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Characteristics and outcomes of lymphaticovenular anastomosis in older patients with bilateral involvement versus younger patients with unilateral involvement in lower extremity lymphedema
Characteristics and outcomes of lymphaticovenular anastomosis in older patients with bilateral involvement versus younger patients with unilateral involvement in lower extremity lymphedema Shuhei Yoshida, MD, PhD,a Isao Koshima, MD, PhD,a Hirofumi Imai, MD,a Toshio Uchiki, MD,b Ayano Sasaki, MD,b Yumio Fujioka, MD,b Shogo Nagamatsu, MD, PhD,b Kazunori Yokota, MD, PhD,b Mitsunobu Harima, MD,c Shuji Yamashita, MD,c and Kensuke Tashiro, MD,d Hiroshima, Tokyo, and Tochigi, Japan
ABSTRACT Objective: We have previously reported that patients with idiopathic primary lymphedema of adult onset can be classified into an older group with bilateral involvement and a younger group with unilateral involvement and that there are significant differences in the characteristics of these groups. The aims of this study were to investigate the features of these two groups further by evaluating the lymphatics while performing lymphaticovenular anastomosis (LVA) and to compare the effectiveness of LVA between the two groups. Methods: This study enrolled 74 patients (136 edematous legs) in whom indocyanine green (ICG) lymphography and LVA were performed. The rate of detection and the diameter of the lymphatic vessels were recorded. The lower extremity lymphedema index (the total sum of the squares of the circumference for five areas in each leg divided by the body mass index) was obtained before and 6 months after LVA. The rate of improvement in the affected lower limbs after LVA was also calculated. Results: The clinical lymphedema pattern was determined to be bilateral in 62 patients and unilateral in 12. Patients with bilateral lymphedema were significantly older than those with unilateral lymphedema (77.1 6 7.8 years vs 55.5 6 12.77 years; P < .01). A linear pattern was seen in 23 patients (46 legs), a low enhancement (LE) pattern in 12 patients (24 legs), a distal dermal backflow (dDB) pattern in 20 patients (40 legs), and an extended dermal backflow (eDB) pattern in 7 patients (14 legs). The lymphedema was unilateral in 12 patients (12 legs). There were significant between-group differences in lymphatic diameter in relation to lower leg area: linear (0.9 6 0.1 mm) vs dDB (0.7 6 0.2 mm), linear vs eDB (0.7 6 0.2 mm), linear vs unilateral (0.5 6 0.1 mm), LE (0.9 6 0.2 mm) vs dDB, LE vs eDB, LE vs unilateral, and dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05. There were also significant between-group differences in the rate of improvement in the lower extremity lymphedema index according to the ICG lymphography pattern and laterality: linear (10.5% 6 2.4%) vs unilateral (6.7% 6 0.6%), LE (10.4% 6 1.5%) vs unilateral, dDB (11.0% 6 1.3%) vs eDB (8.9% 6 1.5%), and dDB vs unilateral, P < .01; linear vs eDB, P < .05; and eDB vs unilateral, P < .05. Conclusions: The lymphatic vessel diameter tended to be greater in older patients with bilateral lymphedema than in younger patients with unilateral lymphedema. The rate of detection and improvement tended to decrease with worsening of the ICG lymphography pattern. LVA is thought to be more effective in older patients with early-stage bilateral lower leg lymphedema than in their younger counterparts with late-stage unilateral lymphedema. (J Vasc Surg: Venous and Lym Dis 2019;-:1-12.) Keywords: Lymphedema; Aging; Lymphaticovenular anastomosis
Several lymphatic reconstruction procedures have been used for treatment of lymphedema.1-6 One of these procedures is lymphaticovenular anastomosis (LVA), which is becoming increasingly popular in the field of microsurgery.1-3
Lymphedema may be primary (of genetic origin) or secondary (a result of trauma, iatrogenic insult, or parasitic infection).7-10 Primary lymphedema can be divided into lymphedema congenita, praecox, and tarda. With the exception of lymphedema tarda, primary lymphedema
From the International Center for Lymphedema,a and Department of Plastic
The editors and reviewers of this article have no relevant financial relationships to
and Reconstructive Surgery,b Hiroshima University, Hiroshima; the Depart-
disclose per the Journal policy that requires reviewers to decline review of any
ment of Plastic and Reconstructive Surgery, Tokyo University, Tokyoc; and the Department of Plastic and Reconstructive Surgery, Jichi Medical University, Tochigi.d Author conflict of interest: none.
manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvsv.2019.10.013
Correspondence: Shuhei Yoshida, MD, PhD, International Center for Lymphedema, Hiroshima University Hospital, 1-2-3, Kasumi, Minami, Hiroshima 7348551, Japan (e-mail: [email protected]).
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is characterized by age-related lymphatic impairment that is thought to develop because of a decline in lymphatic pump function in response to oxidative stress.8,11-14 Aging-induced oxidative stress in the lymphatic vessels facilitates the spread of pathogens from these vessels into perilymphatic tissues.15 We have previously reported that adult-onset lymphedema of unknown cause can be divided into an older group with bilateral involvement and a younger group with unilateral involvement.16 Furthermore, we have identified significant differences in the age distribution, lower extremity lymphedema (LEL) index, and indocyanine green (ICG) lymphography pattern between these two groups of patients.16 We have also detected significant worsening of the LEL index score during the course of ICG lymphography in older patients with bilateral lymphedema.16 This finding suggests that lymphatic accumulation starts from the peripheral region.16 The aims of this study were to compare the detection rate and diameter of lymphatic vessels measured during LVA between a group of older patients with bilateral lymphedema and a group of younger patients with unilateral lymphedema and to investigate the effectiveness of LVA in these two groups of patients by comparing the improvement in lymphedema after the procedure.
METHODS A total of 74 patients (136 edematous lower limbs) who underwent LVA for lymphedema confirmed by ICG lymphography between May 2017 and December 2018 at Hiroshima University Hospital were enrolled in the study. The inclusion criteria were as follows: edema refractory to 6 months of supervised conventional compression therapy using a pressure garment; no history of cirrhosis of the liver, chronic venous obstruction and stenosis, deep venous thrombosis, heart failure, renal failure, hypoproteinemia, drug-induced edema, thyroid dermopathy, edema related to endocrine diseases, or a major invasion for pelvic malignant disease, including radiation therapy to the lower limbs and abdomen; no arterial or venous malformation; no family history of lymphedema; body mass index (BMI) <35 kg/m2; no history of edema earlier in life; edema limited in the lower limbs; and ambulatory without support. Duplex ultrasound was performed in all cases to rule out chronic venous reflux or obstruction. No patient had concomitant chronic venous disease or venous ulcers. The study protocol was approved by the Ethics Committee of Hiroshima University Hospital. All patients provided written informed consent. Preoperative investigations. ICG lymphography was conducted in all cases. ICG was injected subcutaneously into the lateral border of the Achilles tendon and the first web space of both feet. Lymphatic fluorescent images were then obtained by using an infrared camera system.
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ARTICLE HIGHLIGHTS d
d
d
Type of Research: Retrospective cohort study Key Findings: Sixty-two patients with bilateral idiopathic primary lymphedema and 12 patients with unilateral lymphedema underwent indocyanine green lymphangiography and microsurgical lymphaticovenular anastomosis (LVA). Those with bilateral lymphedema were significantly older than those with unilateral lymphedema (77.1 6 7.8 years vs 55.5 6 12.77 years; P < .01). Lymph vessel diameters were larger and clinical improvement was better at 6 months in older patients with bilateral lymphedema. Take Home Message: LVA is thought to be more effective in older patients with early-stage bilateral lower leg lymphedema than in their younger counterparts with late-stage unilateral lymphedema. Therefore, LVA should be performed in the early stages, even in older patients with bilateral lymphedema.
Immediately after injection, lymphatic function was examined by the time taken for fluorescent images to reach the groin. Patients were required to lie still while repeating dorsiflexion and plantar flexion of the ankles and toes during measurement of transit time. The purpose of these repeated movements was to minimize the transient flow delay that often occurs at the ankle joint and could lead to overestimation of the transit time. Transit time was defined as the time taken for the ICG to reach the groin.17 Lymphatic function was deemed to be impaired and to meet the criteria for a diagnosis of lymphedema or edema caused by lymphatic stasis if the transit time was >10 minutes despite acceleration of lymphatic flow by placing the patients in the supine position and instructing them to perform regular skeletal muscle movements as in the previous reports.16,18 ICG lymphography images were also recorded in the plateau phase at 6 to 24 hours after injection. All plateau images were reviewed by two surgeons working independently. The ICG image patterns were then classified according to the patient’s clinical and demographic characteristics and whether the lymphedema was bilateral or unilateral. LVA. LVA was performed precisely along a line traced by marking of the superficial lymphatic vessels if ICG lymphography indicated a linear pattern and along the course of the greater saphenous vein if ICG lymphography showed a dermal backflow pattern or no enhancement. All LVA procedures were performed under local anesthesia. Under a surgical microscopic view, several 1- to 5-cm skin incisions were made in the lower leg and thigh regions, and the subcutaneous
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veins and lymphatic vessels suitable for anastomosis were identified. The lymphatic vessels and veins were anastomosed in an end-to-end manner using 11-0 or 12-0 nylon microsutures. At our institution, LVAs are performed by two surgeons working simultaneously, with one surgeon assigned to perform the LVA procedure in the lower leg and the other to work in the thigh. The surgeon working in the thigh starts at the region above the knee; the surgeon working in the lower leg starts at the ankle area. On completing the LVAs above the knee or ankle, each surgeon moves proximally below the groin or knee. After completing the second round of LVAs, each surgeon starts a third round at the midpoint of the first and second sets of LVAs. Then, after completing the third round, each surgeon starts a fourth round at the midpoint of the first and third sets, proceeding to the midpoint of the second and third. The operating time is limited to 3 hours, and the number of LVAs that can be performed is determined by this time limit. The diameter of each lymphatic vessel identified during the procedure was measured using a Crownjun microscale (Kono Seisakusho Co, Ltd, Ichikawa, Japan). The mean vessel diameters in the lower leg and thigh regions were calculated. The detection rate of lymphatic vessels in each region was calculated by dividing the total number of skin incisions by the number of skin incisions where at least one lymphatic suitable for anastomosis was detected. We also recorded the number of LVAs performed in each region. Compression therapy was resumed 2 weeks after LVA in the same way as before surgery. Preoperative and postoperative evaluation. Limb circumference was measured before and after the LVA procedure. The circumference was measured at foot, ankle, 10 cm below the knee, knee, and 10 cm above the knee with the patient in the supine position before and 6 months after LVA. The LEL index was obtained by dividing the sum of the squares of the circumference in each of five areas of the affected lower extremity by the BMI, with a lower score indicating less severe edema.19 The improvement rate was calculated by normalizing differences in the LEL index between before and after LVA by the pre-LEL index for each case as follows: ([LEL index before LVA] e [LEL index after LVA])/(LEL index before LVA) 100. Tape measurements were obtained once by a physiotherapist or nurse not otherwise involved in the research and randomly assigned to patients to reduce the risk of measurement bias. The measurements were performed in the outpatient clinic in the morning without compression when the patient was awake. Statistical analysis. The data are shown as the mean and standard deviation (range). The patient’s age and the LEL index were compared according to whether
the lymphedema was unilateral or bilateral using the Student t-test. Between-group differences in age distribution were assessed according to whether the lymphedema was unilateral or bilateral using the KruskalWallis test. The patient’s age, LEL index score, lymphatic vessel diameter, number of LVAs performed, and improvement rate were compared between the groups according to type of lymphography pattern using the Tukey-Kramer test. The lymphatic detection rate was compared between the groups using the Steel-Dwass test. Statistical analyses were conducted by Statcel 4 software (OMS Publishing, Inc, Tokyo, Japan). A P value <.05 was considered statistically significant.
