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Imaging of Lymphatic Vessels in Breast Cancer–Related Lymphedema: Intradermal Versus Subcutaneous Injection of ^99mTc-Immunoglobulin

¹ Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge, UK.
² Department of Nuclear Medicine, Addenbrooke's Hospital, Cambridge, UK.
³ Department of Medicine, St. George's Hospital, London, UK.
⁴ Department of Nuclear Medicine, Royal Sussex County Hospital, Eastern Rd., Brighton BN2 5BE, UK.

Received November 16, 2004; accepted after revision March 1, 2005.

 
Supported by The Wellcome Trust.

Address correspondence to A. M. Peters.

Abstract

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OBJECTIVE. The disordered physiology that results from axillary lymph node clearance surgery for breast cancer and that leads to breast cancer–related lymphedema is poorly understood. Rerouting of lymph around the axilla or through new pathways in the axilla may protect women from breast cancer–related lymphedema. The aim of the study was to compare intradermal with subcutaneous injection of technetium-99m (^99mTc)–labeled human polyclonal IgG (HIG) with respect to lymphatic vessel imaging.

MATERIALS AND METHODS. Six women with breast cancer–related lymphedema underwent unilateral upper limb lymphoscintigraphy, using a web space injection of ^99mTc-labeled HIG, after intradermal and subcutaneous injections on separate occasions. Multiple sequential images were obtained of the affected upper limb and torso over 3 hr on each occasion. Accumulation of activity in blood was quantified from venous blood samples taken from the opposite arm.

RESULTS. Imaging after intradermal injection clearly showed discrete lymphatic vessels in five of six patients, in contrast to imaging after subcutaneous injection, which did not show any discrete vessels in any patient. Intradermal injection resulted in more rapid visualization of cutaneous lymph rerouting than subcutaneous injection in six of six patients. Recovery of injected ^99mTc-labeled HIG in venous blood was greater after intradermal injection in six of six patients.

CONCLUSION. In patients with breast cancer–related lymphedema, lymphatic vessels are more clearly depicted after intradermal than subcutaneous injection as a result of direct access of radiotracer to dermal lymphatics. This finding has implications for imaging lymphatic vessel regeneration and lymph rerouting.

Keywords: breast cancer–related lymphedema • intradermal injection • lymphangiography • lymphoscintigraphy • lymph nodes • oncologic imaging • subcutaneous injection • ^99mTc-HIG

Introduction

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Breast cancer–related lymphedema is a serious and distressing condition that affects 20–25% of women who have undergone axillary lymph node clearance for breast cancer [1]. Although treatment to the axilla, by either surgery or radiation therapy (or both), is clearly the most significant event that leads to edema, the physiologic mechanisms are poorly understood and several features of the disorder are unexplained [2].

Investigation of breast cancer–related lymphedema with lymphoscintigraphy has yielded useful functional data [3–5] but little in the way of structural information concerning, for example, possible lymphatic vessel regeneration or lymph rerouting around the axilla. Techniques that could be considered in the pursuit of such information include contrast-enhanced lymphangiography, functional CT, and functional MRI. Contrast lymphangiography is almost obsolete and, in any case, is too invasive for the sequential imaging that we believe is essential to maximize the value of lymphangiography in this condition.

An issue of importance in lymphatic vessel imaging by lymphoscintigraphy is the placement of the injection, and in particular, whether it should be intradermal or subcutaneous. This issue remains controversial [6–9], although, to some extent, one that is colored by the purpose of the study—for example, whether it is to investigate a swollen limb, identify a sentinel node, or use another application. We have recently shown in healthy subjects that for imaging lymphatic vessels with radiotracers (soluble macromolecules and colloids), intradermal injection is clearly superior to subcutaneous placement [10]. This can be explained by the rich lymphatic network within the dermis [11–13] that facilitates a more compact delivery of radioactivity to lymphatic vessels from intradermal injection. Moreover, intradermal, but not subcutaneous, injection even delivers radiolabeled intact RBCs to lymphatic vessels and lymph nodes [14].

