, the iron oxide particles are taken up by initial lymph tracts together with interstitial fluid and selectively undergo phagocytosis by lymph node macrophages (9,12). Via afferent lymphatic vessels, the contrast agent is transported to the lymph nodes and accumulates in the medullary sinuses of the nodes, sparing the germinal centers, in which lymphocytes predominate (15). In lymph nodes with metastatic disease, the macrophages are replaced by cancer cells, which lack reticuloendothelial activity, such that contrast agents cannot accumulate in tumorous areas inside the lymph nodes (8,10, 24,25).

The use of T2-type contrast agents for MR lymphography revealed several disadvantages, such as long plasma circulation times, susceptibility effects of iron, wide CIs, and heterogeneous enhancement of different lymph nodes (11,15,26). Macrocyclic gadolinium chelates as T1-enhancing contrast agents are supposed to avoid these potential drawbacks of T2-type agents, which limit the diagnostic efficacy of T2-weighted MR lymphography.

In our study, we used the lipophilic perfluorinated gadolinium chelates gadofluoramide and gadofluorine 8, which were administered interstitially. Berquist et al (27) reported that interstitially administered particulate contrast agents show optimal uptake in lymph nodes when the diameter of the particles is less than 15 nm. The perfluorinated side chain of the gadolinium chelates used in our study enables the formation of micelles with a diameter of about 4 nm, which results in efficient transportation of the aggregates to the lymph nodes.

Three successive lymph node groups (inguinal, iliac, and paraaortic) demonstrated substantial and rapid enhancement after contrast material administration. A maximum distance of 60 cm was affected by contrast agent distribution. Consequently, enhancement of the human lymphatic system in at least an equivalent dimension can be expected. Enhancement of the lymphatic vessels and thoracic duct was best visualized after interstitial administration of 25 µmol/kg gadofluorine 8, which demonstrated a lymphographic effect superior to that of gadofluoramide. Perhaps the macrocyclic chelate complex of gadofluorine 8, as compared with that of gadofluoramide, is better suited for the formation of micelles, so that the transportation mechanisms of the macromolecules are more efficient.

The lymphatic vessels cannot be demonstrated with T2-weighted MR lymphography because of the negative contrast enhancement of iron oxides. Furthermore, the spatial resolution of the T2-weighted images did not allow visualization of the lymphatic vessels, which have a diameter of less than 0.1 mm (8). In our study, the MIP images allowed easy and clear visualization of the afferent and efferent lymphatic vessels between at least three successive lymph node groups.

As compared with interstitially administered superparamagnetic iron oxides and gadopentetate dimeglumine polyglucose-associated macrocomplex, which lead to the highest signal-to-noise ratios 12–24 hours after injection (11,17,18), both MR lymphographic contrast agents rapidly accumulated within 10 minutes after injection in our study. The optimal diagnostic window was determined within 2 hours after injection; this offers a practical clinical and economic use of both contrast agents. A possible limitation is the large volume of contrast agent to be administered subcutaneously. This problem may be solved by distributing the total amount of lymphographic contrast agent in small portions through five injection sites to avoid pain and swelling in the pig’s hind leg. The development of a more concentrated contrast medium formulation should also resolve that drawback.

Results of this study indicate that lymphotropic perfluorinated gadolinium chelates are potent for the performance of T1-weighted MR lymphography. It is now possible to visualize fine lymphatic vasculature and even the thoracic duct with MR imaging; this, to our knowledge, has not previously been reported in the literature.

Practical applications: Visualization of the thoracic duct with MR imaging offers a potential for detecting traumatic or postoperative leaks or for assessing chylothorax or chylous ascites. Future studies seem warranted to evaluate the diagnostic efficacy of perfluorinated gadolinium chelates in assessing metastatic lymph node disease.


   FOOTNOTES
 
Abbreviations: MIP = maximum intensity projection, 3D = three dimensional

Author contributions: Guarantors of integrity of entire study, G.S., C.C.A.N.E., G.B.A.; study concepts, G.S., G.B.A., B.M., C.C.A.N.E.; study design, G.S., A.B., R.W.G.; literature research, G.S.; experimental studies, G.S., S.G., C.C.A.N.E., A.B.; data acquisition, G.S., S.G., C.C.A.N.E.; data analysis/interpretation, G.S., G.B.A., C.C.A.N.E.; manuscript preparation, G.S., C.C.A.N.E.; manuscript definition of intellectual content, G.S., G.B.A., R.W.G., B.M.; manuscript editing, G.S., G.B.A., C.C.A.N.E., R.W.G.; manuscript revision/review, G.S., R.W.G., C.C.A.N.E., B.M.; manuscript final version approval, G.S., C.C.A.N.E., R.W.G.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

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B. Misselwitz, J. Platzek, and H.-J. Weinmann
Early MR Lymphography with Gadofluorine M in Rabbits
Radiology, June 1, 2004; 231(3): 682 - 688.
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 CirculationHome page
J. Barkhausen, W. Ebert, C. Heyer, J. F. Debatin, and H.-J. Weinmann
Detection of Atherosclerotic Plaque With Gadofluorine-Enhanced Magnetic Resonance Imaging
Circulation, August 5, 2003; 108(5): 605 - 609.
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C. U. Herborn, T. C. Lauenstein, F. M. Vogt, R. B. Lauffer, J. F. Debatin, and S. G. Ruehm
Interstitial MR Lymphography with MS-325: Characterization of Normal and Tumor-Invaded Lymph Nodes in a Rabbit Model
Am. J. Roentgenol., December 1, 2002; 179(6): 1567 - 1572.
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