Differentiation of High and Low Output Lymphatic Failure Using Qualitative Lymphangioscintigraphy

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1 2015 Annals of Vascular Diseases doi: /avd.oa Original Article Differentiation of High and Low Output Lymphatic Failure Using Qualitative Lymphangioscintigraphy Kotaro Suehiro, MD, Noriyasu Morikage, MD, Masanori Murakami, MD, Osamu Yamashita, MD, Takasuke Harada, MD, Koshiro Ueda, MD, Makoto Samura, MD, Yuya Tanaka, MD, and Kimikazu Hamano, MD Purpose: To use qualitative lymphangioscintigraphy (LAS) findings to differentiate leg edema caused by high and low output lymphatic failure. Methods: LAS was performed in legs with secondary lymphedema (LE), i.e., low output failure (N = 79), and functional venous insufficiency (FVI), i.e., high output failure (N = 56), and normal legs (N = 26). Whole body images were obtained, 15, 60, and 180 min after technetium-99m injection. The rate and timing of visualization of lymphatic structures, washout out of tracer, and presence of dermal backflow were assessed. Results: The most significant finding for differentiating LE from other conditions was not the visualization of lymphatic structures, but the washout of the tracer from the leg trunk (LE 27%, FVI 100%, normal leg 100%, P <.0001). On the other hand, the most significant finding for differentiating FVI from other legs was the visualization of inguinal lymph nodes at 15 min (LE 11%, FVI 82%, normal leg 8%, P <.0001). Conclusions: We found that the lack of washout from the leg trunk was most suggestive of a low output status of the lymphatic system, while earlier visualization of inguinal lymph nodes was suggestive of a high output status. Keywords: leg, lymphedema, venous insufficiency, lymphangioscintigraphy Introduction With the recent increase in the number of aged people, the number of patients with severe gait disturbance has been increasing. These patients generally become immobile, Division of Vascular Surgery, Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan Received: April 9, 2015; Accepted: April 23, 2015 Corresponding author: Kotaro Suehiro, MD. Division of Vascular Surgery, Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Minamikogushi, Ube, Yamaguchi, Japan Tel: , Fax: ksuehiro-circ@umin.ac.jp which can cause venous stasis and result in leg edema. 1,2) With increasing age, legs with lymphedema may be complicated by such type of leg edema, each of which should be treated differently. However, any edema may present with symptoms mimicking lymphedema 1) because they are caused by an imbalance between capillary filtration and lymph drainage. 2) This makes it difficult to differentiate between lymphedema and other edemas only by physical examination. As a result, quite a lot of physicians misdiagnose this functional venous insufficiency (FVI) as lymphedema. 3) Since the International Society of Lymphology (ISL) defined lymphedema as a low output failure of the lymphvascular system and stated that high output failure should properly be distinguished from lymphedema, 4) it is necessary to demonstrate the differences in output status for differential diagnosis. Lymphangioscintigraphy (LAS) can offer remarkable insights into lymphatic function and reflect various types of lymphatic abnormality. Among qualitative LAS findings, visualization of ilioinguinal lymph nodes, main lymphatic trunks, and dermal backflow (DBF) have been proposed as diagnostic criteria. 5 7) In the current study, we particularly reviewed these qualitative LAS findings in legs with secondary lymphedema and FVI, each of which represent low and high output failure respectively, as well as in normal legs, and evaluated their diagnostic value in differentiating between these conditions. Methods This retrospective study was approved by the Institutional Review Board of Yamaguchi University Hospital (Ube, Yamaguchi, Japan), and the need for individual patient consent was waived. The subjects included in the current retrospective study were 108 patients who first visited our clinic with a complaint of leg edema between April 2009 and December 2014, and agreed to undergo LAS to confirm their diagnoses before initiating their treatments. The initial diagnoses were made by patient histories, physical examinations, blood tests, chest radiograms, electrocardiograms to exclude edemagenic conditions derived from 1

