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DOI: 10.1148/radiol.2203010090
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(Radiology. 2001;220:816-821.)
© RSNA, 2001

Technical Developments

Interstitial MR Lymphography with Gadoterate Meglumine: Initial Experience in Humans1

Stefan G. Ruehm, MD, Tobias Schroeder, MD and Jörg F. Debatin, MD

1 From the Department of Diagnostic Radiology, University Hospital Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Received December 6, 2000; revision requested January 17, 2001; revision received March 13; accepted March 22. Address correspondence to S.G.R. (e-mail: stefan.ruehm@uni-essen.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Magnetic resonance (MR) lymphography was performed in five healthy volunteers and three patients (two adults and one infant). Subcutaneous administration of gadoterate meglumine in the foot allowed visualization of draining lymph vessels and nodes. In one patient, an inguinal fluid collection could be characterized as a lymphocele. In the infant, a chylothorax was diagnosed. The authors conclude that interstitial MR lymphography with commercially available compounds is feasible.

Index terms: Gadolinium • Iron • Lymphatic system, MR, 99.129412, 99.12942, 99.12943, 99.91


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Materials and Methods
Results
 Discussion
 REFERENCES
 
The status of lymphatic vessels and nodes frequently determines the prognosis and choice of therapy in patients with malignancies. Most approaches for visualization of the lymphatic system require the administration of contrast agents. Thus, direct x-ray lymphography is based on the administration of an iodinated contrast agent directly into a peripheral pedal lymph vessel. Thus, the technique involves making an incision to expose a peripheral lymphatic vessel and then placing a cannula. Although direct lymphography provides the greatest accumulation of contrast agent in lymph vessels and nodes, the invasiveness and associated patient discomfort, long examination times, and potential side effects, including pulmonary embolism and local wound infection, have limited its clinical effect (1).

To overcome these limitations, several intravenously administered compounds have been tested for magnetic resonance (MR) lymphography. Superparamagnetic iron oxide particles of various sizes, which are used to enhance lymph nodes, have been evaluated throughout the body (2–4). Initial enthusiasm was tempered by the inhomogeneous uptake of contrast agent in different lymph node groups and by the persistent inability to differentiate hyperplastic from metastatic lymph nodes (2,4).

As another alternative, subcutaneous administration of a contrast agent has been proposed. To this end, the following contrast agents have been tested: superparamagnetic iron oxide particles (5,6), polymeric gadolinium compounds such as gadopentetate dimeglumine–labeled polyglucose associated macrocomplex (7), and perfluorinated lipophilic compounds, which form aggregates or micelles (8). To date, development of all three compounds has remained in the preclinical phase, and their safety profiles remain largely unknown.

The purpose of this study was to evaluate the performance of gadoterate meglumine (Dotarem; Laboratoire Guerbet, Roissy, France), a conventional extracellular paramagnetic contrast agent, as an interstitial agent for the visualization of draining lymphatic vessels and lymph nodes in humans.


   Materials and Methods
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Contrast Agent
Gadoterate meglumine is a commercially available, extracellular, water-soluble paramagnetic contrast agent. It is typically administered intravenously in a dose up to 0.3 mmol per kilogram of body weight. Gadoterate meglumine is not subject to metabolization, and the chelate structure of the macrocyclic gadolinium complex is extremely stable (9). Extracellular water-soluble agents are characterized by a most favorable safety profile: Anaphylactoid reactions are exceedingly rare, and the agents are not nephrotoxic (10). The agents are well tolerated even when extravasated. When subcutaneously injected in rats, no noticeable inflammatory reaction was demonstrated (11). Therefore, the agent offers a favorable safety profile with good tolerance for nonintravenous routes of administration, such as subcutaneous injection.

