Keywords
lower extremity - lymphaticovenous anastomosis - lymphaticovenous bypass - lymphedema
- lymphovenous anastomosis - lymphovenous bypass
Introduction
Impairment in lymphatic circulation leads to the accumulation of protein-rich fluid
in the interstitial spaces, giving rise to a chronic and debilitating condition known
as lymphedema that is characterized by edema, inflammation, and cellulitis. Individuals
suffering from lymphedema experience pain, fatigue, numbness, swelling, depression,
limitation of daily activities, social impairment, and difficulty wearing normal clothing.[1]
[2] These functional and cosmetic disabilities greatly affect their quality of life.
Eventually, irreversible changes ensue, including fibrosis and proliferation of adipose
tissue.[2] In rare cases, continual angiogenic stimulus resulting from chronic lymphedema can
manifest in the form of malignancies, such as lymphangiosarcoma (Stewart–Treves syndrome),
Kaposi’s sarcoma, and lymphoma.[3]
Primary lymphedema is characterized by a disruption in normal lymphatic fluid transport
due to agenesis or dysgenesis of any component of the lymphatic network.[4]
[5]
[6]
[7]
[8] Occasionally, a lymphatic thrombus may be the cause.9 Secondary lymphedema
is caused by mechanical obstruction of lymphatic drainage due to trauma, infection,
radiation, or surgical disruption.[3]
[10]
[11]
[12]
Lower extremity lymphedema (LEL) has an overall incidence of 20%.[13] It is reported to occur in up to 21% of prostate, 16% of bladder, 4% of penile,
11.1% of ovarian,[14] 12.6% to 27.0% of cervical,[15] 13% of endometrial,[16] and 16.7 to 30.0% of vulvar cancers after radical surgery.[17]
[18]
[19] Several risk factors for LEL have been identified, including older age, higher body
mass index, radiation therapy, cellulitis and wound infection, and the number of removed
lymph nodes.[18]
[20]
Conservative therapies do not address the underlying dysfunction of the lymphatic
drainage system and, hence, are ineffective in halting the progression of the disease.
Surgical techniques, reconstructive or physiologic, target the functional repair of
this intrinsic problem. Among these is a supermicrosurgical procedure known as lymphaticovenous
anastomosis (LVA) or lymphovenous bypass that has gained wide spread acceptance worldwide
due to its improved outcomes and less invasive approach. Anastomosing lymphatic channels
to the adjacent venules redirects the lymphatic flow to the venous circulation, thereby
draining the excess fluid trapped in the lymphedematous district. The lymphatic vessel
and venule are anastomosed in an intima-to-intima coaptation fashion, leading to a
lower anastomotic-site thrombosis rate.[21] The outcome of this technique is influenced by the quality of the lymphatic vessels
bypassed and the number of LVAs made. Functional smooth muscle cells lining the lymphatic
channels are required to generate an effective pressure gradient to force the congested
lymph into the venous system.[22]
This study aims to review the published literature on LVA in the treatment of LEL
and to analyze the surgical outcomes. To our knowledge, this is the first review that
includes all studies to date describing LVA surgery and its effect on primary and
secondary lymphedema of lower extremities.
Methods
PubMed was queried for articles reporting LVA surgery in LEL treatment and their postsurgical
outcomes using the search terms, “lymphovenous” OR “lymphaticovenous” AND “bypass”
OR “anastomosis” OR “shunt” AND “lower extremity lymphedema.” Only human clinical
studies in the English language were eligible for inclusion. Manuscripts mentioning
both upper and lower limb lymphedema were included as long as their results included
extractable data regarding outcomes of LVA for LEL treatment. Literature review articles
were excluded. The publications were further screened manually and reviewed to identify
additional reports for surgical treatment of LEL through LVA. The second author (N.K.)
independently reviewed and extracted data from the papers according to the predetermined
criteria. Demographic data, lymphedema duration, surgical technique, follow-up time,
and outcomes were extracted from the selected articles.
Fig. 1 Flowchart highlighting search strategy and article identification.