RESULTS All surgical procedures were conducted without complications, such as lymphorrhea or delayed wound healing. No patient developed cellulitis during the study period. Furthermore, no patient required treatment with an advanced pump system specifically designed for lymphedema. The mean age of the patients at the time of LVA was 73.6 6 11.8 (33-95) years (Table I); 48 (64.9%) of the 74 patients were women and 26 (35.1%) were men. Mean BMI was 26.0 6 4.7 kg/m2 (14.7-34.7 kg/m2). All patients had a diagnosis of lymphedema or edema caused by lymphatic stasis and none had a negative ICG study result. Lymphedema was bilateral in 62 patients (83.8%) and unilateral in 12 patients (16.2%). Mean age at onset was 67.5 6 15.3 (2593) years, and the duration of edema was 6.1 6 7.2 (1-40) years. According to the International Society of Lymphology scoring system,20 70 (51.5%) of the 136 legs were stage I lymphedema, 40 legs (29.4%) were stage II, and 26 (19.1%) were stage III. The LEL index was 249.1 6 47.4 (159380). Patients with bilateral involvement were significantly older than those with unilateral involvement (77.1 6 7.8 [55-95] years vs 55.5 6 12.8 [33-73] years; P < .01) and were significantly older at onset of lymphedema (72.6 6 9.4 [43-93] years vs 41.2 6 12.7 [25-72] years; P < .01; Table II). The LEL index in the bilateral group was significantly lower than that in the unilateral group (237.6 6 40.1 [159-368] vs 308.8 6 36.8 [260-380]; P < .01; Table II). There were significant differences in the distributions of the patients’ age at the time of LVA and age at onset according to whether the lymphedema was bilateral or unilateral (P < .01; Table III). ICG lymphography images were classified by eye as linear, low enhancement (LE), distal dermal backflow (dDB), or extended dermal backflow (eDB) using a method (Fig 1) according to the ICG lymphography pattern classification for iatrogenic secondary lymphedema21 that we have modified during our series of studies.16 The linear pattern was detected in 23 patients (46 legs), the LE in 12 patients (24 legs), the dDB in 20 patients (40 legs), and the eDB in 7 patients (14 legs). Twelve patients had unilateral involvement (Table IV); all showed the eDB pattern in
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Table I. Patients’ characteristics
demographics
Variable
and
clinical
the lower leg and thigh areas according to ICG lymphography pattern and laterality. Diameter of the lymphatic vessels in the thigh area according to ICG lymphography pattern and laterality was as follows: linear (0.6 6 0.2 mm) vs unilateral (0.4 6 0.1 mm), P < .01; LE (0.6 6 0.2 mm) vs unilateral, P < .05; and dDB (0.5 6 0.2 mm) vs unilateral, P < .05. Diameter of the lymphatic vessels in the lower leg area according to ICG lymphography pattern and laterality was as follows: linear (0.9 6 0.1 mm) vs dDB (0.7 6 0.2 mm), P < .01; linear vs eDB (0.7 6 0.2 mm), P < .01; linear vs unilateral (0.5 6 0.1 mm), P < .01; LE (0.9 6 0.2 mm) vs dDB, P < .01; LE vs eDB, P < .01; LE vs unilateral, P < .01; dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05 (Fig 4). Significant between-group differences were also seen in the lymphatic detection rate per number of skin incisions in the thigh and lower leg areas according to the ICG lymphography pattern and laterality. In the thigh area, the detection rate was as follows: linear (100%) vs eDB (69.2% 6 36.4%), P < .05; unilateral (51.3% 6 41.7%), P < .01; LE (100%) vs unilateral, P < .01; and dDB (94.1 6 29.5%) vs unilateral, P < .01. In the lower leg area, the detection rate was as follows: linear (100%) vs dDB (96.2 6 9.3%), P < .05; linear vs eDB (83.7% 6 23.5%), P < .01; linear vs unilateral (46.2% 6 33.9%), P < .01; LE (100%) vs eDB, P < .05; LE vs unilateral, P < .01; dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05 (Fig 5). There were no significant between-group differences in the number of LVAs performed in the lower leg and thigh areas according to ICG lymphography pattern or laterality except for the following: LE (3.8 6 1.5) vs unilateral (2.2 6 1.6), P < .05; dDB (3.7 6 1.7) vs unilateral, P < .05; linear (3.3 6 1.3); eDB (3.1 6 2.0) in the lower leg area; linear (1.1 6 1.1); LE (1.0 6 1.2); dDB (1.3 6 0.9); eDB (1.4 6 1.2); unilateral (1.4 6 1.5) in the thigh area (Fig 6). There were significant differences in the improvement rate in the LEL index between the groups according to the ICG lymphography pattern and laterality: linear (10.5% 6 2.4%) vs eDB (8.9% 6 1.5%), P < .05; linear vs unilateral (6.7% 6 0.6%), P < .01; LE (10.4% 6 1.5%) vs unilateral, P < .01; dDB (11.0% 6 1.3%) vs eDB, P < .01; dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05 (Fig 7).
74 patients (136 legs) 73.6 6 11.8 (33-95)
Age, years Sex Female
48 (64.9)
Male BMI, kg/m
26 (35.1) 2
26.0 6 4.7 (14.7-34.7)
Laterality of LEL Bilateral
62 (83.8)
Unilateral
12 (16.2)
Age at onset of LEL, years
67.5 6 15.3 (25-93)
Duration of edema, years
6.1 6 7.2 (1-40)
ISL stage I
70 (51.5)
II
40 (29.4)
III LEL index
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26 (19.1) 249.1 6 47.4 (159-380)
BMI, Body mass index; ISL, International Society of Lymphology; LEL, lower extremity lymphedema. Categorical variables are presented as number (%). Continuous variables are presented as mean 6 standard deviation (range).
both the lower leg and thigh regions. There were significant differences in age at the time of LVA and age at onset of lymphedema between the linear, LE, dDB, eDB, and unilateral lymphedema groups. Age at LVA according to ICG lymphography pattern was as follows: linear, 75.7 6 8.9 years; LE, 79.0 6 3.1 years; dDB, 76.9 6 8.7 years; eDB, 78.7 6 7.2 years; vs unilateral, 55.5 6 12.8 years (P < .01). Age at onset according to ICG lymphography pattern was as follows: linear, 72.8 6 9.6 years; LE, 74.5 6 4.7 years; dDB, 70.7 6 11.4 years; eDB, 74.0 6 9.6 years; vs unilateral, 41.2 6 12.7 years (P < .01; Fig 2; Table IV). Significant between-group differences were also seen in the LEL index: linear (216.6 6 26.6) vs dDB (244.1 6 28.1), P < .05; linear vs eDB (306.6 6 37.9), P < .01; linear vs unilateral (308.8 6 36.8), P < .01; LE (226.6 6 34.3) vs eDB, P < .01; LE vs unilateral, P < .01; dDB vs eDB, P < .01; and dDB vs unilateral, P < .01 (Fig 3; Table IV). There were also significant between-group differences in the diameter of the lymphatic vessels identified in
Table II. Patients’ demographics and clinical characteristics according to laterality of lymphedema Clinical lymphedema pattern Bilateral No. of patients (legs)
62 (124)
Unilateral
P value
12 (12)
Age at time of LVA, years
77.1 6 7.8 (55-95)
55.5 6 12.8 (33-73)
<.01
Age at onset of lymphedema, years
72.6 6 9.4 (43-93)
41.2 6 12.7 (25-72)
<.01
237.6 6 40.1 (159-368)
308.8 6 36.8 (260-380)
<.01
LEL index
LEL, Lower extremity lymphedema; LVA, lymphaticovenular anastomosis. Data are shown as the mean 6 standard deviation (range) or the number as appropriate.
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Table III. Distribution of patients’ age at the time of lymphaticovenular anastomosis (LVA) and onset of lymphedema according to laterality of lymphedema Age at onset of LEL, years <50
50-59
60-69
70-79
>80
P value <.01
Laterality of edema Bilateral
2
5
10
30
15
Unilateral
11
0
0
1
0
Age at the time of LVA, years <50
50-59
60-69
70-79
>80
P value
Bilateral
0
4
4
31
23
<.01
Unilateral
5
2
2
3
0
Laterality of edema
LEL, Lower extremity lymphedema. There was a significant difference in distribution of the patients’ age at onset according to laterality (P < .01, Kruskal-Wallis test). There was a significant difference in distribution of age at the time of LVA according to laterality (P < .01, Kruskal-Wallis test).
DISCUSSION Lymphedema is often referred to as primary if there is no obvious cause. However, primary lymphedema has variable features and may have a number of causes. In our study, primary lymphedema that developed after the age of 30 years could be bilateral or unilateral. According to the conventional classification, which relies on age at onset, both our study groups would be classified as lymphedema tarda. However, the two groups differed significantly in their age distribution, LEL index, and ICG lymphography patterns. Therefore, it is reasonable to regard these two groups as having different types of lymphedema and thus having different causes of lymphatic impairment. We can infer that age-related deterioration of lymphatic pump function was the most likely cause of lymphedema in the bilateral group. Although we found that the lymphedema was generally less severe in the older group with bilateral involvement than in the younger group with unilateral involvement, it could be as severe in that the LEL index worsened significantly in these patients as the ICG lymphography pattern progressed from linear to LE, dDB, and eDB. This finding suggests that lymph starts to accumulate distally to proximally in the older group with bilateral involvement. In secondary lymphedema with an iatrogenic etiology, lymphatic function is initially retained; thereafter, accumulation of lymph starts at the proximal region close to the obstructed area21 and eventually extends to the distal region, with progressive deterioration of lymphatic function. However, in older patients with bilateral lymphedema, we suggest that age-related deterioration of lymphatic function occurs in the entire area and that accumulation of lymph starts in the distal region. The mechanism for this deterioration is not understood but is likely to involve an effect of gravity.