Study Design
Five volunteers (three men and two women; age range, 24–39 years; mean age, 31.2 years), two adult male patients (aged 39 and 63 years), and a 1-month-old infant patient were enrolled into the study. The volunteers were randomly selected. Selection criteria included age of 18–60 years, ability and willingness to participate in the study and sign an informed consent, no contraindication to MR imaging (eg, cardiac pacemaker, metal implants, claustrophobia), no allergies, normal renal function, and no pregnancy. In the two adult patients, an inguinal fluid collection had manifested, after placement of either a renal transplant or a vascular bypass graft. In both cases, these collections were suspected to represent lymphoceles. Both patients were referred to our institution for MR imaging to assess the extent of the fluid collections and characterize them. MR lymphography was performed to determine whether the collections communicated with the lymphatic system. The diagnosis for each was subsequently confirmed at surgery.

In the 1-month-old infant, a chylothorax was clinically suspected. At birth, the infant showed symptoms consistent with fetal hydrops with bilateral pleural effusions and generalized accumulation of fluid in soft tissues. Immediately after delivery, bilateral thoracic drainage catheters were placed to tap the pleural effusions. Although the effusion on the right side resolved, the effusion on the left side initially subsided but subsequently the fluid reaccumulated. Biochemical analysis of the fluid confirmed the diagnosis of a chylothorax. Iatrogenic damage of the thoracic duct was suspected to have occurred during placement of the left-sided thoracic drainage catheter. MR imaging was performed to help visualize the thoracic duct and to document a potential leakage of lymph fluid into the pleural space.

This study was approved by the local ethics committee, and all participants gave their informed consent before they were included in the study. The parents of the infant agreed to the examination and gave their informed consent.

Contrast Material Administration
The technique of contrast agent administration was identical for both the volunteers and the adult patients. A thin needle (25 gauge) was used for contrast agent injection. A volume of 5 mL, consisting of 4.5 mL of gadoterate meglumine (0.5 mmol of gadolinium per milliliter) laced with 0.5 mL of lidocaine hydrochloride 2%, was subdivided into five portions of 1 mL each. Each portion was injected subcutaneously into the dorsum of the foot at different locations in the region of the interdigital webs; one portion was injected medial to the first distal metatarsal bone. In the infant, a volume of 0.5 mL of gadoterate meglumine was injected into the dorsum of each foot; therefore, the needle was placed subcutaneously in the region of the interdigital web. The needle tip was repositioned to various angles while the contrast agent was injected slowly.

Immediately after administration of the contrast material, the injection site was massaged slightly for approximately 2 minutes. Massage was repeated in the time between data acquisitions. All volunteers underwent imaging at set times at the levels of the calves and the pelvis. In the infant, the pelvis, abdomen, and thorax were each covered with one three-dimensional (3D) data set.

The condition of the volunteers and patients was monitored during 2 hours after contrast agent administration to document the degree of swelling of the injection site. In addition, the volunteers and patients were asked to describe the intensity and duration of pain and to document the time until they reached full recovery (ability to walk without pain). To describe the intensity of pain, they used the following four-point scale: 0, no pain; 1, mild pain; 2, moderate pain; and 3, severe pain. Assessment of the pain was not possible in the infant.

In the volunteers and patients, a follow-up examination was performed 24 hours after administration of the contrast material. The volunteers went home 1 hour after the examination was finished. All patients remained in the hospital for at least 7 days after MR lymphography.

MR Imaging Examinations
MR imaging was performed with a 1.5-T system (Signa EchoSpeed, GE Medical Systems, Milwaukee, Wis; Magnetom Sonata, Siemens Medical Systems, Erlangen, Germany) equipped with high-performance gradients. To depict the lymphatic structures, coronal 3D MR data sets were acquired with a gradient-recalled-echo sequence (repetition time msec/echo time msec of 5.1/1.4; flip angle of 30°; matrix of 256 x 192, in-plane interpolation to a matrix of 512, through-plane zero interpolation; sampling bandwidth of ±31.2 kHz; two signals acquired). The acquisition volumes were planned on the basis of findings on transverse gradient-recalled-echo (6.9/2.0, 60° flip angle) two-dimensional MR images.