In order ultimately to successfully investigate lymphatic rerouting in women undergoing axillary lymph node clearance surgery, the purpose of the current study was to extend the comparison between intradermal and subcutaneous injections to the challenging scenario of established breast cancer–related lymphedema and to see whether the superiority of the intradermal route was maintained in the setting of severe edema of the subcutis.

Materials and Methods

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Patients
Six female patients with established breast cancer–related lymphedema, ranging in age from 41 to 67 years, were recruited (Table 1). The duration of breast cancer–related lymphedema since surgery was 29–180 months (mean, 66.5 months), and the duration since the onset of the swelling was 23–144 months (mean, 50 months). Arm volume was calculated from circumferential measurements every 4 cm along the length of the arm using a spring-tensioned tape measure, and the values were converted to the volume of a truncated cone using a lymphedema calculator (Lymcalc 1.0 Casio fx-7400G PLUS, Colobri Software Systems) [15]. All patients gave informed consent to the procedure, and the study was approved by the local research ethics committee and the Administration of Radioactive Substances Advisory Committee of the United Kingdom.

Radiopharmaceutical Preparation
Technetium-99m–labeled HIG was prepared by the addition of 800 MBq of sodium ^99mTc-pertechnetate (Amertec II, Amersham Health) in 2 mL of saline to a lyophilized kit (TechneScan HIG, Tyco Healthcare). The pertechnetate was used within 4 hr of elution from a generator that had been eluted within the previous 24 hr. Radiochemical purity was determined by thin-layer chromatography using instant thin-layer mini-chromatography strips impregnated with silica gel (ITLC-SG, Gelman Sciences) as the stationary phase and acetone as the mobile phase (solvent). Using a pipette, a 5-µL sample of ^99mTc-labeled HIG was spotted at the origin line (10 mm) on the strip. The strip was immediately developed until the mobile phase reached the solvent front line (90 mm). The strip was removed from the solvent and dried in air before analysis using a radiochromatogram scanner. The ^99mTc-labeled HIG remained at the origin (ratio of the distance traveled by solute to the distance traveled by a spot of pigment [Rf] = 0.0) while unbound activity (^99mTc-O₄^–) migrated to the solvent front (Rf = 1.0). Labeling efficiency (mean ± SD) was 99.0% ± 0.7% (n = 6). An activity of 40 MBq in 0.1 mL was drawn into a 0.3-mL insulin syringe and assayed in a dose calibrator (model CRC-15R, Capintec).

Injection Techniques
Subcutaneous and intradermal injections, each 0.1 mL, were made using a 30-gauge needle. Both injections were made in the second web space, between the second and third fingers with the needle pointing proximally. Intradermal injections were performed with the patient's metacarpophalangeal (MCP) joints flexed (i.e., with the patient's hand made into a fist) to stretch the skin and provide a flat, taut surface for injection. The needle was gently inserted into the dermis in the web space on the dorsum of the hand. After aspiration was performed to ensure no vascular structure had been entered, the radiopharmaceutical was slowly injected into the dermis. Care was taken to inject slowly to prevent a rapid increase in pressure in the dermis that, first, would be painful for the patient, and second, would risk splitting of the dermis with resultant subdermal passage of the radiopharmaceutical. Immediate evidence that the injection was in fact intradermal was available by visualizing the needle tip within the translucent superficial layers of the dermis; feeling resistance on the syringe plunger as the radiopharmaceutical entered the tight dermis; and observing the raising of a tense, blanched lump at the injection site.

Subcutaneous injections were also made with the MCP joints flexed. The needle was placed into the loose subcutaneous tissues between the heads of the second and third metacarpals. As in intradermal injections, entry into a vascular structure was excluded by gentle aspiration on the syringe before injection. No massaging was applied after injection into either site.

Imaging
Using a double-headed, rectangular field-of-view gamma camera (Helix SPX, Elscint), all patients were imaged on two separate occasions 1–6 weeks apart. Images (five pairs) were acquired at 10–16, 37–68, 82–95, 108–133, and 148–171 min after unilateral intradermal or subcutaneous injection of ^99mTc-labeled HIG to include the upper limb on the affected side and the torso from the neck to the bladder.