2 Suehiro K, et al. Table 1 Subjects and legs characteristics Normal (N = 14) FVI (N = 29) Secondary lymphedema (N = 53) Gender (male:female) 4:10 6:23 7:46 Age (years; median range]) 66 (34 81) 70 (35 83) 69 (43 85) Legs Normal leg 22 Dependent edema 56 s/p Surgery for malignancy 77 General weakness 50 Uterine cancer 57 Obesity 6 Ovarian cancer 8 Prostate cancer 7 Vulvar cancer 2 Penile cancer 1 Malignant melanoma 1 Synovial sarcoma 1 s/p Trauma and surgery 2 Normal legs with LND (counted as stage 0) 6 Asymptomatic counterpart (counted as normal leg) FVI: functional venous insufficiency; s/p: status post; LND: lymph node dissection 2 Asymptomatic counterpart (counted as stage 0) Non-operated leg (counted as normal leg) 25 2 systemic diseases. A duplex venous ultrasound was performed to exclude any reflux in the deep veins, saphenous veins, accessory saphenous veins, and perforators. Subcutaneous tissue ultrasonography 8,9) was also performed to find changes in echogenicity that correlated with inflammatory change and echo-free space that indicated accumulation of free fluid. Of 108 patients, 53 patients were diagnosed as symptomatic secondary leg lymphedema, 29 patients as FVI, and 14 patients as either very mild leg edema within the normal range or no edema and LAS findings of these patients legs were analyzed. The patients and leg characteristics are summarized in Table 1. The clinical severity of lymphedema was judged according to the Consensus Document of the International Society of Lymphology as follows: 4) Stage 0: A latent or subclinical condition in which limb swelling is not yet evident Stage I: An early accumulation of fluid that subsides with limb elevation Stage II: Tissue swelling that is not reduced by limb elevation alone. Pitting manifests in earlier stage II, but the limb may or may not pit in later stage II as excess fat and fibrosis supervenes. Stage III: Lymphostatic elephantiasis in which pitting can be absent and trophic skin changes such as acanthosis, further deposition of fat and fibrosis, and watery overgrowths have developed. In the current study, asymptomatic contralateral legs with unilateral lymphedema and bilateral legs without edema but with a history of intrapelvic lymph node dissection, were all considered included as Stage 0 lymphedema, because all of these legs were considered to have more or less impaired lymph transport. Accordingly, these legs were assessed separately. FVI in this study was defined by the following characteristics: Leg edema with/without concomitant skin lesions (CEAP classification 10,11) of C3 or greater) Severe gait disturbance and inability to walk independently without some form of aid, i.e., crutches, walking frames; or inability to walk, but not bedridden General weakness and/or obesity as a cause of the above condition No reflux or occlusion in the deep veins, saphenous veins, accessory saphenous veins, and perforators on duplex venous ultrasound. FVI has not been well-defined formally. However, we previously studied the group of patients as defined above and found that many of these patients with leg edema (C3) were complicated with symptoms of C4 or greater, namely typical symptoms of chronic venous insufficiency, but not the symptoms of lymphedema, and that these symptoms seemed mainly derived from their immobility. It was also noticed that lymphatic functions in these patients legs were accelerated. 9) Therefore, we regarded these patients legs as in the condition of high output lymphatic failure. For epifascial LAS, 111 MBq of technetium-99m suspended in 0.1 ml human serum albumin was injected intradermally into the first interdigital web of each extremity. Whole body anterior and posterior images were obtained with a gamma camera (E.CAM, Toshiba Medical Co., Tokyo, Japan), 15, 60, and 180 min after a tracer 2