It is difficult to determine whether lymphedema in younger patients with bilateral involvement is congenital22-24 or acquired.25 Late-onset primary lymphedema has been reported to be unilateral rather than bilateral,26,27 which is consistent with the findings in younger patients with unilateral lymphedema in our study. It is possible that unilateral lymphedema can occur at a younger age in individuals with congenitally weakened lymphatics, such that minor events, like trauma or an inflammatory reaction too subtle to be recognized as a cause of secondary lymphedema, can result in lymphedema. These deficits in lymphatic function are likely to be secondary to developmental errors; however, in our study, unilateral lymphedema with a younger age at onset might have been an acquired defect. Alternatively, a defect may be present from birth but the lymphatic system is able to compensate until there is an insult resulting in overload of lymphatic transport capacity.22,28,29 This may explain why the younger group with unilateral involvement in our study had a combination of secondary and congenital characteristics (ie, unilateral and relatively severe lymphedema). We believe that unilateral lymphedema can become bilateral26,30 and vice versa. Furthermore, there is the possibility of overlapping of features of more than one type of lymphedema. Therefore, we attribute the bilateral lymphedema seen in our study population to agerelated deterioration in lymphatic function. LVAs were performed in 74 patients (136 edematous lower limbs) thought to have developed primary lymphedema after the age of 25 years in the study. The purpose of this study was to compare the characteristics of the lymphatics detected during LVA in an older group of patients with bilateral lymphedema with those in a younger group of patients with unilateral lymphedema. We also compared the difference in
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Fig 1. Classification of indocyanine green (ICG) lymphography patterns. In the linear pattern, the superficial lymphatic vessels were arranged in a linear manner from the injection site to the superficial inguinal lymph nodes. The low enhancement (LE) pattern was observed only in the distal portion of the lower extremity, with no enhancement in the proximal part and no dermal backflow pattern observed. The distal dermal backflow (dDB) pattern was limited to the distal part of the lower extremity but not over the knee. The extended dermal backflow (eDB) pattern extended from the distal region of the lower extremity over the knee to the groin. All cases in the unilateral group showed the dermal backflow pattern in both the thigh and lower leg regions.
improvement in lymphedema after LVA between these two groups of patients. This study had three main findings. First, the lymphatic diameter tended to be larger in the older group with bilateral lymphedema and had a marked tendency to be smaller in the pattern order of linear, LE, dDB, eDB, and unilateral. Second, the lymphatic detection rate per number of skin incisions tended to be lowest in both the lower leg and thigh areas in unilateral involvement; furthermore, eDB pattern tended to be less common in this group than in the older group with bilateral lymphedema in both the
lower leg and thigh areas. In particular, lymphatic detection rate was markedly lower in the order of linear to LE, dDB, eDB, and unilateral in the lower leg area. Third, the extent of improvement in the LEL index tended to decrease in the order of dDB, linear, LE, eDB, and unilateral; however, the number of LVAs performed in the thigh and lower leg regions tended to be consistent. Studies in animals have demonstrated age-related decreases in systolic lymphatic flow velocity, pumping activity,12 contraction frequency,14 lymphatic vessel density, and lymphatic network complexity in collecting
Table IV. Indocyanine green (ICG) lymphography pattern according to patients’ age and lower extremity lymphedema (LEL) index ICG lymphography pattern Linear (TTG >10 min) No. of legs (patients)
LE
dDB
eDB
Unilateral
46 (23)
24 (12)
40 (20)
14 (7)
12 (12)
Age at the time of LVA, years
75.7 6 8.9
79.0 6 3.1
76.9 6 8.7
78.7 6 7.2
55.5 6 12.8
Age at onset of LEL, years
72.8 6 9.6
74.5 6 4.7
70.7 6 11.4
74.0 6 9.6
41.2 6 12.7
216.6 6 26.6
226.6 6 34.3
244.1 6 28.1
306.6 6 37.9
LEL index
308.8 6 36.8
dDB, Distal dermal backflow; eDB, extended dermal backflow; LE, low enhancement; LVA, lymphaticovenular anastomosis; TTG, time taken to reach the groin. Data are shown as the mean 6 standard deviation (range) or the number as appropriate.
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Fig 2. Between-group comparison of patients’ age at time of lymphaticovenular anastomosis (LVA) and age at onset of lymphedema according to indocyanine green (ICG) lymphography pattern. Age at time of LVA: linear, 75.7 6 8.9 years; low enhancement (LE), 79.0 6 3.1 years; distal dermal backflow (dDB), 76.9 6 8.7 years; extended dermal backflow (eDB), 78.7 6 7.2 years; unilateral, 55.5 6 12.8 years. Age at onset of lower extremity lymphedema: linear, 72.8 6 9.6 years; LE, 74.5 6 4.7 years; dDB, 70.7 6 11.4 years; eDB, 74.0 6 9.6 years; unilateral, 41.2 6 12.7 years. *P < .01, Tukey-Kramer test.
Fig 3. Between-group comparison of the lower extremity lymphedema (LEL) index score according to indocyanine green (ICG) lymphography pattern: linear, 216.6 6 26.6; low enhancement (LE), 226.6 6 34.3; distal dermal backflow (dDB), 244.1 6 28.1; extended dermal backflow (eDB), 306.6 6 37.9; unilateral, 308.8 6 36.8. *P < .05, **P < .01, Tukey-Kramer test.
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Fig 4. Between-group comparison of diameter of the lymphatic vessels identified in the thigh and lower leg areas according to indocyanine green (ICG) lymphography pattern. Thigh area: linear, 0.6 6 0.2 mm; low enhancement (LE), 0.6 6 0.2 mm; distal dermal backflow (dDB), 0.5 6 0.2 mm; extended dermal backflow (eDB), 0.5 6 0.1 mm; unilateral, 0.4 6 0.1 mm. Lower leg area: linear, 0.9 6 0.1 mm; LE, 0.9 6 0.2 mm; dDB, 0.7 6 0.2 mm; eDB, 0.7 6 0.2 mm; unilateral, 0.5 6 0.1 mm. *P < .05, **P < .01, Tukey-Kramer test.
lymphatic vessels.31 Furthermore, clinical studies using lymphoscintigraphy8 and ICG lymphography13 have shown a reduction in lymph drainage with increasing age. Aging is thought to involve a chronic inflammatory
process with a shift toward a proinflammatory cytokine profile in tissues, which may account for the numerous deleterious vascular changes associated with aging.32-34 This heightened preactivation state as well as an
Fig 5. Between-group comparison of lymphatic detection rate per number of skin incisions in the thigh and lower leg region according to indocyanine green (ICG) lymphography pattern. Thigh area: linear, 100%; low enhancement (LE), 100%; distal dermal backflow (dDB), 94.1% 6 29.5%; extended dermal backflow (eDB), 69.2% 6 36.4%; unilateral, 51.3% 6 41.7%. Lower leg area: linear, 100%; LE, 100%; dDB, 96.2% 6 9.3%; eDB, 83.7% 6 23.5%; unilateral, 46.2% 6 33.9%. *P < .05, **P < .01, Steel-Dwass test.
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Fig 6. Between-group comparison of number of lymphaticovenular anastomoses (LVAs) performed in the thigh and lower leg region according to indocyanine green (ICG) lymphography pattern. Thigh area: linear, 1.1 6 1.1; low enhancement (LE), 1.0 6 1.2; distal dermal backflow (dDB), 1.3 6 0.9; extended dermal backflow (eDB), 1.4 6 1.2; unilateral, 1.4 6 1.5. Lower leg area: linear, 3.3 6 1.3; LE, 3.8 6 1.5; dDB, 3.7 6 1.7; eDB, 3.1 6 2.0; unilateral, 2.2 6 1.6. *P < .05, Tukey-Kramer test.
increased number of activated mast cells would cause release of preformed inflammatory mediators, such as proteases, histamine, and cytokines like tumor necrosis factor a. The chronic inflammatory environment associated with aging may be an important cause of the changes in lymphatic pump function seen in older animals.14
Another animal study showed that the diameters of lymphatic vessels in the same anatomic location are significantly larger in aged animals than in younger adult animals.35 In that study, the end-systolic and enddiastolic diameters of the mesenteric lymphatic vessels in 24-month-old murine leukemia virus-infected rats were 79% and 71% greater, respectively, than those in
Fig 7. Between-group comparison of improvement rate for the lower extremity lymphedema (LEL) index according to indocyanine green (ICG) lymphography pattern: linear, 10.5% 6 2.4%; low enhancement (LE), 10.4% 6 1.5%; distal dermal backflow (dDB), 11.0% 6 1.3%; extended dermal backflow (eDB), 8.9% 6 1.5%; unilateral, 6.7% 6 0.6%. *P < .05, **P < .01, Tukey-Kramer test.
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their adult counterparts. It can be assumed that the same pathophysiologic deterioration occurs in human patients. Our empirical data show that the mean diameter of lymphatics in the lower extremities is around 0.5 mm in Japanese individuals.36 However, the consensus is that this diameter may be larger in Japanese patients with lymphedema.37 Furthermore, clinical studies have shown that advanced lymphedema results in fibrosis of the collecting lymphatics, which causes failure of the pump mechanism and luminal obliteration.38,39 Progression of lymphedema in the limbs is accompanied initially by smoothing of the endothelial cells in the collecting lymphatic vessels, then by disassembly of focal adhesions (desmosomes), growth and transformation of smooth muscle cells, thickening of the basal membrane, and finally proliferation of collagen fibers. In the early stages of lymphedema, the lymphatic vessels become ectatic in response to an increase in endolymphatic pressure.38 As the lymphedema progresses, lymphatic smooth muscle cells are transformed into cells involved in the synthesis of collagen, thereby promoting growth of collagen fibers and leading to irreversible contraction of the lymphatics. In the advanced stage of lymphedema, most components of the lymphatics undergo fibrosis, such that these vessels lose their transport and concentrating abilities and the lumens become either narrowed or completely obstructed. Failure of lymphatic flow also occurs in immune disorders that involve chronic inflammation and fibrosis.40,41 These pathophysiologic and immunologic changes appeared to occur in our older patients with bilateral lymphedema. The lymphatics in these patients were initially dilated when the linear or LE pattern was present; however, as the lymphedema progressed (with worsening of the LEL index), lymphatic diameter decreased in the order of dDB to eDB until the end stage of lymphedema, as in the unilateral pattern in younger patients. This phenomenon is particularly marked in the lower leg region in older patients with bilateral lymphedema. The detection rate in our study was almost the same as the findings for lymphatic diameter. As lymphedema worsens, the lymphatics become more difficult to recognize because they become increasingly mixed in with the fibrous tissue until they are eventually no longer visible. In this study, unlike the findings for detection rate and vessel diameter, there was little difference in the number of LVAs performed between the LE, dDB, and unilateral groups, except in the lower leg area. A potential explanation for this finding is that we always try to perform as many LVAs as possible in the belief that there is a positive correlation between therapeutic efficacy and the number of LVAs.42 Therefore, the number of LVAs performed tended to be consistent despite the marked between-group differences in detection rate and vessel diameter. Nevertheless, there were marked differences
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among the LE, dDB, and unilateral groups, which we believe to indicate that the lymphedema starts to deteriorate from distal to proximal. However, unlike in the LE and dDB groups, no marked difference was seen in the number of LVAs performed in the lower leg region between the linear and unilateral groups, probably because we judged the linear pattern to indicate mild lymphedema and performed fewer LVAs in this group of patients. Although there were no marked between-group differences in the number of LVAs performed, the rate of improvement in the LEL index tended to be smaller in the groups with more severe lymphedema. On the other hand, the improvement in the linear, LE, and dDB groups was relatively greater and not markedly different between the three groups. We assume that the lymphatic vessels in these three groups were still in sufficiently good condition for LVA to be performed. Our findings suggest that the unfavorable outcomes of LVA in the eDB and unilateral groups were attributable to smaller lymphatic diameter and low detection rate and that the lymphatic vessels in older patients with late-stage bilateral lymphedema and in younger patients with unilateral lymphedema are less amenable to improvement. Therefore, LVA would be indicated in patients with the linear, LE, and dDB pattern but not in those with the eDB pattern or unilateral involvement. As in patients with secondary lymphedema, LVA should be performed in the early stages, even in older patients with bilateral lymphedema.43-45 We used end-to-end anastomosis in all patients in this study. Although it has been suggested that there is no significant difference in the success rate between endto-end and end-to-side anastomosis, the end-to-side method has been found to have a lower success rate.46,47 Moreover, our experience is that the end-toside technique is more difficult to perform. The main limitations of this study are that it did not include a pathologic analysis and the number of patients included was small. Further pathologic investigation in a greater number of patients will be necessary in the future.