To image the lymphatic structures of the lower extremities in the adult patients and volunteers, both calves were placed in a standard transmit-receive quadrature head coil to maximize the signal-to-noise ratio. One hundred twenty images were acquired with a section thickness of 1.2–1.4 mm and a field of view of 36 x 28.8 cm, which resulted in a total imaging time of 3 minutes 8 seconds. To image the pelvic region, a phased-array torso coil was used for signal reception. The field of view was adapted to 38 x 30 cm. Ninety-eight contiguous 1.6-mm-thick sections were acquired during 2 minutes 40 seconds. The 3D data sets were acquired before and after administration of the contrast agent. In the volunteers, the calves were imaged at 15, 30, and 45 minutes after subcutaneous injection of the contrast agent and the pelvis was imaged at 20, 35, and 50 minutes after injection. In both adult patients, data sets of the pelvis were obtained before and at 10, 20, and 30 minutes after injection.

To undergo MR imaging, the infant was placed supine into a standard receive head coil, with the head directed toward the imager bore. Data were acquired with a 3D gradient-recalled-echo sequence with a reduced field of view of 28 x 17.5 cm, a 256 x 160 matrix interpolated to a matrix of 512 x 320, and an effective section thickness of 0.59 cm. The pelvis, abdomen, and thorax were each covered with one 3D data set. Precontrast and postcontrast 5-, 15-, and 30-minute 3D data sets were acquired after bilateral subcutaneous administration of contrast agent followed by massage of the injection site. The massage was repeated in the intervals between data acquisition. To minimize motion artifacts, the infant was sedated with propofol 1% administered intravenously with an infusion pump at a rate of 4 mg/kg. The infant was free breathing during imaging.

Data Analysis
The images were analyzed qualitatively and quantitatively to assess the contrast agent uptake in lymphatic vessels and lymph nodes. For qualitative evaluation, two experienced MR radiologists (S.G.R., J.F.D.) inspected the images visually and determined a diagnosis by consensus. Data sets were available on a workstation, which permitted review of the source images and interactive reformation of the images. Qualitative evaluation included assessment of enhancement of lymph vessels and lymph nodes and of concomitant enhancement of veins in the field of view. Patient images were evaluated for the presence and location of suspected lymph leakage. The onset and time course of contrast agent uptake were visually analyzed in the fluid collection suspected of being of lymphatic origin.

For quantitative analysis, signal-to-noise ratios were calculated as the signal intensity of the vessel or node divided by noise. Noise was defined as the SD of the signal intensity in a region of interest placed in air outside the subject. The size of the region of interest for air sampling was kept constant at 120 mm2. To determine nodal contrast agent uptake on source images, regions of interest were placed within individual lymph nodes in the iliac and inguinal region. To assess enhancement of lymph vessels, regions of interest were placed within their outer borders. To determine nodal contrast agent uptake, the size of the region of interest was adapted to encompass as much as possible of the node detected on a source image. If several lymph nodes showed contrast agent uptake, signal-to-noise ratios were measured in those lymph nodes that showed the most signal intensity enhancement on successive 3D maximum intensity projection images. To assess contrast agent uptake in lymphatic vessels, measurements were performed in the region of interest in the lymphatic vessel with the maximum enhancement on consecutive images acquired at the level of the lower third of the calf. The range of area of the regions of interest was 18–51 mm2 in lymph nodes and 3–5 mm2 in lymph vessels. The regions of interest were placed by one author (T.S.).

The source images obtained after contrast agent injection facilitated identification of the nonenhanced lymph nodes or vessels on the precontrast images. Measurements were performed at identical locations within the same subject.


