Lymphedema is a debilitating disease with a pronounced tendency to progression without adequate treatment, resulting in increasing physical disability, recurrent erysipelas/cellulitis infections, and a significantly reduced quality of life.1–5 The burden of disease in terms of treatment expenses can be significant, even for those with relatively well-controlled swelling, because of the continuous need for at least compressive garments, if not other conservative treatments, in the vast majority of cases.1,4 Prompt recognition and diagnosis is key to reducing morbidity.
Lymphoscintigraphy has been used in the diagnosis of lymphedema for decades and is considered to be the gold standard for imaging diagnosis (made upon the demonstration of slowing or absence of lymphatic flow in the affected swollen limb).6–10 Lymphoscintigraphy is able to demonstrate the flow of lymph in both the superficial and deep lymphatic pathways and can detect abnormal lymphatic circulation patterns, such as aplasia, hypoplasia, or hyperplasia of vessels and nodes and dermal backflow.11–13 It has been shown to have high sensitivity (96%) and specificity (100%) for lymphedema,14 definitively distinguishing lymphedema from other sources of edema (eg, venous incompetence).7
Lymphoscintigraphy is undoubtedly a useful tool; however, there are no clear guidelines to standardize its usage. Studies differ in terms of type of radiotracer used, injection site, with or without exercise, and timing of the images.15,16 Similarly, studies vary in their investigation of the lymphatic vessels themselves. The majority of research is based on examination of the superficial lymphatic pathways (epifascial), either by subcutaneous or intradermal injection of the radiotracer. Far fewer studies investigate the functioning of the deep lymphatic vessels (subfascial) that surround the deep blood vessels in the muscles.16–19 When both superficial and deep lymphatic vessels are examined, it is called a 2-compartment lymphoscintigraphy.17 The inclusion of the deep lymphatic vessels may be important. A recent study showed that in peripheral lymphedema secondary to breast treatment the deep lymphatic vessels were primarily affected, leading to subsequent poor function of the superficial vessels.20 In the small number of studies that include subfascial lymphoscintigraphy, inclusion of the deep lymphatic vessels has been shown to increase diagnostic accuracy.16 But there is a lack of research in this area to allow us to recommend the consistent use of subfacial lymphatic measurements in lymphoscintigraphy.
In the current study, we investigated the lymphatic flow by lymphoscintigraphy in 258 patients with primary and secondary lymphedema using a 2-compartment lymphoscintigraphic study. We aimed to semiquantify the lymphatic flow in the superficial and deep lymphatic vessels in these patients and determine if there was a match between lymphoscintigraphic findings and clinical signs of limb swelling.
Lymphoscintigraphic data for 258 patients in Genoa, Italy, at the Department of Nuclear Medicine, University Polyclinic Hospital “San Martino” were collected during the period of August 2012 to February 2017 for patients undergoing lymphoscintigraphy scans to diagnose a lymphatic basis for arm, unilateral leg, or bilateral leg swelling. The average age of the patients was 51.2 years (range, 9–84 years). No patient had a body mass index (BMI) greater than 41 kg/m2 (mean, 25.9 kg/m2; range, 17–41 kg/m2), indicating that they were not affected by obesity-related lymphedema, as this occurs for people with BMI of greater than 54 kg/m2.21,22 Other demographic information can be found in Table 1. Patients gave written consent for the anonymous use of their data. Lymphoscintigraphy examinations were completed to clearly indicate whether the edema was of lymphatic origin and to provide useful data about the etiology and pathohistological nature of the lymphedema.
Lymphoscintigraphies were performed with 99mTc-nanocolloid human serum albumin (90% of the particles were >80 nm in size) injected into the subcutaneous tissue of the second interdigital space of the hand and foot (epifascial injections for superficial vessels) and the palmar surface of the hands and feet (subfascial injection of the aponeurotic sites for deep lymphatic vessels); 30 to 50 MBq of nanocolloid per limb and per compartment was injected with insulin syringes and a 25-gauge needle. The locations of the injections can be seen in Figure 1. Both limbs were studied in order to use one side as a control for patients with unilateral lymphedema. Patients were asked to walk for 15 minutes after the administration of the tracer and the completion of the early dynamic images to ensure good uptake of the tracer. Patients with arm lymphedema instead completed a number of arm-raising exercises (lifting arms to shoulder height and straightening them out and bringing them down to the waist again, while in a standing position, 2 cycles of 10 repetitions).