CONCLUSIONS We have investigated the features of the lymphatics in patients with lower limb lymphedema that developed in adulthood without any obvious cause by evaluating the findings when performing LVAs. The lymphatic vessel diameter tended to be greater in older patients with bilateral lymphedema than in younger patients with unilateral lymphedema. The rates of detection and improvement tended to decrease with worsening of the ICG lymphography pattern. LVA is thought to be more effective in older patients with early-stage bilateral lower leg lymphedema than in their younger counterparts with late-stage unilateral lymphedema.
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AUTHOR CONTRIBUTIONS Conception and design: ShuhY, IK, ShujY, KT Analysis and interpretation: ShuhY, IK, MH, ShujY, KT Data collection: ShuhY, IK, HI, TU, AS, YF, SN, KY Writing the article: ShuhY Critical revision of the article: ShuhY, IK, HI, TU, AS, YF, SN, KY, MH, ShujY, KT Final approval of the article: ShuhY, IK, HI, TU, AS, YF, SN, KY, MH, ShujY, KT Statistical analysis: ShuhY, IK, HI, TU, AS, YF, SN, KY, MH, ShujY, KT Obtained funding: Not applicable Overall responsibility: ShuhY
REFERENCES 1. Koshima I, Kawada S, Moriguchi T, Kajiwara Y. Ultrastructural observations of lymphatic vessels in lymphedema in human extremities. Plast Reconstr Surg 1996;97:397-405; discussion: 406-7. 2. Yamamoto T, Yoshimatsu H, Narushima M, Yamamoto N, Shim TW, Seki Y, et al. Sequential anastomosis for lymphatic supermicrosurgery: multiple lymphaticovenular anastomoses on 1 venule. Ann Plast Surg 2014;73:46-9. 3. Yamamoto T, Narushima M, Yoshimatsu H, Seki Y, Yamamoto N, Oka A, et al. Minimally invasive lymphatic supermicrosurgery (MILS): indocyanine green lymphography-guided simultaneous multisite lymphaticovenular anastomoses via millimeter skin incisions. Ann Plast Surg 2014;72:67-70. 4. Masià J, Pons G, Rodríguez-Bauzà E. Barcelona lymphedema algorithm for surgical treatment in breast cancerrelated lymphedema. J Reconstr Microsurg 2016;32:329-35. 5. Yamamoto T, Yoshimatsu H, Yamamoto N. Complete lymph flow reconstruction: a free vascularized lymph node true perforator flap transfer with efferent lymphaticolymphatic anastomosis. J Plast Reconstr Aesthet Surg 2016;69:1227-33. 6. Brorson H. Liposuction normalizes lymphedema induced adipose tissue hypertrophy in elephantiasis of the leg: a prospective study with a ten-year follow-up. Plast Reconstr Surg 2015;136(Suppl):133-4. 7. Paskett ED, Dean JA, Oliveri JM, Harrop JP. Cancer-related lymphedema risk factors, diagnosis, treatment, and impact: a review. J Clin Oncol 2012;30:3726-33. 8. Bull RH, Gane JN, Evans JE, Joseph AE, Mortimer PS. Abnormal lymph drainage in patients with chronic venous leg ulcers. J Am Acad Dermatol 1993;28:585-90. 9. Chakraborty S, Gurusamy M, Zawieja DC, Muthuchamy M. Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis. Microcirculation 2013;20:349-64. 10. Stöberl C, Partsch H. Erysipelas and lymphedemadegg or hen? Z Hautkr 1987;62:56-62. 11. Rockson SG. The lymphatic biology of aging. Lymphat Res Biol 2012;10:45. 12. Zolla V, Nizamutdinova IT, Scharf B, Clement CC, Maejima D, Akl T, et al. Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance. Aging Cell 2015;14:582-94. 13. Unno N, Tanaka H, Suzuki M, Yamamoto N, Mano Y, Sano M, et al. Influence of age and gender on human lymphatic pumping pressure in the leg. Lymphology 2011;44:113-20.
14. Gashev AA, Chatterjee V. Aged lymphatic contractility: recent answers and new questions. Lymphat Res Biol 2013;11:2-13. 15. Pal S, Meininger CJ, Gashev AA. Aged lymphatic vessels and mast cells in perilymphatic tissues. Int J Mol Sci 2017;18:E965. 16. Yoshida S, Koshima I, Imai H, Sasaki A, Fujioka Y, Nagamatsu S, et al. Indocyanine green lymphography findings in older patients with lower limb lymphedema. J Vasc Surg Venous Lymphat Disord 2019 Jun 20. [Epub ahead of print]. 17. Unno N, Nishiyama M, Suzuki M, Yamamoto N, Inuzuka K, Sagara D, et al. Quantitative lymph imaging for assessment of lymph function using indocyanine green fluorescence lymphography. Eur J Vasc Endovasc Surg 2008;36:230-6. 18. Unno N, Nishiyama M, Suzuki M, Tanaka H, Yamamoto N, Sagara D, et al. A novel method of measuring human lymphatic pumping using indocyanine green fluorescence lymphography. J Vasc Surg 2010;52:946-52. 19. Yamamoto T, Matsuda N, Todokoro T, Yoshimatsu H, Narushima M, Mihara M, et al. Lower extremity lymphedema (LEL) index: a simple method for severity evaluation of lower extremity lymphedema. Ann Plast Surg 2011;67:637-40. 20. Executive Committee. The diagnosis and treatment of peripheral lymphedema: 2016 Consensus Document of the International Society of Lymphology. Lymphology 2016;49:170-84. 21. Yamamoto T, Narushima M, Doi K, Oshima A, Ogata F, Mihara M, et al. Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns. Plast Reconstr Surg 2011;127:1979-86. 22. Tiwari A, Cheng K, Button M, Myint F, Hamilton G. Differential diagnosis, investigation, and current treatment of lower limb lymphedema. Arch Surg 2003;138:152-61. 23. Wolfe JH, Kinmonth JB. The prognosis of primary lymphedema of the lower limbs. Arch Surg 1981;116:1157-60. 24. Kinmonth JB, Taylor GW, Tracy GD, Marsh JD. Primary lymphoedema; clinical and lymphangiographic studies of a series of 107 patients in which the lower limbs were affected. Br J Surg 1957;45:1-9. 25. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 2013;84:303-14. 26. Schook CC, Mulliken JB, Fishman SJ, Grant FD, Zurakowski D, Greene AK. Primary lymphedema: clinical features and management in 138 pediatric patients. Plast Reconstr Surg 2011;127:2419-31. 27. Yamamoto T, Yoshimatsu H, Narushima M, Yamamoto N, Hayashi A, Koshima I. Indocyanine green lymphography findings in primary leg lymphedema. Eur J Vasc Endovasc Surg 2015;49:95-102. 28. Ely JW, Osheroff JA, Chambliss ML, Ebell MH. Approach to leg edema of unclear etiology. J Am Board Fam Med 2006;19:148-60. 29. Roy H, Bhardwaj S, Ylä-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett 2006;580:2879-87. 30. Burnand KM, Glass DM, Mortimer PS, Peters AM. Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling. Clin Nucl Med 2012;37:9-13. 31. Karaman S, Buschle D, Luciani P, Leroux JC, Detmar M, Proulx ST. Decline of lymphatic vessel density and function in murine skin during aging. Angiogenesis 2015;18:489-98.
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32. Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol 2001;8: 131-6. 33. Bruunsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 2003;23:15-39. 34. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G. Aginginduced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J 2003;17:1183-5. 35. Benoit JN. Relationships between lymphatic pump flow and total lymph flow in the small intestine. Am J Physiol 1991;261: H1970-8. 36. Yoshida S, Koshima I, Imai H, Eldahshoury TE, Sasaki A, Fujioka Y, et al. Line production system for multiple lymphaticovenular anastomoses. J Plast Reconstr Aesthet Surg 2019;72:1334-9. 37. Yamamoto T, Narushima M, Koshima I. Lymphatic vessel diameter in female pelvic cancer-related lower extremity lymphedematous limbs. J Surg Oncol 2018;117:1157-63. 38. Mihara M, Hara H, Hayashi Y, Narushima M, Yamamoto T, Todokoro T, et al. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLoS One 2012;7:e41126. 39. Modi S, Stanton AW, Svensson WE, Peters AM, Mortimer PS, Levick JR. Human lymphatic pumping measured in healthy and lymphoedematous arms by lymphatic congestion lymphoscintigraphy. J Physiol 2007;583:271-85. 40. Yoshida S, Koshima I, Hamada Y, Sasaki A, Fujioka Y, Nagamatsu S, et al. Lymphovenous anastomosis aids wound healing in lymphedema: relationship between lymphedema and delayed wound healing from a view of immune mechanisms. Adv Wound Care 2019;8:263-9.
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41. Kataru RP, Baik JE, Park HJ, Wiser I, Rehal S, Shin JY, et al. Regulation of immune function by the lymphatic system in lymphedema. Front Immunol 2019;10:470. 42. Mihara M, Hara H, Tange S, Zhou HP, Kawahara M, Shimizu Y, et al. Multisite lymphaticovenular bypass using supermicrosurgery technique for lymphedema management in lower lymphedema cases. Plast Reconstr Surg 2016;138:262-72. 43. Chang DW, Suami H, Skoracki R. A prospective analysis of 100 consecutive lymphovenous bypass cases for treatment of extremity lymphedema. Plast Reconstr Surg 2013;132:1305-14. 44. Seki Y, Kajikawa A, Yamamoto T, Takeuchi T, Terashima T, Kurogi N. Single lymphaticovenular anastomosis for earlystage lower extremity lymphedema treated by the superior-edge-of-the-knee incision method. Plast Reconstr Surg Glob Open 2018;6:e1679. 45. Mihara M, Hara H, Kikuchi K, Yamamoto T, Iida T, Narushima M, et al. Scarless lymphatic venous anastomosis for latent and early-stage lymphoedema using indocyanine green lymphography and non-invasive instruments for visualising subcutaneous vein. J Plast Reconstr Aesthet Surg 2012;65:1551-8. 46. Heidekrueger PI, Ninkovic M, Heine-Geldern A, Herter F, Broer PN. End-to-end versus end-to-side anastomoses in free flap reconstruction: single centre experiences. J Plast Surg Hand Surg 2017;51:362-5. 47. Ueda K, Harii K, Nakatsuka T, Asato H, Yamada A. Microsurgery. Comparison of end-to-end and end-to-side venous anastomosis in free-tissue transfer following resection of head and neck tumors. Microsurgery 1996;17:146-9.