   Results
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
Discussion
 REFERENCES
 
Subcutaneous injection of gadoterate meglumine was well tolerated by both the volunteers and patients. The condition of each subject returned to normal by 24 hours after injection (range, 2–10 hours; mean, 4.4 hours). Immediately after injection, the degree of pain was graded as mild by five of the seven adult subjects and as moderate by two subjects. Swelling was minor in all subjects. All seven adult subjects were able to walk well and without pain approximately 1 hour after subcutaneous injection of the contrast agent. In the infant, the dorsal foot pad was mildly swollen as long as 1 hour after injection but was completely normal after 3 hours. All the patients were inpatients and under observation for at least 7 days after the contrast agent injection. No additional late reactions were reported within this period.

In all volunteers and patients, lymphatic vessels that extended from the injection site were reliably detected 15 minutes after contrast agent administration. Concomitant venous enhancement in the calf was present 15 minutes after injection. The best delineation of the lymph vessels in the calves was present at 30 minutes after injection (Fig 1b, 1c), and the degree of enhancement was reduced at 45 minutes after injection (Figs 1c, 2a).



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  		Figure 1a. Bilateral frontal gradient-recalled-echo 3D MR lymphographic images (5.4/1.4, 30° flip angle), obtained with the extremities placed in a standard head coil, show the lower extremity of a 39-year old male volunteer at (a) 15, (b) 30, and (c) 45 minutes after subcutaneous injection of a total volume of 4.5 mL of gadoterate meglumine laced with 0.5 mL of lidocaine hydrochloride in the dorsal aspect of the foot. Enhancing lymphatic vessels (arrows) are clearly depicted. The best enhancement is seen in b.

 


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  		Figure 1b. Bilateral frontal gradient-recalled-echo 3D MR lymphographic images (5.4/1.4, 30° flip angle), obtained with the extremities placed in a standard head coil, show the lower extremity of a 39-year old male volunteer at (a) 15, (b) 30, and (c) 45 minutes after subcutaneous injection of a total volume of 4.5 mL of gadoterate meglumine laced with 0.5 mL of lidocaine hydrochloride in the dorsal aspect of the foot. Enhancing lymphatic vessels (arrows) are clearly depicted. The best enhancement is seen in b.

 


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  		Figure 1c. Bilateral frontal gradient-recalled-echo 3D MR lymphographic images (5.4/1.4, 30° flip angle), obtained with the extremities placed in a standard head coil, show the lower extremity of a 39-year old male volunteer at (a) 15, (b) 30, and (c) 45 minutes after subcutaneous injection of a total volume of 4.5 mL of gadoterate meglumine laced with 0.5 mL of lidocaine hydrochloride in the dorsal aspect of the foot. Enhancing lymphatic vessels (arrows) are clearly depicted. The best enhancement is seen in b.

 


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  		Figure 2a. Graphs depict the enhancement profiles at 0, 15, 30, and 45 minutes after subcutaneous injection of gadoterate meglumine, as determined on the basis of signal-to-noise ratios (SNR), in individual lymph vessels in the lower third of the (a) calf and (b) inguinal and iliac lymph nodes. Error bars represent the standard error of the mean. The highest signal-to-noise ratios in a were present at 30 minutes after injection, while the highest ratios in b were present at 35 and 50 minutes after injection.

 


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  		Figure 2b. Graphs depict the enhancement profiles at 0, 15, 30, and 45 minutes after subcutaneous injection of gadoterate meglumine, as determined on the basis of signal-to-noise ratios (SNR), in individual lymph vessels in the lower third of the (a) calf and (b) inguinal and iliac lymph nodes. Error bars represent the standard error of the mean. The highest signal-to-noise ratios in a were present at 30 minutes after injection, while the highest ratios in b were present at 35 and 50 minutes after injection.

 
In all volunteers, inguinal lymph nodes with ascending lymph vessels were reliably detected at 20 minutes after injection (Figs 3, 4). In four of the five volunteers, external iliac nodes were depicted in addition to the inguinal nodes on the 35- and 50-minute images; the strongest enhancement of the inguinal and external iliac nodes was obtained at 35 and 50 minutes after injection (Fig 2b). Iliac lymph nodes were detected in four of the five volunteers. Contrast enhancement was not detected in the paraaortic lymph nodes or veins in the pelvis in any of the participants.