Anterior and posterior images were taken sequentially 30 and 60 minutes after injection of the radiotracer for both the superficial and deep pathways. The superficial lymphatic vessel scans (with epifascial injection) were completed at least 48 hours after that of the deep lymphatic vessels (with subfascial injection) to allow for washout of the radiotracer between scans.
The scans were interpreted by an experienced anatomy-pathologist/radiologist (G.V.). A semiquantitative transport index (TI) from Kleinhans et al23 was calculated using the following formula to categorize the lymphatic flow as normal or pathological: TI = K + D + (0.04 × T) + N + V, where K = transport kinetics, D = distribution of the tracer, T = time to visualize the lymph nodes (in minutes, but no appearance gives a score of 9), N = visualization of lymph nodes, and V = visualization of lymph vessels. A score of less than 10 signifies a normal TI, and a score of 10 to 45 signifies a pathological TI. The TI was calculated for the superficial and deep lymphatic pathways for the affected limb and the contralateral limb in unilateral lymphedema and for both limbs in bilateral lymphedema.
Patients with completely normal TI scores (for both superficial and deep lymphatic pathways in both limbs) were excluded from the study, as there was no lymphatic basis to their edema (Fig. 2). This included 2 with unilateral arm swelling and 4 each with unilateral or bilateral leg swelling.
Data were analyzed using SPSS software (IBM SPSS Statistics for Windows version 24.0, released 2016; IBM Corp, Armonk, NY). For the purposes of this study, secondary lymphedema was defined as occurring after a surgery to remove lymph nodes (for cancer diagnosis or treatment) or otherwise interrupting the lymphatic vessel pathway (eg, hysterectomy or saphenous vein stripping with interruption of femoral triangle). All other lymphedemas were considered to be of primary origin, notwithstanding a potential “triggering event” such as infection or minor trauma. Unilateral arms, legs, and bilateral legs were analyzed separately. There is an a priori reason to think that the arm lymphedema group is fundamentally different from the other groups in that primary arm lymphedema is rare and most patients with arm lymphedema are predominantly female (92%) with secondary lymphedema due to breast cancer treatment.
A mixed 3-way analysis of variance was conducted with TI as the dependent variable and the between-subjects factor of type of lymphedema (primary or secondary), within subject variable of side of body (right or left), and within-subjects variable of vessel type (superficial or deep). The TI scores were in a range from 0 to a possible 45,23 where a higher score indicated a greater level of pathological lymph flow.
Secondary analysis was conducted to see the “match” between clinical presentation of limb swelling and pattern of lymphatic abnormalities on the lymphoscintigraphy. Each patient had a working clinical diagnosis of arm, leg, or bilateral lymphedema prior to lymphoscintigraphy. The “match” between the clinical presentation and the TI findings was noted as follows: score of 1 (“match”) = unilateral right (left arm)/leg lymphedema with abnormal TI on right (left) side (superficial or deep), score of 1 (“match”) = bilateral leg lymphedema with abnormal TI bilaterally (superficial or deep), score of 0 (“nonmatch”) = unilateral left arm/leg lymphedema with abnormal TI bilaterally or right side (superficial or deep) or vice versa, score of 0 (“nonmatch”) = bilateral leg lymphedema with abnormal TI only on left or right side (superficial or deep). A χ2 test for independence (Pearson χ2) was performed for each type of lymphedema on the match scores.
We also examined the vessel type abnormality involved in the swelling by looking to see whether the abnormal lymphatic findings occurred in the superficial lymphatic pathways, deep lymphatic pathways, or both vessel types in each patient. Hypothetically, lymphedema could be caused by injury only to the superficial vessels or only to deep or to both. This vessel-type data are presented in Table 2.
The average TI for patients with primary and secondary lymphedema according to type of limb swelling and superficial or deep lymphatic vessels is reported in Table 2. There was no significant difference in TI scores between patients with primary lymphedema and those with secondary lymphedema for patients with unilateral arm swelling (F 1,46 = 2.49, not statistically significant) or bilateral leg swelling (F 1,112 = 0.38, not statistically significant). In patients with unilateral leg lymphedema, there was a significant difference between patients with primary lymphedema and those with secondary lymphedema (F 1,84 = 5.33, P < 0.05). Patients with secondary causes of unilateral leg lymphedema showed greater impairment in lymphatic flow in terms of higher TI scores compared with patients with primary lymphedema.
