DOI:10.2214/AJR.05.1750
AJR 2006; 187:556-561
© American Roentgen Ray Society
High-Resolution MR Lymphangiography in Patients with Primary and Secondary Lymphedema
Christian Lohrmann1,
Etelka Foeldi2,
Oliver Speck1 and
Mathias Langer1
1 Department of Radiology, Division of Diagnostic Radiology, University Hospital
of Freiburg, Hugstetter Strasse 55, D-79106, Freiburg, Germany.
2 Foeldi Clinic for Lymphology, Hinterzarten, Germany.
Received October 4, 2005;
accepted after revision December 7, 2005.
Address correspondence to C. Lohrmann
(lohrmann{at}mrs1.ukl.uni-freiburg.de).
Abstract
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.
Keywords: high-resolution angiography • leg • lymphangiography • MRI
Introduction
Amajor 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 Agent
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 August 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, 20-79 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 Administration
For injection of gadodiamide, a thin needle (24 gauge) was used. A 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 injectedcutaneously 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.
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Fig. 1A —Four cases of lymphedema: two primary and two secondary.
33-year-old man with primary lymphedema. Frontal 3D spoiled gradient-echo
high-resolution 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.
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Fig. 1B —Four cases of lymphedema: two primary and two secondary.
46-year-old man with primary lymphedema. Bilateral frontal 3D spoiled
gradient-echo 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.
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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. All patients were asked to describe the
intensity of pain at the time of gadodiamide application. A 4-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 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. 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. 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, 256 x 256; bandwidth, 247
Hz/pixel; 6/8 rectangular field of view, 480 mm; slices, 96; voxel size, 2.0
x 1.9 x 1.7 mm; acquisition time, 4 minutes 4 seconds). To
highlight the edema, 3D maximum-intensity-projection (MIP) reconstructions
were performed.
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Fig. 1C —Four cases of lymphedema: two primary and two secondary.
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.
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Fig. 1D —Four cases of lymphedema: two primary and two secondary.
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.
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Fig. 2 —20-year-old woman with primary lymphedema. Angled 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.
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For HR MR lymphangiography a 3D spoiled gradient-echo sequence (volumetric
interpolated breath-hold examination [VIBE]) with the following parameters was
used: TR/TE, 3.4/1.47; flip angle, 25°; matrix, 448 x 448;
bandwidth, 490 Hz/pixel; 6/8 rectangular field of view with a maximum
dimension of 500 mm; slices, 128; voxel size, 2.2 x 1.1 x 1.5 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.
Image Analysis
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. An area of
progressive dispersion of the contrast medium into the soft tissues was
regarded as dermal backflow. A diagnosis was made by consensus. One author
quantitatively analyzed the time course of enhancement by recording the
maximal 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-to-noise 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. All 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 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.
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Fig. 3 —20-year-old woman with primary lymphedema (not same patient
as in Fig. 2). Angled 3D
spoiled gradient-echo high-resolution 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.
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In all patients, the beaded appearance of the lymphatic vessels extending
from the injection site was reliably detected 15 minutes after injection
(Figs. 1A,
1B,
1C, and
1D). After 5 minutes of
contrast material application, concomitant venous enhancement was detected in
the lower and upper leg of each patient (Figs.
1A,
1B, and
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]. After 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].
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 (Figs.
4A,
4B, and
4C). Additional
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.
Although 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.
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Abstract
Introduction