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  		Figure 3. Coronal gradient-recalled-echo 3D MR lymphographic image (5.4/1.4, 30° flip angle), depicted as a targeted maximum intensity projection image, was obtained at 30 minutes after subcutaneous injection of gadoterate meglumine in a 24-year-old male volunteer. Inguinal lymph nodes (arrows) and individual ascending draining lymph vessels (arrowheads) can be detected.

 


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  		Figure 4. Frontal gradient-recalled-echo 3D MR lymphographic image (5.4/1.4, 30° flip angle) of the pelvis was obtained with a phased-array torso coil at 50 minutes after subcutaneous injection of gadoterate meglumine in a 29-year-old male volunteer. Inguinal (arrows) and iliac (arrowhead) lymph nodes and lymph vessels can be detected.

 
At 20 minutes after injection in the patient with an inguinal fluid collection, enhancement of the collection and slight enhancement of the cavity became evident. Ascending lymphatic vessels were depicted at 10 minutes after injection. Enhancement of the entire fluid collection was evident at 30 minutes after injection; this finding helped confirm the lymphatic origin of the fluid collection. Findings at fluid aspiration and at subsequent surgery helped confirm the diagnosis of a lymphocele (Fig 5). In the other patient, the fluid collection was not enhanced. Findings at surgery confirmed that his lesion represented an infected seroma without communication to the lymphatic system.



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  		Figure 5a. Images show a vascular bypass graft placed in the right pelvis of a 63-year-old patient. (a, b) T2-weighted transverse MR images (4,500/99 [effective]), obtained at two different levels in the pelvis, depict two fluid collections (arrows) in the right iliac fossa and inguinal area. (c) Gradient-recalled-echo 3D MR image (5.4/1.4, 30° flip angle), acquired at 30 minutes after subcutaneous injection of gadoterate meglumine in the right foot, demonstrates enhancement of inguinal fluid collections (arrowheads), which characterizes the collections as lymphoceles.

 


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  		Figure 5b. Images show a vascular bypass graft placed in the right pelvis of a 63-year-old patient. (a, b) T2-weighted transverse MR images (4,500/99 [effective]), obtained at two different levels in the pelvis, depict two fluid collections (arrows) in the right iliac fossa and inguinal area. (c) Gradient-recalled-echo 3D MR image (5.4/1.4, 30° flip angle), acquired at 30 minutes after subcutaneous injection of gadoterate meglumine in the right foot, demonstrates enhancement of inguinal fluid collections (arrowheads), which characterizes the collections as lymphoceles.

 


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  		Figure 5c. Images show a vascular bypass graft placed in the right pelvis of a 63-year-old patient. (a, b) T2-weighted transverse MR images (4,500/99 [effective]), obtained at two different levels in the pelvis, depict two fluid collections (arrows) in the right iliac fossa and inguinal area. (c) Gradient-recalled-echo 3D MR image (5.4/1.4, 30° flip angle), acquired at 30 minutes after subcutaneous injection of gadoterate meglumine in the right foot, demonstrates enhancement of inguinal fluid collections (arrowheads), which characterizes the collections as lymphoceles.

 
On images obtained at 20 minutes after injection in the infant, the following findings were detected: ascending lymph vessels that extended from the injection site, enhancing inguinal and iliac nodes, ascending lumbar trunks, cisterna chyli, thoracic duct, and right and left lymphatic ducts that drained into the venous angle bilaterally (Fig 6a). A small leak of contrast agent immediately cranial to the left hemidiaphragm was suspected on the frontal maximum intensity projection images. This leak was depicted more clearly on the source or transverse reformatted images (Fig 6b) and might have corresponded to the site of the disrupted thoracic duct. Findings at biochemical fluid analysis confirmed the diagnosis of a chylothorax. Since the infant was sedated and continued free breathing throughout the imaging examination, the image quality was hampered by motion artifacts.