Submitted Jul 11, 2019; accepted Oct 10, 2019.
ABSTRACT Objective: We have previously reported that patients with idiopathic primary lymphedema of adult onset can be classified into an older group with bilateral involvement and a younger group with unilateral involvement and that there are significant differences in the characteristics of these groups. The aims of this study were to investigate the features of these two groups further by evaluating the lymphatics while performing lymphaticovenular anastomosis (LVA) and to compare the effectiveness of LVA between the two groups. Methods: This study enrolled 74 patients (136 edematous legs) in whom indocyanine green (ICG) lymphography and LVA were performed. The rate of detection and the diameter of the lymphatic vessels were recorded. The lower extremity lymphedema index (the total sum of the squares of the circumference for five areas in each leg divided by the body mass index) was obtained before and 6 months after LVA. The rate of improvement in the affected lower limbs after LVA was also calculated. Results: The clinical lymphedema pattern was determined to be bilateral in 62 patients and unilateral in 12. Patients with bilateral lymphedema were significantly older than those with unilateral lymphedema (77.1 6 7.8 years vs 55.5 6 12.77 years; P < .01). A linear pattern was seen in 23 patients (46 legs), a low enhancement (LE) pattern in 12 patients (24 legs), a distal dermal backflow (dDB) pattern in 20 patients (40 legs), and an extended dermal backflow (eDB) pattern in 7 patients (14 legs). The lymphedema was unilateral in 12 patients (12 legs). There were significant between-group differences in lymphatic diameter in relation to lower leg area: linear (0.9 6 0.1 mm) vs dDB (0.7 6 0.2 mm), linear vs eDB (0.7 6 0.2 mm), linear vs unilateral (0.5 6 0.1 mm), LE (0.9 6 0.2 mm) vs dDB, LE vs eDB, LE vs unilateral, and dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05. There were also significant between-group differences in the rate of improvement in the lower extremity lymphedema index according to the ICG lymphography pattern and laterality: linear (10.5% 6 2.4%) vs unilateral (6.7% 6 0.6%), LE (10.4% 6 1.5%) vs unilateral, dDB (11.0% 6 1.3%) vs eDB (8.9% 6 1.5%), and dDB vs unilateral, P < .01; linear vs eDB, P < .05; and eDB vs unilateral, P < .05. Conclusions: The lymphatic vessel diameter tended to be greater in older patients with bilateral lymphedema than in younger patients with unilateral lymphedema. The rate of detection and improvement tended to decrease with worsening of the ICG lymphography pattern. LVA is thought to be more effective in older patients with early-stage bilateral lower leg lymphedema than in their younger counterparts with late-stage unilateral lymphedema. (J Vasc Surg: Venous and Lym Dis 2019;-:1-12.) Keywords: Lymphedema; Aging; Lymphaticovenular anastomosis
Several lymphatic reconstruction procedures have been used for treatment of lymphedema.1-6 One of these procedures is lymphaticovenular anastomosis (LVA), which is becoming increasingly popular in the field of microsurgery.1-3
Lymphedema may be primary (of genetic origin) or secondary (a result of trauma, iatrogenic insult, or parasitic infection).7-10 Primary lymphedema can be divided into lymphedema congenita, praecox, and tarda. With the exception of lymphedema tarda, primary lymphedema
From the International Center for Lymphedema,a and Department of Plastic
The editors and reviewers of this article have no relevant financial relationships to
and Reconstructive Surgery,b Hiroshima University, Hiroshima; the Depart-
disclose per the Journal policy that requires reviewers to decline review of any
ment of Plastic and Reconstructive Surgery, Tokyo University, Tokyoc; and the Department of Plastic and Reconstructive Surgery, Jichi Medical University, Tochigi.d Author conflict of interest: none.
manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvsv.2019.10.013
Correspondence: Shuhei Yoshida, MD, PhD, International Center for Lymphedema, Hiroshima University Hospital, 1-2-3, Kasumi, Minami, Hiroshima 7348551, Japan (e-mail: [email protected]).
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is characterized by age-related lymphatic impairment that is thought to develop because of a decline in lymphatic pump function in response to oxidative stress.8,11-14 Aging-induced oxidative stress in the lymphatic vessels facilitates the spread of pathogens from these vessels into perilymphatic tissues.15 We have previously reported that adult-onset lymphedema of unknown cause can be divided into an older group with bilateral involvement and a younger group with unilateral involvement.16 Furthermore, we have identified significant differences in the age distribution, lower extremity lymphedema (LEL) index, and indocyanine green (ICG) lymphography pattern between these two groups of patients.16 We have also detected significant worsening of the LEL index score during the course of ICG lymphography in older patients with bilateral lymphedema.16 This finding suggests that lymphatic accumulation starts from the peripheral region.16 The aims of this study were to compare the detection rate and diameter of lymphatic vessels measured during LVA between a group of older patients with bilateral lymphedema and a group of younger patients with unilateral lymphedema and to investigate the effectiveness of LVA in these two groups of patients by comparing the improvement in lymphedema after the procedure.
METHODS A total of 74 patients (136 edematous lower limbs) who underwent LVA for lymphedema confirmed by ICG lymphography between May 2017 and December 2018 at Hiroshima University Hospital were enrolled in the study. The inclusion criteria were as follows: edema refractory to 6 months of supervised conventional compression therapy using a pressure garment; no history of cirrhosis of the liver, chronic venous obstruction and stenosis, deep venous thrombosis, heart failure, renal failure, hypoproteinemia, drug-induced edema, thyroid dermopathy, edema related to endocrine diseases, or a major invasion for pelvic malignant disease, including radiation therapy to the lower limbs and abdomen; no arterial or venous malformation; no family history of lymphedema; body mass index (BMI) <35 kg/m2; no history of edema earlier in life; edema limited in the lower limbs; and ambulatory without support. Duplex ultrasound was performed in all cases to rule out chronic venous reflux or obstruction. No patient had concomitant chronic venous disease or venous ulcers. The study protocol was approved by the Ethics Committee of Hiroshima University Hospital. All patients provided written informed consent. Preoperative investigations. ICG lymphography was conducted in all cases. ICG was injected subcutaneously into the lateral border of the Achilles tendon and the first web space of both feet. Lymphatic fluorescent images were then obtained by using an infrared camera system.
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ARTICLE HIGHLIGHTS d
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Type of Research: Retrospective cohort study Key Findings: Sixty-two patients with bilateral idiopathic primary lymphedema and 12 patients with unilateral lymphedema underwent indocyanine green lymphangiography and microsurgical lymphaticovenular anastomosis (LVA). Those with bilateral lymphedema were significantly older than those with unilateral lymphedema (77.1 6 7.8 years vs 55.5 6 12.77 years; P < .01). Lymph vessel diameters were larger and clinical improvement was better at 6 months in older patients with bilateral lymphedema. Take Home Message: LVA is thought to be more effective in older patients with early-stage bilateral lower leg lymphedema than in their younger counterparts with late-stage unilateral lymphedema. Therefore, LVA should be performed in the early stages, even in older patients with bilateral lymphedema.
Immediately after injection, lymphatic function was examined by the time taken for fluorescent images to reach the groin. Patients were required to lie still while repeating dorsiflexion and plantar flexion of the ankles and toes during measurement of transit time. The purpose of these repeated movements was to minimize the transient flow delay that often occurs at the ankle joint and could lead to overestimation of the transit time. Transit time was defined as the time taken for the ICG to reach the groin.17 Lymphatic function was deemed to be impaired and to meet the criteria for a diagnosis of lymphedema or edema caused by lymphatic stasis if the transit time was >10 minutes despite acceleration of lymphatic flow by placing the patients in the supine position and instructing them to perform regular skeletal muscle movements as in the previous reports.16,18 ICG lymphography images were also recorded in the plateau phase at 6 to 24 hours after injection. All plateau images were reviewed by two surgeons working independently. The ICG image patterns were then classified according to the patient’s clinical and demographic characteristics and whether the lymphedema was bilateral or unilateral. LVA. LVA was performed precisely along a line traced by marking of the superficial lymphatic vessels if ICG lymphography indicated a linear pattern and along the course of the greater saphenous vein if ICG lymphography showed a dermal backflow pattern or no enhancement. All LVA procedures were performed under local anesthesia. Under a surgical microscopic view, several 1- to 5-cm skin incisions were made in the lower leg and thigh regions, and the subcutaneous
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veins and lymphatic vessels suitable for anastomosis were identified. The lymphatic vessels and veins were anastomosed in an end-to-end manner using 11-0 or 12-0 nylon microsutures. At our institution, LVAs are performed by two surgeons working simultaneously, with one surgeon assigned to perform the LVA procedure in the lower leg and the other to work in the thigh. The surgeon working in the thigh starts at the region above the knee; the surgeon working in the lower leg starts at the ankle area. On completing the LVAs above the knee or ankle, each surgeon moves proximally below the groin or knee. After completing the second round of LVAs, each surgeon starts a third round at the midpoint of the first and second sets of LVAs. Then, after completing the third round, each surgeon starts a fourth round at the midpoint of the first and third sets, proceeding to the midpoint of the second and third. The operating time is limited to 3 hours, and the number of LVAs that can be performed is determined by this time limit. The diameter of each lymphatic vessel identified during the procedure was measured using a Crownjun microscale (Kono Seisakusho Co, Ltd, Ichikawa, Japan). The mean vessel diameters in the lower leg and thigh regions were calculated. The detection rate of lymphatic vessels in each region was calculated by dividing the total number of skin incisions by the number of skin incisions where at least one lymphatic suitable for anastomosis was detected. We also recorded the number of LVAs performed in each region. Compression therapy was resumed 2 weeks after LVA in the same way as before surgery. Preoperative and postoperative evaluation. Limb circumference was measured before and after the LVA procedure. The circumference was measured at foot, ankle, 10 cm below the knee, knee, and 10 cm above the knee with the patient in the supine position before and 6 months after LVA. The LEL index was obtained by dividing the sum of the squares of the circumference in each of five areas of the affected lower extremity by the BMI, with a lower score indicating less severe edema.19 The improvement rate was calculated by normalizing differences in the LEL index between before and after LVA by the pre-LEL index for each case as follows: ([LEL index before LVA] e [LEL index after LVA])/(LEL index before LVA) 100. Tape measurements were obtained once by a physiotherapist or nurse not otherwise involved in the research and randomly assigned to patients to reduce the risk of measurement bias. The measurements were performed in the outpatient clinic in the morning without compression when the patient was awake. Statistical analysis. The data are shown as the mean and standard deviation (range). The patient’s age and the LEL index were compared according to whether
the lymphedema was unilateral or bilateral using the Student t-test. Between-group differences in age distribution were assessed according to whether the lymphedema was unilateral or bilateral using the KruskalWallis test. The patient’s age, LEL index score, lymphatic vessel diameter, number of LVAs performed, and improvement rate were compared between the groups according to type of lymphography pattern using the Tukey-Kramer test. The lymphatic detection rate was compared between the groups using the Steel-Dwass test. Statistical analyses were conducted by Statcel 4 software (OMS Publishing, Inc, Tokyo, Japan). A P value <.05 was considered statistically significant.