Patients with unilateral leg lymphedema had a significant main effect of vessel type, where deep lymphatic pathways showed greater TI abnormality than superficial pathways, regardless of side of the body (F 1,82 = 10.78, P < 0.01). Similarly for patients with bilateral lymphedema, there was a significant main effect of vessel type (F 1,110 = 34,16, P < 0.001). The deep lymphatic pathways, on both the right and left sides, had worse TI scores than those for the superficial vessels. In contrast, for patients with unilateral arm swelling, there was a significant interaction between type of lymphatic vessel (superficial and deep) and side of body (left and right) (F 1,44 = 8.81, P < 0.01). The difference occurs in the deep lymphatic vessels in these patients, where the TI is worse on the left side.
For patients with unilateral arm lymphedema, there was a significant difference between patients with primary lymphedema and those with secondary lymphedema (χ2 2 [n = 48] = 6.52, P < 0.01). As can be seen in Table 3, whereas 50% of patients with primary lymphedema had a match between clinical problem and the lymphoscintigraphic findings, 50% had bilateral lymphoscintigraphic abnormalities but unilateral clinically apparent swelling. Instead, for patients with secondary causes of lymphedema, 86.8% had a match between the clinical swelling and the lymphoscintigraphy abnormalities, but 13.2% demonstrated bilateral problems on lymphoscintigraphy and unilateral swelling. Likewise for patients with bilateral leg lymphedema, almost all patients with secondary lymphedema had the expected bilateral lymphoscintigraphic abnormalities (97.1%). However, in patients with primary lymphedema 26.3% had unilateral lymphoscintigraphic abnormalities with bilaterally evident limb swelling. This gave a significant difference between primary and secondary lymphedema (χ2 2 [n = 114] = 8.32 P < 0.01) in terms of match between clinical presentation and lymphoscintigraphic findings
The findings were different for patients with unilateral leg lymphedema where no significant difference in match score was found between primary and secondary lymphedema (χ2 2 [n = 86] = 2.58, not statistically significant). Approximately 60% of both primary and secondary lymphedema patients had bilateral lymphoscintigraphic abnormalities despite having a unilateral leg swelling (59% and 60.0%, respectively, for primary and secondary lymphedema).
Vessel Type Affected
As can be seen in Table 4, 87.5% of patients with arm lymphedema had either deep lymphatic vessel abnormalities or deep and superficial abnormalities, and only 12.5% of patients had superficial vessel injury alone. A similar pattern was observed for unilateral leg lymphedema. This trend was even more evident for bilateral leg lymphedema, with 97.4% with deep vessels affected (either alone or also with superficial) and 2.6% with only superficial vessels affected. As can be seen in Figure 3, the deep lymphatic pathways are less evident on the lymphoscintigraphy.
This comparison of lymphoscintigraphic findings among 248 patients with lymphedema was useful to delineate a number of differences, but also similarities, among primary and secondary lymphedema patients and type of limbs affected. In the vast majority of the analysis, we found few differences in lymphoscintigraphic findings between patients with primary lymphedema and patients with secondary lymphedema, suggesting that different causes of damage to the lymphatic vessels will give the same pathological effects to lymphatic flow. The differences that were found must also be considered within the context of the limb types and therefore some basic anatomical differences. For example, patients with arm lymphedema demonstrated greater pathological lymphatic flow in deep lymphatic vessels like patients with leg lymphedema, but this effect was present only on the left side of the body. On the right side, the level of TI abnormality was the same for the superficial and deep lymphatic vessels. This may have something to do with the fact that the right arm drains into the right lymphatic duct, instead of part of the chain into the thoracic duct, as on the left side.24 The natural anatomic segregation could lead to differences in the lymphatic transport. It is known, for example, that primary arm lymphedema is more likely to occur on the right side than the left,25 perhaps related to these anatomical differences. In addition, we must also consider the effect of handedness on the results. There is some suggestion that handedness influences measurements of excess volume in patients with lymphedema (the dominant arm being slightly larger)26 and the development of lymphedema after cancer treatment (excessive use of the dominant arm results in onset of lymphedema).27 We also know that handedness affects the lymphoscintigraphic results in people without lymphedema (there is a greater lymphatic flow in the dominant arm in right-handed individuals).28 Data regarding handedness were not collected in this study; nevertheless, it should be acknowledged as a possible contributing factor for our findings in unilateral arm lymphedema
Similarly, the clinical match analysis in the current study revealed differences between limb types and primary and secondary lymphedema patients that are interesting and can possibly be explained by anatomical differences. We know that primary lymphedema is a congenital low-flow vascular malformation associated with hypoplasia, hyperplasia, or aplasia of the lymphatic vessels and/or lymph nodes and may clinically manifest as obstruction or dilatation, even years after birth because of a triggering event.29 This is fundamentally different from a secondary form of lymphedema with presumably normal lymphatic vessels and nodes prior to a surgical event (as per the definition of secondary lymphedema adopted in the current study) that disrupts these pathways, such as the removal of lymph nodes for cancer treatment. We assume in patients with secondary lymphedema that the rest of the lymphatic pathways in the body is normal; however, it is possible, in patients with primary lymphedema instead, that all lymphatic vessels are somewhat malformed.