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  		Figure 6a. Images show recurrent left-sided pleural effusion and suspected chylothorax in a 1-month-old infant patient. (a) Gradient-recalled-echo 3D MR lymphographic image, depicted as a targeted frontal maximum intensity projection image (5.4/1.4, 30° flip angle), was acquired at 20 minutes after subcutaneous injection of gadoterate meglumine. The image shows enhancing inguinal and iliac lymph nodes (curved arrows) and multiple ascending left and right lumbar trunks (short solid arrows) draining into the cisterna chyli (open arrow). From there, the thoracic duct (arrowheads) was depicted as ascending in a left paravertebral location. Normal variants, left and right lymphatic ducts in continuation with the thoracic duct and draining into the venous angle bilaterally, were detected. Immediately cranial to the left diaphragm, a small leak of contrast agent (long arrow) is depicted. This finding is consistent with a focal disruption of the thoracic duct. (b) Reformatted transverse MR lymphographic image depicts the focal disruption (arrow) of the thoracic duct. Image quality was slightly reduced owing to motion artifacts. The infant was sedated, and continued free breathing throughout the examination; hence, motion artifacts reduced image quality.

 


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  		Figure 6b. Images show recurrent left-sided pleural effusion and suspected chylothorax in a 1-month-old infant patient. (a) Gradient-recalled-echo 3D MR lymphographic image, depicted as a targeted frontal maximum intensity projection image (5.4/1.4, 30° flip angle), was acquired at 20 minutes after subcutaneous injection of gadoterate meglumine. The image shows enhancing inguinal and iliac lymph nodes (curved arrows) and multiple ascending left and right lumbar trunks (short solid arrows) draining into the cisterna chyli (open arrow). From there, the thoracic duct (arrowheads) was depicted as ascending in a left paravertebral location. Normal variants, left and right lymphatic ducts in continuation with the thoracic duct and draining into the venous angle bilaterally, were detected. Immediately cranial to the left diaphragm, a small leak of contrast agent (long arrow) is depicted. This finding is consistent with a focal disruption of the thoracic duct. (b) Reformatted transverse MR lymphographic image depicts the focal disruption (arrow) of the thoracic duct. Image quality was slightly reduced owing to motion artifacts. The infant was sedated, and continued free breathing throughout the examination; hence, motion artifacts reduced image quality.

 

   Discussion
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
REFERENCES
 
The lymphatic system of the lower extremities was depicted on 3D MR images after subcutaneous injection of gadoterate meglumine, a commercially available extracellular paramagnetic contrast agent. Subcutaneous injection of gadoterate meglumine mixed with a small amount of lidocaine hydrochloride in the interdigital region on the dorsum of the foot was well tolerated. Interstitial MR lymphography depicted regional lymphatic vessels clearly. The technique could be used to examine the morphologic integrity of lymph vessels, such as the thoracic duct, and to demonstrate the lymphatic origin of inguinal fluid collections.

The appearance of contrast agent in the lymph vessels of the calves after 15 minutes (Fig 1) confirmed the rapid uptake of the agent from the pedal injection site. Concomitant enhancement of small veins in the calves suggested considerable absorption of contrast agent through the capillary system. This finding reflected the extracellular nature of the agent, which was confirmed by early enhancement of the bladder (Fig 5) or collecting system in the infant (Fig 6). At no time was enhancement of veins in the pelvis detected. The lymph vessels and several inguinal and iliac lymph nodes were depicted. Although the contrast agent volume was sufficient to enhance afferent lymph vessels, a lymphocele, several inguinal and iliac lymph nodes, and the thoracic duct in the infant, analysis of nodal morphology might not be sufficient to exclude metastatic disease.

In contrast to findings in prior experiments in rabbits, in which the same agent caused more avid enhancement of inguinal and paraaortic lymph nodes after pedal subcutaneous injections, paraaortic lymph nodes were invisible in all participants, and iliac nodes were visible in four of the five volunteers. Lack of depiction of more distal nodes likely reflects the small volume (4.5 mL) of contrast material chosen for these initial human experiments. Adjusted for weight differences, this volume of 4.5 mL corresponds to 45% of the 0.5-mL volume of gadoterate meglumine injected into the hind legs of rabbits (12).