RESULTS All surgical procedures were conducted without complications, such as lymphorrhea or delayed wound healing. No patient developed cellulitis during the study period. Furthermore, no patient required treatment with an advanced pump system specifically designed for lymphedema. The mean age of the patients at the time of LVA was 73.6 6 11.8 (33-95) years (Table I); 48 (64.9%) of the 74 patients were women and 26 (35.1%) were men. Mean BMI was 26.0 6 4.7 kg/m2 (14.7-34.7 kg/m2). All patients had a diagnosis of lymphedema or edema caused by lymphatic stasis and none had a negative ICG study result. Lymphedema was bilateral in 62 patients (83.8%) and unilateral in 12 patients (16.2%). Mean age at onset was 67.5 6 15.3 (2593) years, and the duration of edema was 6.1 6 7.2 (1-40) years. According to the International Society of Lymphology scoring system,20 70 (51.5%) of the 136 legs were stage I lymphedema, 40 legs (29.4%) were stage II, and 26 (19.1%) were stage III. The LEL index was 249.1 6 47.4 (159380). Patients with bilateral involvement were significantly older than those with unilateral involvement (77.1 6 7.8 [55-95] years vs 55.5 6 12.8 [33-73] years; P < .01) and were significantly older at onset of lymphedema (72.6 6 9.4 [43-93] years vs 41.2 6 12.7 [25-72] years; P < .01; Table II). The LEL index in the bilateral group was significantly lower than that in the unilateral group (237.6 6 40.1 [159-368] vs 308.8 6 36.8 [260-380]; P < .01; Table II). There were significant differences in the distributions of the patients’ age at the time of LVA and age at onset according to whether the lymphedema was bilateral or unilateral (P < .01; Table III). ICG lymphography images were classified by eye as linear, low enhancement (LE), distal dermal backflow (dDB), or extended dermal backflow (eDB) using a method (Fig 1) according to the ICG lymphography pattern classification for iatrogenic secondary lymphedema21 that we have modified during our series of studies.16 The linear pattern was detected in 23 patients (46 legs), the LE in 12 patients (24 legs), the dDB in 20 patients (40 legs), and the eDB in 7 patients (14 legs). Twelve patients had unilateral involvement (Table IV); all showed the eDB pattern in
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Table I. Patients’ characteristics
demographics
Variable
and
clinical
the lower leg and thigh areas according to ICG lymphography pattern and laterality. Diameter of the lymphatic vessels in the thigh area according to ICG lymphography pattern and laterality was as follows: linear (0.6 6 0.2 mm) vs unilateral (0.4 6 0.1 mm), P < .01; LE (0.6 6 0.2 mm) vs unilateral, P < .05; and dDB (0.5 6 0.2 mm) vs unilateral, P < .05. Diameter of the lymphatic vessels in the lower leg area according to ICG lymphography pattern and laterality was as follows: linear (0.9 6 0.1 mm) vs dDB (0.7 6 0.2 mm), P < .01; linear vs eDB (0.7 6 0.2 mm), P < .01; linear vs unilateral (0.5 6 0.1 mm), P < .01; LE (0.9 6 0.2 mm) vs dDB, P < .01; LE vs eDB, P < .01; LE vs unilateral, P < .01; dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05 (Fig 4). Significant between-group differences were also seen in the lymphatic detection rate per number of skin incisions in the thigh and lower leg areas according to the ICG lymphography pattern and laterality. In the thigh area, the detection rate was as follows: linear (100%) vs eDB (69.2% 6 36.4%), P < .05; unilateral (51.3% 6 41.7%), P < .01; LE (100%) vs unilateral, P < .01; and dDB (94.1 6 29.5%) vs unilateral, P < .01. In the lower leg area, the detection rate was as follows: linear (100%) vs dDB (96.2 6 9.3%), P < .05; linear vs eDB (83.7% 6 23.5%), P < .01; linear vs unilateral (46.2% 6 33.9%), P < .01; LE (100%) vs eDB, P < .05; LE vs unilateral, P < .01; dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05 (Fig 5). There were no significant between-group differences in the number of LVAs performed in the lower leg and thigh areas according to ICG lymphography pattern or laterality except for the following: LE (3.8 6 1.5) vs unilateral (2.2 6 1.6), P < .05; dDB (3.7 6 1.7) vs unilateral, P < .05; linear (3.3 6 1.3); eDB (3.1 6 2.0) in the lower leg area; linear (1.1 6 1.1); LE (1.0 6 1.2); dDB (1.3 6 0.9); eDB (1.4 6 1.2); unilateral (1.4 6 1.5) in the thigh area (Fig 6). There were significant differences in the improvement rate in the LEL index between the groups according to the ICG lymphography pattern and laterality: linear (10.5% 6 2.4%) vs eDB (8.9% 6 1.5%), P < .05; linear vs unilateral (6.7% 6 0.6%), P < .01; LE (10.4% 6 1.5%) vs unilateral, P < .01; dDB (11.0% 6 1.3%) vs eDB, P < .01; dDB vs unilateral, P < .01; and eDB vs unilateral, P < .05 (Fig 7).
74 patients (136 legs) 73.6 6 11.8 (33-95)
Age, years Sex Female
48 (64.9)
Male BMI, kg/m
26 (35.1) 2
26.0 6 4.7 (14.7-34.7)
Laterality of LEL Bilateral
62 (83.8)
Unilateral
12 (16.2)
Age at onset of LEL, years
67.5 6 15.3 (25-93)
Duration of edema, years
6.1 6 7.2 (1-40)
ISL stage I
70 (51.5)
II
40 (29.4)
III LEL index
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26 (19.1) 249.1 6 47.4 (159-380)
BMI, Body mass index; ISL, International Society of Lymphology; LEL, lower extremity lymphedema. Categorical variables are presented as number (%). Continuous variables are presented as mean 6 standard deviation (range).
both the lower leg and thigh regions. There were significant differences in age at the time of LVA and age at onset of lymphedema between the linear, LE, dDB, eDB, and unilateral lymphedema groups. Age at LVA according to ICG lymphography pattern was as follows: linear, 75.7 6 8.9 years; LE, 79.0 6 3.1 years; dDB, 76.9 6 8.7 years; eDB, 78.7 6 7.2 years; vs unilateral, 55.5 6 12.8 years (P < .01). Age at onset according to ICG lymphography pattern was as follows: linear, 72.8 6 9.6 years; LE, 74.5 6 4.7 years; dDB, 70.7 6 11.4 years; eDB, 74.0 6 9.6 years; vs unilateral, 41.2 6 12.7 years (P < .01; Fig 2; Table IV). Significant between-group differences were also seen in the LEL index: linear (216.6 6 26.6) vs dDB (244.1 6 28.1), P < .05; linear vs eDB (306.6 6 37.9), P < .01; linear vs unilateral (308.8 6 36.8), P < .01; LE (226.6 6 34.3) vs eDB, P < .01; LE vs unilateral, P < .01; dDB vs eDB, P < .01; and dDB vs unilateral, P < .01 (Fig 3; Table IV). There were also significant between-group differences in the diameter of the lymphatic vessels identified in
Table II. Patients’ demographics and clinical characteristics according to laterality of lymphedema Clinical lymphedema pattern Bilateral No. of patients (legs)
62 (124)
Unilateral
P value
12 (12)
Age at time of LVA, years
77.1 6 7.8 (55-95)
55.5 6 12.8 (33-73)
<.01
Age at onset of lymphedema, years
72.6 6 9.4 (43-93)
41.2 6 12.7 (25-72)
<.01
237.6 6 40.1 (159-368)
308.8 6 36.8 (260-380)
<.01
LEL index
LEL, Lower extremity lymphedema; LVA, lymphaticovenular anastomosis. Data are shown as the mean 6 standard deviation (range) or the number as appropriate.
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Table III. Distribution of patients’ age at the time of lymphaticovenular anastomosis (LVA) and onset of lymphedema according to laterality of lymphedema Age at onset of LEL, years <50
50-59
60-69
70-79
>80
P value <.01
Laterality of edema Bilateral
2
5
10
30
15
Unilateral
11
0
0
1
0
Age at the time of LVA, years <50
50-59
60-69
70-79
>80
P value
Bilateral
0
4
4
31
23
<.01
Unilateral
5
2
2
3
0
Laterality of edema
LEL, Lower extremity lymphedema. There was a significant difference in distribution of the patients’ age at onset according to laterality (P < .01, Kruskal-Wallis test). There was a significant difference in distribution of age at the time of LVA according to laterality (P < .01, Kruskal-Wallis test).
DISCUSSION Lymphedema is often referred to as primary if there is no obvious cause. However, primary lymphedema has variable features and may have a number of causes. In our study, primary lymphedema that developed after the age of 30 years could be bilateral or unilateral. According to the conventional classification, which relies on age at onset, both our study groups would be classified as lymphedema tarda. However, the two groups differed significantly in their age distribution, LEL index, and ICG lymphography patterns. Therefore, it is reasonable to regard these two groups as having different types of lymphedema and thus having different causes of lymphatic impairment. We can infer that age-related deterioration of lymphatic pump function was the most likely cause of lymphedema in the bilateral group. Although we found that the lymphedema was generally less severe in the older group with bilateral involvement than in the younger group with unilateral involvement, it could be as severe in that the LEL index worsened significantly in these patients as the ICG lymphography pattern progressed from linear to LE, dDB, and eDB. This finding suggests that lymph starts to accumulate distally to proximally in the older group with bilateral involvement. In secondary lymphedema with an iatrogenic etiology, lymphatic function is initially retained; thereafter, accumulation of lymph starts at the proximal region close to the obstructed area21 and eventually extends to the distal region, with progressive deterioration of lymphatic function. However, in older patients with bilateral lymphedema, we suggest that age-related deterioration of lymphatic function occurs in the entire area and that accumulation of lymph starts in the distal region. The mechanism for this deterioration is not understood but is likely to involve an effect of gravity.