In line with this idea, in the current study, we found that 50% or more of patients with unilateral arm or leg primary lymphedema had bilateral TI abnormalities. This is consistent with other studies of primary lymphedema.30,31 We also found; however, that 13% of patients with unilateral secondary arm lymphedema had bilateral lymphoscintigraphic abnormalities. This trend was even greater for unilateral leg lymphedema where 60% of secondary leg lymphedema patients had bilateral abnormalities on the lymphoscintigraphy. These results suggest some percentage of patients with secondary lymphedema have an underlying vulnerability to the lymphatic vessels, which predisposes them to lymphatic injury. Or perhaps this group is actually a primary lymphedema group with a congenital lymphatic malformation who underwent a surgical intervention and therefore was inaccurately considered to be “secondary” lymphedema. This pattern of unusual lymphatic vessel formation and flow on lymphoscintigraphy in patients with a “secondary” cause for lymphedema was previously noted by Baulieu et al12 and is consistent with other studies of lymphoscintigraphy in patients with unilateral swelling.12,29,32,33 In fact, it is for this reason that stage 0 (or stage 1A, depending on the classification used) is included in the classification of peripheral lymphedema.10 This captures the notion that it is possible to have subclinical changes to lymphatic vessels before clinical evidence of disease, and these changes can be detected by lymphoscintigraphy. This “subclinical” or “latent” lymphedema is considered to be a reason why some patients develop lymphedema after lymphadenectomy in cancer treatment, whereas others, undergoing the same surgery, do not. Those who develop overt lymphedema with clinical evidence of swelling likely had preexisting abnormalities in their lymphatic vessels
One of the main aims of the current study was to investigate abnormalities in lymphatic flow in both deep and superficial lymphatic vessels to determine the utility of a 2-compartment approach to lymphoscintigraphy that includes also the study of deep lymphatic vessels. To this end, we quantified the resulting TI scores as normal or pathological for each vessel type for each patient. The TI was published by Kleinhans et al23 in 1985 to provide a method to standardize the lymphoscintigraphy, something that could be used in the same patient multiple times (such as presurgically and postsurgically) in order to quantify an improvement or worsening in lymphatic flow over time. The TI has the advantage of an easily adopted system of scoring a lymphoscintigraphy and has acceptable statistical validity.23 Several authors have adopted the TI in published work regarding lymphoscintigraphy where, as a semiquantitative analysis, it is considered to enhance the sensitivity and specificity of the lymphoscintigraphy examination. Furthermore, quantitative methods such as the TI have been shown to be useful in “borderline” cases providing a more standard way to categorize the lymphatic flow as pathological or normal.34–36 There has been a suggestion that the TI may be somehow invalidated by the fact that an abnormal TI can be found in the presence of no clinical sign of swelling. However, as noted above, there are many studies that have found abnormal lymphatic transport in the contralateral limb of patients with lymphedema, and this is reflected in the staging of disease. Given that the index is made up of many parts of a lymphoscintigraphy including visualization of the nodes and vessels and lymphatic kinetics, a person could have a pathological score of 11 by having only faint visualization of the vessels and nodes, a slightly diffuse pattern of radiotracer (score of 3 for each of these) but normal kinetics. This may not translate into clinical swelling, but an abnormality of the lymphatic system exists all the same. This is an example of the additional information that can be communicated using a TI with lymphoscintigraphy.