3 Lymphangioscintigraphy in Various Leg Edema (A) (B) 15 min 60 min 180 min 15 min 60 min 180 min (C) 15 min 60 min 180 min Fig. 1 (A) Bilateral normal legs. Only the lower parts of both the leg trunks are visualized, 15 min after tracer injection to the foot. At 60 min, the entire leg trunk and inguinal lymph nodes are visible. At 180 min, the entire iliac trunk is visualized. The visualization of the leg trunks is decreased at this time, which indicates that the tracer in the leg trunk is washed out. (B) Bilateral functional venous insufficiency (dependent edema). The entire leg trunk as well as the inguinal lymph nodes are visualized, 15 min after tracer injection to the foot. On the right, the iliac trunk is also visible at this time. By 180 min, the tracer is washed out from the leg trunk. Dermal backflow can be observed in the lower right leg (arrow). (C) Unilateral lymphedema (Right: stage 0, Left: Stage II). In the left leg, which has symptomatic lymphedema, neither the leg trunk nor the inguinal lymph nodes are visualized. Coarse dermal backflow is seen in the thigh and calf. In the asymptomatic right leg, the entire leg trunk and the inguinal lymph nodes are visible up to 60 min. Note that the iliac trunk is not visualized at all; this was supposed be dissected at the time of surgery. injection. In the current study, the following findings, previously discussed with respect to diagnosing lymphedema were assessed: For the iliac and leg lymphatic trunk: When the entire length of the iliac trunk (between the abdominal trunk bifurcation and inguinal lymph nodes) or the leg trunk (between the inguinal lymph nodes and injection site) was enhanced by the tracer, they were considered to be visualized. For the inguinal lymph nodes: When the most inferior inguinal lymph node in the groin was enhanced by the tracer, it was regarded to be visualized. For DBF: The presence of DBF either in the thigh or in the calf 180 min after tracer injection was assessed. For the washout of the tracer from the leg trunk: The washout of the tracer from the leg trunk was assessed between 60 and 180 min after tracer injection. When the trunk was less enhanced at 180 min, the trunk was regarded as washed out. Particularly, when the trunk was not visualized at all at 180 min, it was regarded as a complete washout. Statistical analysis Results are expressed as the mean ± standard deviation or count, unless otherwise indicated. The c 2 test was used to compare the rate of visualization/washout of the lymphatic structures, or DBF among the groups. To test the determinant factors for differentiating each leg condition, 3

4 Suehiro K, et al. Table 2 Qualitative lymphangioscintigraphy findings Normal (N = 26) Stage 0 (N = 31) FVI (N = 56) Lymphedema (N = 79) Iliac trunk 15 min 1 (4%) 3 (10%) 29 (52%) * 1 (1%) 60 min 24 (92%) 11 (35%) * 52 (93%) 14 (18%) * 180 min 26 (100%) 12 (39%) * 54 (96%) 20 (25%) * Inguinal lymph nodes 15 min 2 (8%) 8 (26%) 46 (82%) * 9 (11%) 60 min 26 (100%) 29 (94%) 56 (100%) 32 (41%) * 180 min 26 (100%) 30 (97%) 56 (100%) 42 (53%) * Leg trunk 15 min 8 (31%) 12 (39%) 46 (82%) * 27 (34%) 60 min 26 (100%) 29 (94%) 56 (100%) 41 (52%) * 180 min 26 (100%) 29 (94%) 56 (100%) 42 (53%) * Dermal backflow Thigh 0 (0%) 1 (3%) 0 (0%) 36 (46%) * Lower leg 0 (0%) 2 (6%) 10 (18%) * 45 (57%) * Washout of leg trunk (N = 42) Incomplete 26 (100%) 31 (100%) 56 (100%) 20 (48%) * Complete 11 (42%) 12 (39%) 21 (38%) 1 (2%) * LAS: lymphangioscintigraphy; *: <.05 vs. Normal; : <.05 vs. Stage 0; : <.05 vs. Venous edema multivariate logistic regression was used. Statistical analyses were performed using JMP 11.0 (SAS Institute, Cary, NC, USA). A P-value <.05 was considered statistically significant. Results As shown in Table 1, legs were classified as normal legs (N = 26), legs with Stage 0 lymphedema (Stage 0; N = 31), legs with FVI (N = 56), and legs with stage I III, namely symptomatic, lymphedema (LE; N = 79). Typical LAS images in these legs are shown in Fig. 1. Qualitative LAS findings for these legs are summarized in Table 2. Iliac trunk In the case of normal legs, the iliac trunk was visualized only in 4% of legs at 15 min, but it was visualized in 92% at 60 min and in 100% at 180 min. Even in Stage 0 and LE, in which the intrapelvic lymph nodes and lymphatics were supposed to be dissected, the iliac trunk was visualized in 39% and 25% of legs until 180 min, respectively. At 15 min, the iliac trunk was visualized in 52% of FVI legs, which was significantly higher than