It is difficult to determine whether lymphedema in younger patients with bilateral involvement is congenital22-24 or acquired.25 Late-onset primary lymphedema has been reported to be unilateral rather than bilateral,26,27 which is consistent with the findings in younger patients with unilateral lymphedema in our study. It is possible that unilateral lymphedema can occur at a younger age in individuals with congenitally weakened lymphatics, such that minor events, like trauma or an inflammatory reaction too subtle to be recognized as a cause of secondary lymphedema, can result in lymphedema. These deficits in lymphatic function are likely to be secondary to developmental errors; however, in our study, unilateral lymphedema with a younger age at onset might have been an acquired defect. Alternatively, a defect may be present from birth but the lymphatic system is able to compensate until there is an insult resulting in overload of lymphatic transport capacity.22,28,29 This may explain why the younger group with unilateral involvement in our study had a combination of secondary and congenital characteristics (ie, unilateral and relatively severe lymphedema). We believe that unilateral lymphedema can become bilateral26,30 and vice versa. Furthermore, there is the possibility of overlapping of features of more than one type of lymphedema. Therefore, we attribute the bilateral lymphedema seen in our study population to agerelated deterioration in lymphatic function. LVAs were performed in 74 patients (136 edematous lower limbs) thought to have developed primary lymphedema after the age of 25 years in the study. The purpose of this study was to compare the characteristics of the lymphatics detected during LVA in an older group of patients with bilateral lymphedema with those in a younger group of patients with unilateral lymphedema. We also compared the difference in
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Fig 1. Classification of indocyanine green (ICG) lymphography patterns. In the linear pattern, the superficial lymphatic vessels were arranged in a linear manner from the injection site to the superficial inguinal lymph nodes. The low enhancement (LE) pattern was observed only in the distal portion of the lower extremity, with no enhancement in the proximal part and no dermal backflow pattern observed. The distal dermal backflow (dDB) pattern was limited to the distal part of the lower extremity but not over the knee. The extended dermal backflow (eDB) pattern extended from the distal region of the lower extremity over the knee to the groin. All cases in the unilateral group showed the dermal backflow pattern in both the thigh and lower leg regions.
improvement in lymphedema after LVA between these two groups of patients. This study had three main findings. First, the lymphatic diameter tended to be larger in the older group with bilateral lymphedema and had a marked tendency to be smaller in the pattern order of linear, LE, dDB, eDB, and unilateral. Second, the lymphatic detection rate per number of skin incisions tended to be lowest in both the lower leg and thigh areas in unilateral involvement; furthermore, eDB pattern tended to be less common in this group than in the older group with bilateral lymphedema in both the
lower leg and thigh areas. In particular, lymphatic detection rate was markedly lower in the order of linear to LE, dDB, eDB, and unilateral in the lower leg area. Third, the extent of improvement in the LEL index tended to decrease in the order of dDB, linear, LE, eDB, and unilateral; however, the number of LVAs performed in the thigh and lower leg regions tended to be consistent. Studies in animals have demonstrated age-related decreases in systolic lymphatic flow velocity, pumping activity,12 contraction frequency,14 lymphatic vessel density, and lymphatic network complexity in collecting
Table IV. Indocyanine green (ICG) lymphography pattern according to patients’ age and lower extremity lymphedema (LEL) index ICG lymphography pattern Linear (TTG >10 min) No. of legs (patients)
LE
dDB
eDB
Unilateral
46 (23)
24 (12)
40 (20)
14 (7)
12 (12)
Age at the time of LVA, years
75.7 6 8.9
79.0 6 3.1
76.9 6 8.7
78.7 6 7.2
55.5 6 12.8
Age at onset of LEL, years
72.8 6 9.6
74.5 6 4.7
70.7 6 11.4
74.0 6 9.6
41.2 6 12.7
216.6 6 26.6
226.6 6 34.3
244.1 6 28.1
306.6 6 37.9
LEL index
308.8 6 36.8
dDB, Distal dermal backflow; eDB, extended dermal backflow; LE, low enhancement; LVA, lymphaticovenular anastomosis; TTG, time taken to reach the groin. Data are shown as the mean 6 standard deviation (range) or the number as appropriate.
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Fig 2. Between-group comparison of patients’ age at time of lymphaticovenular anastomosis (LVA) and age at onset of lymphedema according to indocyanine green (ICG) lymphography pattern. Age at time of LVA: linear, 75.7 6 8.9 years; low enhancement (LE), 79.0 6 3.1 years; distal dermal backflow (dDB), 76.9 6 8.7 years; extended dermal backflow (eDB), 78.7 6 7.2 years; unilateral, 55.5 6 12.8 years. Age at onset of lower extremity lymphedema: linear, 72.8 6 9.6 years; LE, 74.5 6 4.7 years; dDB, 70.7 6 11.4 years; eDB, 74.0 6 9.6 years; unilateral, 41.2 6 12.7 years. *P < .01, Tukey-Kramer test.
Fig 3. Between-group comparison of the lower extremity lymphedema (LEL) index score according to indocyanine green (ICG) lymphography pattern: linear, 216.6 6 26.6; low enhancement (LE), 226.6 6 34.3; distal dermal backflow (dDB), 244.1 6 28.1; extended dermal backflow (eDB), 306.6 6 37.9; unilateral, 308.8 6 36.8. *P < .05, **P < .01, Tukey-Kramer test.
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Fig 4. Between-group comparison of diameter of the lymphatic vessels identified in the thigh and lower leg areas according to indocyanine green (ICG) lymphography pattern. Thigh area: linear, 0.6 6 0.2 mm; low enhancement (LE), 0.6 6 0.2 mm; distal dermal backflow (dDB), 0.5 6 0.2 mm; extended dermal backflow (eDB), 0.5 6 0.1 mm; unilateral, 0.4 6 0.1 mm. Lower leg area: linear, 0.9 6 0.1 mm; LE, 0.9 6 0.2 mm; dDB, 0.7 6 0.2 mm; eDB, 0.7 6 0.2 mm; unilateral, 0.5 6 0.1 mm. *P < .05, **P < .01, Tukey-Kramer test.
lymphatic vessels.31 Furthermore, clinical studies using lymphoscintigraphy8 and ICG lymphography13 have shown a reduction in lymph drainage with increasing age. Aging is thought to involve a chronic inflammatory
process with a shift toward a proinflammatory cytokine profile in tissues, which may account for the numerous deleterious vascular changes associated with aging.32-34 This heightened preactivation state as well as an
Fig 5. Between-group comparison of lymphatic detection rate per number of skin incisions in the thigh and lower leg region according to indocyanine green (ICG) lymphography pattern. Thigh area: linear, 100%; low enhancement (LE), 100%; distal dermal backflow (dDB), 94.1% 6 29.5%; extended dermal backflow (eDB), 69.2% 6 36.4%; unilateral, 51.3% 6 41.7%. Lower leg area: linear, 100%; LE, 100%; dDB, 96.2% 6 9.3%; eDB, 83.7% 6 23.5%; unilateral, 46.2% 6 33.9%. *P < .05, **P < .01, Steel-Dwass test.
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Fig 6. Between-group comparison of number of lymphaticovenular anastomoses (LVAs) performed in the thigh and lower leg region according to indocyanine green (ICG) lymphography pattern. Thigh area: linear, 1.1 6 1.1; low enhancement (LE), 1.0 6 1.2; distal dermal backflow (dDB), 1.3 6 0.9; extended dermal backflow (eDB), 1.4 6 1.2; unilateral, 1.4 6 1.5. Lower leg area: linear, 3.3 6 1.3; LE, 3.8 6 1.5; dDB, 3.7 6 1.7; eDB, 3.1 6 2.0; unilateral, 2.2 6 1.6. *P < .05, Tukey-Kramer test.
increased number of activated mast cells would cause release of preformed inflammatory mediators, such as proteases, histamine, and cytokines like tumor necrosis factor a. The chronic inflammatory environment associated with aging may be an important cause of the changes in lymphatic pump function seen in older animals.14
Another animal study showed that the diameters of lymphatic vessels in the same anatomic location are significantly larger in aged animals than in younger adult animals.35 In that study, the end-systolic and enddiastolic diameters of the mesenteric lymphatic vessels in 24-month-old murine leukemia virus-infected rats were 79% and 71% greater, respectively, than those in
Fig 7. Between-group comparison of improvement rate for the lower extremity lymphedema (LEL) index according to indocyanine green (ICG) lymphography pattern: linear, 10.5% 6 2.4%; low enhancement (LE), 10.4% 6 1.5%; distal dermal backflow (dDB), 11.0% 6 1.3%; extended dermal backflow (eDB), 8.9% 6 1.5%; unilateral, 6.7% 6 0.6%. *P < .05, **P < .01, Tukey-Kramer test.
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their adult counterparts. It can be assumed that the same pathophysiologic deterioration occurs in human patients. Our empirical data show that the mean diameter of lymphatics in the lower extremities is around 0.5 mm in Japanese individuals.36 However, the consensus is that this diameter may be larger in Japanese patients with lymphedema.37 Furthermore, clinical studies have shown that advanced lymphedema results in fibrosis of the collecting lymphatics, which causes failure of the pump mechanism and luminal obliteration.38,39 Progression of lymphedema in the limbs is accompanied initially by smoothing of the endothelial cells in the collecting lymphatic vessels, then by disassembly of focal adhesions (desmosomes), growth and transformation of smooth muscle cells, thickening of the basal membrane, and finally proliferation of collagen fibers. In the early stages of lymphedema, the lymphatic vessels become ectatic in response to an increase in endolymphatic pressure.38 As the lymphedema progresses, lymphatic smooth muscle cells are transformed into cells involved in the synthesis of collagen, thereby promoting growth of collagen fibers and leading to irreversible contraction of the lymphatics. In the advanced stage of lymphedema, most components of the lymphatics undergo fibrosis, such that these vessels lose their transport and concentrating abilities and the lumens become either narrowed or completely obstructed. Failure of lymphatic flow also occurs in immune disorders that involve chronic inflammation and fibrosis.40,41 These pathophysiologic and immunologic changes appeared to occur in our older patients with bilateral lymphedema. The lymphatics in these patients were initially dilated when the linear or LE pattern was present; however, as the lymphedema progressed (with worsening of the LEL index), lymphatic diameter decreased in the order of dDB to eDB until the end stage of lymphedema, as in the unilateral pattern in younger patients. This phenomenon is particularly marked in the lower leg region in older patients with bilateral lymphedema. The detection rate in our study was almost the same as the findings for lymphatic diameter. As lymphedema worsens, the lymphatics become more difficult to recognize because they become increasingly mixed in with the fibrous tissue until they are eventually no longer visible. In this study, unlike the findings for detection rate and vessel diameter, there was little difference in the number of LVAs performed between the LE, dDB, and unilateral groups, except in the lower leg area. A potential explanation for this finding is that we always try to perform as many LVAs as possible in the belief that there is a positive correlation between therapeutic efficacy and the number of LVAs.42 Therefore, the number of LVAs performed tended to be consistent despite the marked between-group differences in detection rate and vessel diameter. Nevertheless, there were marked differences
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among the LE, dDB, and unilateral groups, which we believe to indicate that the lymphedema starts to deteriorate from distal to proximal. However, unlike in the LE and dDB groups, no marked difference was seen in the number of LVAs performed in the lower leg region between the linear and unilateral groups, probably because we judged the linear pattern to indicate mild lymphedema and performed fewer LVAs in this group of patients. Although there were no marked between-group differences in the number of LVAs performed, the rate of improvement in the LEL index tended to be smaller in the groups with more severe lymphedema. On the other hand, the improvement in the linear, LE, and dDB groups was relatively greater and not markedly different between the three groups. We assume that the lymphatic vessels in these three groups were still in sufficiently good condition for LVA to be performed. Our findings suggest that the unfavorable outcomes of LVA in the eDB and unilateral groups were attributable to smaller lymphatic diameter and low detection rate and that the lymphatic vessels in older patients with late-stage bilateral lymphedema and in younger patients with unilateral lymphedema are less amenable to improvement. Therefore, LVA would be indicated in patients with the linear, LE, and dDB pattern but not in those with the eDB pattern or unilateral involvement. As in patients with secondary lymphedema, LVA should be performed in the early stages, even in older patients with bilateral lymphedema.43-45 We used end-to-end anastomosis in all patients in this study. Although it has been suggested that there is no significant difference in the success rate between endto-end and end-to-side anastomosis, the end-to-side method has been found to have a lower success rate.46,47 Moreover, our experience is that the end-toside technique is more difficult to perform. The main limitations of this study are that it did not include a pathologic analysis and the number of patients included was small. Further pathologic investigation in a greater number of patients will be necessary in the future.