Overwhelmingly in the current study, we found that deep lymphatic vessels showed the pathological TI, either independently or in combination with superficial vessels. More than 87% of patients and up to 97% with bilateral leg lymphedema had abnormalities in lymph transport in the deep lymphatic vessels regardless of limb type affected. Stanton et al20 had already demonstrated that arm lymphedema secondary to breast cancer is associated with slowed drainage in the subfascial deep lymphatic pathways. They found that the deep lymphatic vessels in swollen arms (compared with the contralateral unaffected arm) had slower lymphatic drainage. The level of impairment was correlated to the clinical picture, with greater swelling in the arm correlated to slower drainage.
McClellan et al37 instead investigated the lymphoscintigraphic findings of 134 patients with limb lymphedema. They found no association between lymphoscintigraphy findings and the clinical presentation of swelling and concluded that lymphoscintigraphy did not provide further useful information beyond a binary abnormal/normal measure. However, it should be noted that their study did not examine the deep lymphatic vessels. Stanton and colleagues'20 study emphasized the importance of the deep lymphatic vessels, postulating that the subfascial deep lymphatic vessels are initially affected in arm lymphedema and undergo increased afterload to the point that the microvascular filtration rate in the subfascial compartment reduces, which subsequently leads to dilation and overload of the superficial pathways and development of dermal backflow. Similarly, Hassanein et al14 investigated a group with presumed lymphedema and found a number of “false-negative” lymphoscintigraphies in patients who had clinical limb swelling but normal superficial lymphatic flow on lymphoscintigraphy, some of whom later demonstrated abnormal flows on subsequent scans. These too may have had undetected abnormalities involving the deep subfascial lymphatics, which, according to the rationale of Stanton et al,20 could occur prior to damage to the superficial lymphatic pathways and thus remain undetected by Hassanein and colleagues'14 lymphoscintigraphy protocol.
If we compare the sensitivity in detecting abnormal lymphatic flow of the current study and that of Hassanein et al,14 they are comparable at 96.2% and 96%, respectively. Yet, Hassanein et al14 studied only the superficial lymphatic vessel flow, whereas the current studied investigated both the superficial and deep flows. The current study was able to exclude patients without a lymphatic basis for their swelling and to categorize patients into different types of lymphatic swelling. Hassanein and colleagues'14 study was similar, but it also had a group of 7 patients with limb swelling that its authors could not explain as being related to venous or superficial lymphatic vessel problems. We postulate that these patients had abnormalities in deep lymphatic flow. In reality, 7 patients are only 4.3% of their sample. However, given that conservative estimates of the incidence of lymphedema worldwide are of 90 million patients,38 this translates to more than 3.8 million people potentially misdiagnosed. Furthermore, given the high propensity of lymphedema to progress into advanced stages with increasing physical disability and risk of serious infection, despite conservative treatments, such a large group could put significant strain on health care resources. Other differences in patient population between our study and that of Hassanein et al14 must also be considered as an explanation for the current study's findings; they have a slightly smaller age range, with fewer elderly patients. However, age is not generally considered to be a risk factor for lymphedema.39 Obesity is a risk factor for lymphedema development in general, and radiation and lymphadenectomy are risk factors associated to lymphedema development after cancer treatment.5,39,40 As both our study and Hassanein and colleagues'14 study excluded obesity, and neither group found significant differences in lymphoscintigraphy findings between primary and secondary lymphedema, we can only conclude that the current study found that the deep lymphatic vessels were primarily affected in patients with lymphedema because it specifically investigated differences between lymphatic vessel types, which was not the case in Hassanein and colleagues'14 study.