the rate of visualization in the other groups. This was followed by 93% and 96% of legs at 60 and 180 min respectively, which were similar to the rate of visualization in the normal legs. Inguinal lymph node In normal legs, the inguinal lymph nodes were visualized only in 8% of legs at 15 min, while they were visualized in 100% of legs at 60 and 180 min. The inguinal lymph nodes were visualized in 94% of Stage 0 legs at 60 min, which was equivalent to that of normal legs. Even in LE, they were visualized in 41% of legs at 60 min. In FVI, they were visualized in as many as 82% of legs at 15 min, which was significantly higher than the rate of visualization in the other groups. Leg trunk The leg trunk was visualized in up to 31% of normal legs at 15 min, which was similar to the rate of visualization in Stage 0 (39%) and LE (34%) legs. Rate of visualization of the leg trunk in the FVI group was again significantly higher (82%) at 15 min. Almost all leg trunks in the normal, Stage 0, and FVI groups were visualized until 60 min, while this was seen in only 52% of legs in the LE group. Dermal backflow In the normal and FVI groups, DBF in the thigh was not observed at all. It was seen in only 1 (3%) leg in the Stage 0 group but was seen in 46% in the LE group. DBF in the calf was seen in 57% of the LE legs. It was also seen in 18% of FVI legs, which was significantly higher than the rate of visualization in normal (0%) but lower than the rate of visualization in the LE legs. Washout of leg trunk In normal, Stage 0, and FVI legs, the tracer was washed out from all leg trunks, although complete washout was seen only in 42, 39, and 38%, respectively. Among 42 4

5 Lymphangioscintigraphy in Various Leg Edema Table 3 Significant factors for differentiation LE vs Non-LE LE vs Normal LE vs Stage 0 LE vs FVI FVI vs Normal Stage 0 vs Normal Iliac trunk 15 min 60 min 180 min Inguinal lymph nodes 15 min < min min Leg trunk 15 min 60 min 180 min Dermal backflow Thigh Lower leg Washout of leg trunk < <.0001 <.0001 Numbers indicate P-values obtained from multivariate logistic regressions. (53%) of LE legs whose leg trunk was visualized, the washout was observed only in 20 (48%), which corresponded to 25% of total LE legs (N = 79). Factors for differentiation The results of multivariate logistic regressions to differentiate each group are summarized in Table 3. For the differentiation of an LE leg from a normal one, the most significant factor was the washout of the leg trunk rather than the visualization of structures. This was persistent when LE legs were compared to the other legs. On the other hand, in order to differentiate FVI legs from normal legs, the visualization of inguinal lymph nodes 15 min after the tracer injection was the most significant factor. Although the presence of DBF was highly suggestive of lymphedema, it was also a significant factor to differentiate between normal and FVI legs. Discussion Delayed or no visualization of certain lymphatic structures can be considered to represent the low output status of the lymph transport system. Since the visualization of the iliac trunk, the inguinal lymph nodes, and the leg trunk was not different for the normal and LE groups at 15 min, the evaluation of the low output status should be done in the later phase. However, it was found that as many as 18% of the iliac trunks, 41% of the inguinal lymph nodes, and 52% of the leg trunks in LE legs could be visualized at 60 min. These values were sufficiently high to hinder clear differentiation. The results of the multivariate analysis suggested that the lack of washout in the leg trunk was more suggestive of low output status than delayed or absent visualization of these structures. Contrary to the low output status, the earlier visualization of certain structures can be considered to represent the high output status of the lymph transport system. The rate of visualization of the iliac trunk, the inguinal lymph nodes, and the leg trunk in FVI, where lymph transport was considered to be increased in response to the increased preload to the lymphatic system, was significantly higher than those in the normal group at 15 min. Among them, the visualization of inguinal lymph nodes at 15 min was found to