CONCLUSIONS We have investigated the features of the lymphatics in patients with lower limb lymphedema that developed in adulthood without any obvious cause by evaluating the findings when performing LVAs. The lymphatic vessel diameter tended to be greater in older patients with bilateral lymphedema than in younger patients with unilateral lymphedema. The rates of detection and improvement tended to decrease with worsening of the ICG lymphography pattern. LVA is thought to be more effective in older patients with early-stage bilateral lower leg lymphedema than in their younger counterparts with late-stage unilateral lymphedema.
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AUTHOR CONTRIBUTIONS Conception and design: ShuhY, IK, ShujY, KT Analysis and interpretation: ShuhY, IK, MH, ShujY, KT Data collection: ShuhY, IK, HI, TU, AS, YF, SN, KY Writing the article: ShuhY Critical revision of the article: ShuhY, IK, HI, TU, AS, YF, SN, KY, MH, ShujY, KT Final approval of the article: ShuhY, IK, HI, TU, AS, YF, SN, KY, MH, ShujY, KT Statistical analysis: ShuhY, IK, HI, TU, AS, YF, SN, KY, MH, ShujY, KT Obtained funding: Not applicable Overall responsibility: ShuhY
REFERENCES 1. Koshima I, Kawada S, Moriguchi T, Kajiwara Y. Ultrastructural observations of lymphatic vessels in lymphedema in human extremities. Plast Reconstr Surg 1996;97:397-405; discussion: 406-7. 2. Yamamoto T, Yoshimatsu H, Narushima M, Yamamoto N, Shim TW, Seki Y, et al. Sequential anastomosis for lymphatic supermicrosurgery: multiple lymphaticovenular anastomoses on 1 venule. Ann Plast Surg 2014;73:46-9. 3. Yamamoto T, Narushima M, Yoshimatsu H, Seki Y, Yamamoto N, Oka A, et al. Minimally invasive lymphatic supermicrosurgery (MILS): indocyanine green lymphography-guided simultaneous multisite lymphaticovenular anastomoses via millimeter skin incisions. Ann Plast Surg 2014;72:67-70. 4. Masià J, Pons G, Rodríguez-Bauzà E. Barcelona lymphedema algorithm for surgical treatment in breast cancerrelated lymphedema. J Reconstr Microsurg 2016;32:329-35. 5. Yamamoto T, Yoshimatsu H, Yamamoto N. Complete lymph flow reconstruction: a free vascularized lymph node true perforator flap transfer with efferent lymphaticolymphatic anastomosis. J Plast Reconstr Aesthet Surg 2016;69:1227-33. 6. Brorson H. Liposuction normalizes lymphedema induced adipose tissue hypertrophy in elephantiasis of the leg: a prospective study with a ten-year follow-up. Plast Reconstr Surg 2015;136(Suppl):133-4. 7. Paskett ED, Dean JA, Oliveri JM, Harrop JP. Cancer-related lymphedema risk factors, diagnosis, treatment, and impact: a review. J Clin Oncol 2012;30:3726-33. 8. Bull RH, Gane JN, Evans JE, Joseph AE, Mortimer PS. Abnormal lymph drainage in patients with chronic venous leg ulcers. J Am Acad Dermatol 1993;28:585-90. 9. Chakraborty S, Gurusamy M, Zawieja DC, Muthuchamy M. Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis. Microcirculation 2013;20:349-64. 10. Stöberl C, Partsch H. Erysipelas and lymphedemadegg or hen? Z Hautkr 1987;62:56-62. 11. Rockson SG. The lymphatic biology of aging. Lymphat Res Biol 2012;10:45. 12. Zolla V, Nizamutdinova IT, Scharf B, Clement CC, Maejima D, Akl T, et al. Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance. Aging Cell 2015;14:582-94. 13. Unno N, Tanaka H, Suzuki M, Yamamoto N, Mano Y, Sano M, et al. Influence of age and gender on human lymphatic pumping pressure in the leg. Lymphology 2011;44:113-20.
14. Gashev AA, Chatterjee V. Aged lymphatic contractility: recent answers and new questions. Lymphat Res Biol 2013;11:2-13. 15. Pal S, Meininger CJ, Gashev AA. Aged lymphatic vessels and mast cells in perilymphatic tissues. Int J Mol Sci 2017;18:E965. 16. Yoshida S, Koshima I, Imai H, Sasaki A, Fujioka Y, Nagamatsu S, et al. Indocyanine green lymphography findings in older patients with lower limb lymphedema. J Vasc Surg Venous Lymphat Disord 2019 Jun 20. [Epub ahead of print]. 17. Unno N, Nishiyama M, Suzuki M, Yamamoto N, Inuzuka K, Sagara D, et al. Quantitative lymph imaging for assessment of lymph function using indocyanine green fluorescence lymphography. Eur J Vasc Endovasc Surg 2008;36:230-6. 18. Unno N, Nishiyama M, Suzuki M, Tanaka H, Yamamoto N, Sagara D, et al. A novel method of measuring human lymphatic pumping using indocyanine green fluorescence lymphography. J Vasc Surg 2010;52:946-52. 19. Yamamoto T, Matsuda N, Todokoro T, Yoshimatsu H, Narushima M, Mihara M, et al. Lower extremity lymphedema (LEL) index: a simple method for severity evaluation of lower extremity lymphedema. Ann Plast Surg 2011;67:637-40. 20. Executive Committee. The diagnosis and treatment of peripheral lymphedema: 2016 Consensus Document of the International Society of Lymphology. Lymphology 2016;49:170-84. 21. Yamamoto T, Narushima M, Doi K, Oshima A, Ogata F, Mihara M, et al. Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns. Plast Reconstr Surg 2011;127:1979-86. 22. Tiwari A, Cheng K, Button M, Myint F, Hamilton G. Differential diagnosis, investigation, and current treatment of lower limb lymphedema. Arch Surg 2003;138:152-61. 23. Wolfe JH, Kinmonth JB. The prognosis of primary lymphedema of the lower limbs. Arch Surg 1981;116:1157-60. 24. Kinmonth JB, Taylor GW, Tracy GD, Marsh JD. Primary lymphoedema; clinical and lymphangiographic studies of a series of 107 patients in which the lower limbs were affected. Br J Surg 1957;45:1-9. 25. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 2013;84:303-14. 26. Schook CC, Mulliken JB, Fishman SJ, Grant FD, Zurakowski D, Greene AK. Primary lymphedema: clinical features and management in 138 pediatric patients. Plast Reconstr Surg 2011;127:2419-31. 27. Yamamoto T, Yoshimatsu H, Narushima M, Yamamoto N, Hayashi A, Koshima I. Indocyanine green lymphography findings in primary leg lymphedema. Eur J Vasc Endovasc Surg 2015;49:95-102. 28. Ely JW, Osheroff JA, Chambliss ML, Ebell MH. Approach to leg edema of unclear etiology. J Am Board Fam Med 2006;19:148-60. 29. Roy H, Bhardwaj S, Ylä-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett 2006;580:2879-87. 30. Burnand KM, Glass DM, Mortimer PS, Peters AM. Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling. Clin Nucl Med 2012;37:9-13. 31. Karaman S, Buschle D, Luciani P, Leroux JC, Detmar M, Proulx ST. Decline of lymphatic vessel density and function in murine skin during aging. Angiogenesis 2015;18:489-98.
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Yoshida et al
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32. Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol 2001;8: 131-6. 33. Bruunsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 2003;23:15-39. 34. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G. Aginginduced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J 2003;17:1183-5. 35. Benoit JN. Relationships between lymphatic pump flow and total lymph flow in the small intestine. Am J Physiol 1991;261: H1970-8. 36. Yoshida S, Koshima I, Imai H, Eldahshoury TE, Sasaki A, Fujioka Y, et al. Line production system for multiple lymphaticovenular anastomoses. J Plast Reconstr Aesthet Surg 2019;72:1334-9. 37. Yamamoto T, Narushima M, Koshima I. Lymphatic vessel diameter in female pelvic cancer-related lower extremity lymphedematous limbs. J Surg Oncol 2018;117:1157-63. 38. Mihara M, Hara H, Hayashi Y, Narushima M, Yamamoto T, Todokoro T, et al. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLoS One 2012;7:e41126. 39. Modi S, Stanton AW, Svensson WE, Peters AM, Mortimer PS, Levick JR. Human lymphatic pumping measured in healthy and lymphoedematous arms by lymphatic congestion lymphoscintigraphy. J Physiol 2007;583:271-85. 40. Yoshida S, Koshima I, Hamada Y, Sasaki A, Fujioka Y, Nagamatsu S, et al. Lymphovenous anastomosis aids wound healing in lymphedema: relationship between lymphedema and delayed wound healing from a view of immune mechanisms. Adv Wound Care 2019;8:263-9.
2019
41. Kataru RP, Baik JE, Park HJ, Wiser I, Rehal S, Shin JY, et al. Regulation of immune function by the lymphatic system in lymphedema. Front Immunol 2019;10:470. 42. Mihara M, Hara H, Tange S, Zhou HP, Kawahara M, Shimizu Y, et al. Multisite lymphaticovenular bypass using supermicrosurgery technique for lymphedema management in lower lymphedema cases. Plast Reconstr Surg 2016;138:262-72. 43. Chang DW, Suami H, Skoracki R. A prospective analysis of 100 consecutive lymphovenous bypass cases for treatment of extremity lymphedema. Plast Reconstr Surg 2013;132:1305-14. 44. Seki Y, Kajikawa A, Yamamoto T, Takeuchi T, Terashima T, Kurogi N. Single lymphaticovenular anastomosis for earlystage lower extremity lymphedema treated by the superior-edge-of-the-knee incision method. Plast Reconstr Surg Glob Open 2018;6:e1679. 45. Mihara M, Hara H, Kikuchi K, Yamamoto T, Iida T, Narushima M, et al. Scarless lymphatic venous anastomosis for latent and early-stage lymphoedema using indocyanine green lymphography and non-invasive instruments for visualising subcutaneous vein. J Plast Reconstr Aesthet Surg 2012;65:1551-8. 46. Heidekrueger PI, Ninkovic M, Heine-Geldern A, Herter F, Broer PN. End-to-end versus end-to-side anastomoses in free flap reconstruction: single centre experiences. J Plast Surg Hand Surg 2017;51:362-5. 47. Ueda K, Harii K, Nakatsuka T, Asato H, Yamada A. Microsurgery. Comparison of end-to-end and end-to-side venous anastomosis in free-tissue transfer following resection of head and neck tumors. Microsurgery 1996;17:146-9.
Submitted Jul 11, 2019; accepted Oct 10, 2019.