Although findings in animal studies have shown that considerably larger volumes of the inert extracellular gadolinium-based contrast agents can be extravasated into subcutaneous tissues without incurring the risk of necrosis or inflammation (11), volume limits are determined on the basis of tolerability. In this study, swelling was minor, and all volunteers and both adult patients were able to walk with ease after the subcutaneous injection. Nevertheless, all adult subjects reported initial pain associated with the injection of the small volume of 4.5 mL of gadoterate meglumine, despite the addition of 0.5 mL of lidocaine hydrochloride. Two subjects rated the pain as moderate. Additional pain and swelling caused by the injection of larger volumes of contrast agent would reduce patient acceptance to the point of rendering the examination impracticable.

Instead of increasing the contrast agent volume, a more promising approach involves the use of a more concentrated gadolinium formulation (1.0 instead of 0.5 mol/L), such as gadobutrol (Gadovist; Schering, Berlin, Germany) (13). In many countries, gadobutrol is available as an intravenous agent for assessing cerebral perfusion. Thus, the amount of T1-reducing gadolinium could be doubled without increasing the volume. Further studies are needed, however, to show comparable efficacy with regard to lymphatic uptake in the presence of differences concerning viscosity, osmolality, and lipophilicity. In addition, safety issues would need to be addressed, especially in light of the higher osmolarity of the more concentrated compounds. The repetition and echo times in the pulse sequence used in this study might need to be modified to avoid T2-shortening effects induced by the higher concentration of gadolinium.

Interstitial MR lymphography has been performed with other T1-enhancing contrast agents in animal experiments. Several of these agents have provided more favorable results with regard to duration, maximal signal intensity, and number of successively enhancing lymph node groups within the lymphatic system (7,8,14). Larger protein-bound gadolinium compounds have fared particularly well. These agents, many of which are being developed for the prolonged enhancement of the vascular system (blood pool agents), have lymphotropic properties because they are being preferentially phagocytized (15). They do not penetrate the capillary membranes and are thus not absorbed by the vascular system. None of the agents, however, is close to being commercially available, to our knowledge.

The three dimensionality inherent in the underlying T1-weighted gradient-recalled-echo data sets should help morphologic analysis of individual nodes. The microstructural anatomy of the lymph node itself, which contains nonenhancing follicles largely devoid of macrophages and enhancing follicles with medullary sinuses (16), will render any attempt to differentiate metastatic from nonmetastatic nodal enhancement highly challenging.

This study is a first step toward clinically relevant MR lymphography in humans. In its current implementation, possible indications are limited to evaluation of peripheral lymphedema (17); documentation of lymphatic vessel regeneration after transplantation of extremities; determination of lymphatic leaks in a suspected chylothorax, as shown in the infant; or characterization of postoperative fluid collections such as lymphoceles, as shown in the two adult patients. On the basis of findings in this study, we conclude that commercially available paramagnetic contrast agents may be used to depict proximal lymph nodes after interstitial injection of small volumes. With this imaging strategy, 3D image sets can be obtained to demonstrate regional lymphatic drainage. Further investigation is required to optimize gadolinium dosage with more concentrated agents and to assess the performance when injected in regions other than the feet, such as the breast for possible sentinel node imaging.


   FOOTNOTES
 
Abbreviation: 3D = three-dimensional

Author contributions: Guarantors of integrity of entire study, S.G.R., J.F.D.; study concepts and design, S.G.R.; literature research, S.G.R.; clinical studies, S.G.R.; data acquisition, S.G.R., T.S.; data analysis/interpretation, S.G.R., J.F.D.; manuscript preparation, S.G.R.; manuscript definition of intellectual content and editing, S.G.R., J.F.D.; manuscript revision/review and final version approval, J.F.D.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 

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