Images were evaluated by a nuclear medicine physician experienced in lymphoscintigraphy who was blinded to the clinical details and injection site. The following scintigraphic features were evaluated: clarity and speed of visualization of lymphatics (both dermal and subdermal), speed of ^99mTc-labeled HIG transit to the axilla, and speed of appearance and prominence of a blood pool signal.

Estimates of activity in the upper limb were made by drawing a region of interest around the upper limb (excluding the depot injection site) in each image. The geometric mean of anterior and posterior counts was calculated. A calibration from counts to activity was obtained by adding a known activity of ^99mTc (20 MBq) to a uniformly filled cylindric phantom (10 cm diameter, 60 cm long). The same collimator was used for both imaging and phantom measurements. The geometric mean of counts per megabecquerels (MBq) in the phantom was used to convert limb counts to limb activity. After decay correction, the limb activity was expressed as a percentage of the injected activity.

View larger version (93K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A —Lymphoscintigraphy images of upper limb and torso in female patient. Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images obtained 52 and 48 min after intradermal (A) and subcutaneous (B) injections, respectively. There is greater clarity and earlier visualization of lymphatic structures after intradermal injection. Left and right panels are posterior and anterior images, respectively.

View larger version (79K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B —Lymphoscintigraphy images of upper limb and torso in female patient. Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images obtained 52 and 48 min after intradermal (A) and subcutaneous (B) injections, respectively. There is greater clarity and earlier visualization of lymphatic structures after intradermal injection. Left and right panels are posterior and anterior images, respectively.

View larger version (98K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A —Lymphoscintigraphy images of upper limb and torso in female patients (A–D). Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images obtained after intradermal (A and C) and subcutaneous (B and D) injections in two patients show clear definition of proximal lymphatic vessels after intradermal injection, obtained at 50 (A) and 54 (C) min, but not after subcutaneous injection, obtained at 154 (B) and 163 (D) min. As previously shown [10], images with best definition are recorded much earlier after intradermal injection. Note presence of shoulder markers.

View larger version (115K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B —Lymphoscintigraphy images of upper limb and torso in female patients (A–D). Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images obtained after intradermal (A and C) and subcutaneous (B and D) injections in two patients show clear definition of proximal lymphatic vessels after intradermal injection, obtained at 50 (A) and 54 (C) min, but not after subcutaneous injection, obtained at 154 (B) and 163 (D) min. As previously shown [10], images with best definition are recorded much earlier after intradermal injection. Note presence of shoulder markers.

View larger version (105K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C —Lymphoscintigraphy images of upper limb and torso in female patients (A–D). Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images obtained after intradermal (A and C) and subcutaneous (B and D) injections in two patients show clear definition of proximal lymphatic vessels after intradermal injection, obtained at 50 (A) and 54 (C) min, but not after subcutaneous injection, obtained at 154 (B) and 163 (D) min. As previously shown [10], images with best definition are recorded much earlier after intradermal injection. Note presence of shoulder markers.

View larger version (113K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2D —Lymphoscintigraphy images of upper limb and torso in female patients (A–D). Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images obtained after intradermal (A and C) and subcutaneous (B and D) injections in two patients show clear definition of proximal lymphatic vessels after intradermal injection, obtained at 50 (A) and 54 (C) min, but not after subcutaneous injection, obtained at 154 (B) and 163 (D) min. As previously shown [10], images with best definition are recorded much earlier after intradermal injection. Note presence of shoulder markers.

View larger version (117K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A —Lymphoscintigraphy images of upper limb and torso in female patient. Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images show more marked and earlier blood pool signal was obtained after intradermal (A) compared with subcutaneous (B) injection. Images at third imaging times (A = 86 min, B = 108 min) are shown.

View larger version (111K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B —Lymphoscintigraphy images of upper limb and torso in female patient. Downward-pointing arrowheads = shoulders, lateral arrowheads = elbows, upward-pointing arrowheads = pubic bone. Images show more marked and earlier blood pool signal was obtained after intradermal (A) compared with subcutaneous (B) injection. Images at third imaging times (A = 86 min, B = 108 min) are shown.

View larger version (16K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4 —Activity within arm quantified from region-of-interest analyses from gamma camera imaging and initial phantom studies after subcutaneous injection (left graph) and after intradermal injection (right graph). Data for all six patients are shown separately as different symbols, with each symbol repeated for the same patient in Figures 5 and 6.