On the face of it, to arrive at a diagnosis of lymphedema based on lymphoscintigraphy, Hassanein and colleagues'14 study is evidence that in the vast majority of cases a lymphoscintigraphy scan of the superficial vessels is sufficient. However, we emphasize the necessity of also examining the flow of lymph in the deep lymphatic vessels when performing a diagnostic lymphoscintigraphy in a patient suspected of having lymphedema. We believe that it will add important information for the diagnosis of lymphedema. It is not sufficient to use a lymphoscintigraphy protocol for superficial lymphatic vessels when we have the ability to determine which type of vessel is affected in each patient. Despite the large number of patients affected, the exact pathogenesis of lymphedema is not entirely clear. It is still not certain why some patients develop lymphedema after lymph node dissection during cancer treatment, and some do not. Certainly, the possibility of preexisting subclinical lymphatic vessel abnormalities should be considered, but also other mitigating factors such as BMI seem to be important.39,40 Knowing that some patients with lymphedema have abnormal lymphatic drainage affecting the superficial vessels and others, the deep vessels may have important implications for treatment. For example, manual lymphatic massage techniques are widely accepted as part of conservative treatment programs for lymphedema; however, there is conflicting evidence about their utility as both a standalone treatment or as part of a conservative treatment package.41,42 We consider the possibility that the difference in study outcomes from manual lymphatic drainage may be related to difference in lymphatic vessels; perhaps manual lymphatic drainage is less effective in patients with only deep lymphatic vessels abnormalities, given that it is a light massage and their superficial lymphatic drainage is intact. We hope that our study is the basis upon which new investigations for the utility of the various treatments for lymphedema can be undertaken, considering also the type of lymphatic drainage abnormalities.
Furthermore, the importance of being aware of deep vessel impairment in peripheral lymphedema has wider implications. A fundamental treatment for peripheral lymphedema is lymphatic-venous anastomosis, a microsurgical procedure to bypass lymphatic obstruction and reroute lymph into the bloodstream before the natural anatomic deviation in the thoracic duct. By now, this technique is an established and effective treatment, particularly in the early stages of disease.43–51 However, there are vast differences in volume reduction achieved and long-term outcomes across centers worldwide.45–47 One main difference between centers is the choice of lymphatic vessels to anastomose: supermicrosurgery uses 1 superficial vessel to 1 small venule, whereas multiple lymphatic-venous anastomoses attach several superficial and deep lymphatic vessels (15 per anastomosis on average) into a vein branch at the site of a functioning valve.50 The multiple lymphatic-venous anastomoses technique appears to have better long-term outcomes,5 and the current study suggests that this may be, in part, due to the inclusion of the deep lymphatic vessels in the anastomosis. If both the superficial and deep vessels are affected in peripheral lymphedema, it makes sense to intervene surgically with a technique that improves the lymphatic flow in both vessel types.
We must acknowledge the limitations of the current study. We excluded patients with a TI of less than 10, on the basis that there was no lymphatic cause to the limb swelling. However, it is possible that a score of 6 or 9 could be considered “borderline,” and these patients should be reexamined in time. Given that we had only 10 patients with scores of less than 10 (3.8% of the sample), we do not believe that their exclusion will have affected our results. We must also acknowledge the cost of the dual-compartment lymphoscintigraphy procedure, given that it requires 2 separate appointments and scans. On the other hand, using a dual-compartment lymphoscintigraphy to categorize patients with lymphedema into those with superficial, deep, or mixed lymphatic vessel damage may be a way forward for research studies in order to gain further information about the utility of various treatment options, leading toward more individualized care. In the case of a surgical center that uses the lymphoscintigraphy data not only for diagnosis but also for surgical planning, the 2-compartment procedure is particularly recommended to give valuable information about the presurgical state of all lymphatic vessels.
In summary, a 2-compartment lymphoscintigraphy is able to accurately detect lymphatic flow abnormalities in patients with limb swelling, showing many similarities between patients with primary lymphedema and those with secondary causes. In particular, we noted the possibility of bilateral lymphatic transport abnormalities not only in patients with unilateral primary lymphedema but also in a subgroup of patients with unilateral secondary lymphedema. This gives further evidence to the concept of an underlying vulnerability toward the development of lymphedema in some people in terms of preexisting lymphatic vessel abnormalities. We also found that up to 97% of patients have abnormalities in the deep lymphatic vessels that underlie this limb swelling, in contrast to previous lymphoscintigraphy research. This emphasizes the importance of including these deep lymphatic vessels in a lymphoscintigraphic study in patients with limb swelling, presumed to be due to a lymphatic basis, especially if a lymphoscintigraphy of the superficial vessels was negative and for surgical planning.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
2-compartment protocol; lymphoscintigraphy; peripheral lymphedema; subfascial lymphatic vessels