be the most suggestiveof high output status. In the previous reports, however, decreased lymph transport in chronic venous diseases was described ) In these reports, the majority of patients with chronic venous diseases had anatomical venous problems such as superficial/deep venous occlusion/insufficiency, while the patients in the current study had functional venous stasis without evident anatomical problems. Therefore, we assumed that the anatomical venous disorder might have caused perivascular inflammation, which further affected the adjacent lymphatics anatomically and/or functionally. Although quantitative or semi-quantitative LAS assessments have been reported, 6,16 19) we experienced difficulty in achieving consistent results using them because of the difficulties in avoiding tracer injection into small veins or the subfascial space and setting a proper region of interest. Accordingly, we concluded that qualitative assessment could be achieved easily, and provided more stable results. DBF represents lymph drainage through dermal lymphatic collaterals, which is the end result of lymphatic obstruction; 20,21) thus, the presence of DBF in any part of 5

6 Suehiro K, et al. the extremity may indicate abnormal lymphatic transport. As seen in the current result, DBF in the thigh and/ or lower leg was a significant factor for differentiating LE from other legs. However, DBF, particularly in the lower leg, was also seen in 18% of FVI legs, which was significantly higher than the proportion of normal legs. It has been reported that lymphatic abnormality can be seen in 20% 30% of patients with chronic venous disease possibly due to secondary damage from lymphatic overload or otherwise recurrent cellulitis. 15) Namely, DBF can be seen in legs with either low or high output failure. High output lymphatic failure is essentially a result of underlying pathology including anatomical/functional venous insufficiency and/or systemic diseases such as heart/renal/ hepatic failure. Raju et al. reported that some abnormal lymph transport in venous lymphedema such as that caused by events such as deep venous occlusion was normalized after venous intervention. 15) Accordingly, firstline treatment should be directed at these conditions rather than at providing complex physical therapy or lymphatic surgery, and therefore they should be clearly differentiated from ordinary lymphedema. Interestingly, the iliac trunks in Stage 0 and LE, both of whose pelvic lymph nodes were supposed to be dissected at the time of cancer surgery, were visualized in 39% and 25% of legs, respectively, until 180 min. The mechanism of this visualization was not clear, but the difference between these groups was most evident in the washout of the leg trunk, but again not in the visualization of any structures. When the stage 0 and normal groups were compared, the only significant difference was the visualization of the iliac trunk. Considered together, stage 0 lymphedema is a condition in which the normal function of the inguinal lymph nodes and the leg trunk is maintained, despite the impairment or absence of the iliac trunk. This also supports the idea that symptoms caused by lymph stasis may be avoided if the function of the inguinal lymph nodes is preserved or restored. Recently indocyanine green (ICG) lymphography has increasingly been used to diagnose lymphedema, 22) because, compared to LAS, it prevent patients from irradiation and is easily available in the outpatient clinic. However, ICG lymphography can only visualize very superficial lymphatic structures but not deeper structures which are often functioning as lymph drainage route. It is not suitable to observe the washout of tracer as well. These mean that ICG lymphography may not truly diagnose lymphedema, i.e. low output failure, but only shows the local phenomena caused either by high or low output failure. For this reason, we did not employ ICG lymphography in the current study. Limitations Since this study was a single-center, retrospective study including a limited number of subjects, reaching a definite conclusion was difficult. This study mainly included functional venous edema caused by the dependency syndrome and obesity. However, there are wide varieties