View larger version (23K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5 —Disappearance of activity from depot after subcutaneous injection (right graph) and after intradermal injection (left graph). Data for all six patients are shown separately. Symbols correspond to same patients shown in Figures 4 and 6. It was assumed that first probe count corresponded to 100% of injected activity.

View larger version (21K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 6 —Accumulation of activity in central blood expressed as percentage of administered activity after subcutaneous injection (right graph) and after intradermal injection (left graph). Blood volume was calculated from height, weight, age, and sex [16]. Radioprotein clearance from blood was considered negligible over 3 hr [17, 18]. Data for all six patients are shown separately. Symbols correspond to same patients in Figures 4 and 5.

Residual activity remaining in the depot (as a percentage of the initial activity) was added to the activity recovered in the blood and then subtracted from 100% to give the total activity unaccounted for (i.e., "lost" activity) [3]. It could be assumed that lost activity comprised ^99mTc-labeled HIG that was in transit in the injected limb and activity that had previously arrived in and then been cleared from the blood.

Statistical Analysis
This was essentially an observational study. Nevertheless, the three variables measured (k, b, and arm activity) were subjected to nonparametric paired analysis. When n = 6, this simply means that for statistical significance at the 5% level, any variable needs to change in the same direction in all six patients so that p = 0.03.

Results

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Imaging
Lymphatic structures were visualized earlier and with unequivocally greater clarity after intradermal injection compared with subcutaneous injection in all six patients (Figs. 1A and 1B). Because of the presence of breast cancer–related lymphedema, few lymphatic vessels were clearly defined. Instead, cutaneous rerouting of ^99mTc-labeled HIG in lymphatics was clearly seen "encasing" the arm. This rerouting was more clearly seen after intradermal injection than after subcutaneous injection in all patients. Discrete lymphatic vessels in the upper arm were seen in five patients, but only after intradermal injection (Figs. 2A, 2B, 2C, and 2D).

In one patient, activity was visible in the axilla at the first imaging time after both subcutaneous and intradermal injection, although clearly more prominently with the latter. In the other five patients, axillary activity could be identified earlier after intradermal injection, at the first imaging time in one patient and the second in four patients. After subcutaneous injection in these five patients, however, axillary activity was never seen in two patients and only from the third or fourth imaging time in three patients.

A blood pool signal was visible in three of six patients after subcutaneous injection but not prominently in any of them and only from the fourth (one patient) or fifth (three patients) imaging times. In contrast, a blood pool signal was present in five of six patients after intradermal injection. Starting with the second imaging time, it was prominent in four (Figs. 3A and 3B).

Arm activity outside the depot, measured by region-of-interest analysis, was greater in all six patients after intradermal than after subcutaneous injection (p = 0.03) (Fig. 4). After subcutaneous injection, arm activity steadily increased, whereas after intradermal injection it tended to reach a peak before declining (Fig. 4). In all six patients after subcutaneous injection, there was less activity in the arm compared with lost activity (i.e., activity that could not be accounted for either in blood or remaining in the depot). In contrast and paradoxically, arm activity after intradermal injection was greater than lost activity in all six patients (data not shown).

^99mTc-Labeled HIG Clearance Kinetics
The rate constant of ^99mTc-labeled HIG clearance from the depot, k, ranged from 0.073% to 0.23% x min^-1 after intradermal injection compared with 0.019% to 0.14% x min^-1 after subcutaneous injection. It was higher after intradermal injection in four patients and lower in two (Fig. 5). The value of b ranged from 0.02% to 0.16% x min^-1 after intradermal injection compared with 0.008% to 0.038% x min^-1 after subcutaneous injection (Fig. 6). It was higher after intradermal injection in all six patients (p = 0.03), by a factor of 5 or more in three.

Discussion

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Intradermal injection delivers radiotracers more rapidly to lymphatic structures than subcutaneous injection. As we have recently shown in healthy subjects [10], this allows better imaging of lymphatic vessels. Nevertheless, it is not universally accepted that intradermal injection is the preferred technique for routine lymphoscintigraphy. This is partly because the principal clinical indication for lymphoscintigraphy is investigation of a swollen limb of unknown cause. Deposition of the radiotracer in the interstitial space, as by subcutaneous injection, is a rational approach in this clinical setting because the main issue under investigation is the efficacy with which protein is transported from the interstitial space into central blood, and subcutaneous injection more appropriately tests this ability. When, however, the primary issue is lymphatic vessel anatomy—for example, in the investigation of the pathophysiologic consequences of axillary lymph node resection, it seems clear that intradermal injection is the preferred technique.

The current study confirms, moreover, that, in addition to normal limbs, intradermal injection provides much better definition of lymphatic vessels in the challenging scenario of the grossly swollen upper limb of breast cancer–related lymphedema. Thus, detail of lymph drainage routes and speed of transport through these routes were consistently better and faster, respectively, with intradermal injection, and discrete lymphatic vessels were seen only after intradermal injection. This will be important for further research into the cause of this disorder.

The more rapid delivery of radiotracer to the lymphatic system that underlies the superior imaging obtained from intradermal injection is reflected in a higher blood recovery. This is consistent with more rapid transport of radioprotein up the limb to central lymphovenous communications in the neck. An alternative event that might explain the higher blood recovery, some of the features of the depot clearance kinetics (such as the biphasic shape of some of the depot clearance curves), and the shapes of the arm activity profiles recorded after intradermal injection is vascular injury at the site of injection. In previous studies using coinjected epinephrine [3, 4], vascular injury in association with subcutaneous injection was ruled out, but similar studies after intradermal injection have not been performed, to our knowledge. Vascular clearance after intradermal but not subcutaneous injection, however, seems unlikely because it would have resulted in poorer definition of lymphatic vessels after intradermal injection, not better definition. The time courses of blood accumulation are not consistent with early traumatic vascular access, and less activity, not more, would have been recorded in the injected arms.

Moreover, we have recently recorded zero recovery in the central circulation of intact radiolabeled RBCs administered to healthy volunteers by both intradermal and subcutaneous injection, even though these RBCs entered locoregional lymph nodes after intradermal (but not subcutaneous) injection [14]. Indeed, our findings contradict the explanation offered by critics of intradermal injection that significant uptake of radioprotein from the depot into local blood vessels degrades images of lymphatic structures [8]. The way to resolve the issue of vascular access through vessel injury would have been to take ipsilateral and contralateral blood samples, as we did in an earlier study based on subcutaneous injection [4], but we did not do this in the current study because the primary focus was on imaging.

Whereas blood recovery was higher after intradermal compared with subcutaneous injection, there was no clear difference between the two routes with respect to depot clearance rate, k. Thus, the disproportionately faster access to blood after intradermal injection appears to occur after activity has left the depot, presumably as a result of more rapid progress in lymphatic vessels. The apparent imbalance between higher blood recovery and seemingly unchanged depot clearance is probably because, even though probe counting is started more or less immediately after intradermal injection, some activity has already left the depot before the first probe count is completed. So whereas after subcutaneous injection the first probe count faithfully represents 100% of the injected activity, it represents less than 100% for intradermal injection. This is supported by the finding that, in some patients, blood recovery after intradermal injection paradoxically exceeded the activity that had apparently left the depot. Moreover, in all six patients, arm activity quantified from region-of-interest analysis was greater than lost activity. In all six patients after subcutaneous injection, in contrast, arm activity was less than lost activity, as would be expected because blood clearance of IgG, once it arrives in the circulation, is low [18] but not negligible [19].

In conclusion, this study clearly shows that the differing kinetics of radioprotein clearance recorded after intradermal and subcutaneous injection in healthy subjects is also seen in patients with breast cancer–related lymphedema. The superiority of intradermal over subcutaneous injection with respect to imaging lymphatic vessels has implications for lymphoscintigraphy of patients with breast cancer–related lymphedema and indeed for those with other lymphedemas secondary to lymph node excision, for both clinical and research purposes.

References

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This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by O'Mahony, S. Articles by Peters, A. M. Search for Related Content PubMed PubMed Citation Articles by O'Mahony, S. Articles by Peters, A. M. Social Bookmarking                      What's this? Hotlight (NEW!) What's Hotlight?