of chronic venous insufficiency in terms of pathology and severity. Moreover, the current study didn t include primary lymphedema, which again includes a wide variety of pathology. Thus, LAS findings in these edemas may be different and different conclusions may be drawn. In the current study, LAS images were analyzed by single observer. However, it is sometimes difficult to properly evaluate the visualization of the lymph nodes and/or lymphatic trunks, and therefore current result needs be verified by multiple observers. We routinely inject the tracer into the first web space only for technical simplicity and for reduction of patients pains, but this cannot reveal whole flows of the lymph channels in the lower limb. Visualization of the posterior superficial trunk and deep trunk at a same time may further extend the information. Conclusion In the current study, we found that the lack of washout from the leg trunk rather than the lack of visualization of any lymphatic structure was highly suggestive of the low output status of the lymph transport system. On the other hand, the early visualization of the inguinal lymph nodes was suggestive of high output status. In addition, we found that DBF alone is not necessarily suggestive of low output failure; hence, combinations of these findings would aid more accurate differentiation. Conflict of Interest Statement All authors have no conflict of interest. Acknowledgement None. References 1) Mortimer PS, Levick JR. Chronic peripheral oedema: the critical role of the lymphatic system. Clin Med 2004; 4: ) Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res 2010; 87: ) Suehiro K, Furutani A, Morikage N, et al. Routine diagnostic venous ultrasound and las for leg edema of unknown cause. Ann Vasc Dis 2010; 3: ) International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology. Lymphology 2013; 46:

7 Lymphangioscintigraphy in Various Leg Edema 5) Szuba A, Shin WS, Strauss HW, et al. The third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema. J Nucl Med 2003; 44: ) Burnand KM, Glass DM, Mortimer PS, et al. Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling. Clin Nucl Med 2012; 37: Suehiro K, Morikage N, Murakami M, et al. Re-evaluation of qualitative lymphangioscintigraphic findings in secondary lower extremity lymphedema. Surg Today. 2014; 44: ) Suehiro K, Morikage N, Murakami M, et al. Significance of ultrasound examination of skin and subcutaneous tissue in secondary lower extremity lymphedema. Ann Vasc Dis 2013; 6: ) Suehiro K, Morikage N, Murakami M, et al. A study of leg edema in immobile patients. Circ J 2014; 78: ) Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995; 21: ) Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: Gloviczki P, Calcagno D, Schirger A, et al. Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations. J Vasc Surg 1989; 9: 683-9; discussion ) Collins PS, Villavicencio JL, Abreu SH, et al. Abnormalities of lymphatic drainage in lower extremities: a lymphoscintigraphic study. J Vasc Surg 1989; 9: ) Bull RH, Gane JN, Evans JE, et al. Abnormal lymph drainage in patients with chronic venous leg ulcers. J Am Acad Dermatol 1993; 28: ) Raju S, Furrh JB, Neglan P. Diagnosis and treatment of venous lymphedema. J Vasc Surg 2012; 55: ) Brautigam P, Foldi E, Schaiper I, et al. Analysis of lymphatic drainage in various forms of leg edema using two compartment lymphoscintigraphy. Lymphology 1998; 31: ) Weissleder H, Weissleder R. Lymphedema: evaluation of qualitative and quantitative lymphoscintigraphy in 238 patients. Radiology 1988; 167: ) Vaqueiro M, Gloviczki P, Fisher J, et al. Lymphoscintigraphy in lymphedema: an aid to microsurgery. J Nucl Med 1986; 27: ) Ohtake E, Matsui K. Lymphoscintigraphy in patients with lymphedema. A new approach using intradermal injections of technetium-99m human serum albumin. Clin Nucl Med 1986; 11: Bruna J. Collateral lymphatic circulation. Eur J Plast Surg 2000; 23: ) Sty JR, Boedecker RA, Scanlon GT, et al. Radionuclide dermal backflow in lymphatic obstruction. J Nucl Med 1979; 20: ) Mihara M, Hara H, Araki J, et al. Indocyanine green (ICG) lymphography is superior to lymphoscintigraphy for diagnostic imaging of early lymphedema of the upper limbs. PLoS ONE 2012; 7: e