Results
We found a total of 95 articles in our first search. From these, only 58 studies met
inclusion criteria ([Fig. 1]). The manuscripts included were published from November 1985 to July 2019 and reported
data for a total of 1,363 patients with LEL who had undergone LVA [Supplemnetary Table S1], (available online only). The number of patients in each study ranged from 1[23]
[24]
[25]
[26]
[27] to 216,[28] with a female predominance in all. The mean age at presentation ranged from 6[29] to 94 years,[30] and the mean duration of LEL ranged from 22 days[31] to 585 months.[1] Patients included in the studies more commonly had secondary lymphedema.
Campisi’s lymphedema grading system[32] was used in 12 studies, while the Yamamoto classification system[33] based on lymphatic dermal backflow patterns seen on indocyanine green lymphography
(ICG-L) was used in 17 studies. Mihara et al,[34] Akita et al,[35] and Maegawa et al[36] used the grading system based on lymphoscintigraphy findings, described by Maegawa
et al[37] in one of their earlier reports. Ito and collegues[38] used Cheng’s classification system[39] and Olszewski[28] used a grading system based on evaluation of the level of edema embracing the limb
from foot to groin and the advancement of skin keratosis and fibrosis. However, the
most widely used classification in 20 studies was the one presented by the International
Society of Lymphology.[40]
The preoperative and operative details along with the outcomes are summarized in [Supplementary Table S2] (available online only). Lower limb circumference and volume change were the most
frequently assessed parameters, followed by subjective improvement. Mihara et al[30] and Gloviczki et al[41] used lymphoscintigraphy, while Chen and colleagues used ICG-L[42] to assess postoperative efficacy of LVA. Akita et al[43] used computed tomography to calculate thickness of the subcutaneous fat layer on
the lateral edge of the rectus femoris muscle at the level of the lesser trochanter
of the femur and subsequently evaluated postoperative improvement of lymphedema.
ICG-L was the most commonly used investigation to assess the severity of lymphedema
and preoperatively outline the location of lymphatic vessels. End-to-end (E-E) and
side-to-end (S-E) anastomosis were the most frequently employed surgical techniques.
A modified version of the E-E LVA, the sleeve-in technique, in which a lymphatic vessel
is implanted into the lumen of a vein, was used by Yamamoto and Sugihara,[44] Olszewski,[28] and Chung et al.[45]
Yamamoto et al[46] introduced the l-shaped anastomosis with intravascular stent (IVaS) method for cases in which only
one lymphatic channel and one venule could be found. They suggested identifying vessels
appropriate for anastomosis and transecting them. After that, an IVaS, a piece of
nylon monofilament suture, is placed in the vessels to keep the lumen open and assist
safe anastomosis. An end-to-side (E-S) LVA followed by an E-E LVA is performed, creating
a l-shaped anastomosis.[46] Furthermore, when only one venule and two lymphatic channels were found, they reported
the use of sequential anastomosis, consisting of S-S and S-E LVA. Four directions
of lymphatic flow can be diverted from two lymphatic vessels into one venule via this
arrangement.[47] They also described the use of ladder-shaped anastomosis for cases when only one
vein and three lymphatic vessels were identified intraoperatively.[48] In this technique, the two lymphatic vessels next to the vein are anastomosed to
the vein in a S-S fashion, and the other lymphatic vessel is anastomosed to the nearby
lymphatic vessel in a S-S fashion.
Ayestaray and Bekara[49] developed a configuration based on two E-S LVA, or π-shaped LVA. They called it
a venous flow-sparing technique that resulted in an average circumferential differential
reduction rate of 19.4% (range, 6.1–24.6%).[49] In an attempt to solve the problem of mismatch between the number of lymphatic vessels
and venules and their calibers, Chen et al[50] presented the octopus LVA. This technique allows multiple lymphatic vessels to be
bypassed using a single vein. An out-to-in transluminal suture is placed through a
vein with a large diameter, followed by an in-to-out transluminal suture, which intussuscepts
all the lymphatic vessels into the vein, and forms an LVA complex that resembles an
octopus.[50]
Per case 1[29]
[30]
[36]
[51]
[52]
[53] to 18[46] anastomoses were performed, and it took an average of 3 to 4 hours[29]
[35]
[44]
[45]
[46]
[54]
[55]
[56]
[57]
[58] for surgeons to perform the entire procedure. Follow-up time ranged from 1[59]
[60] to 87 months.[61] Complex decongestive physical therapy was advised to be continued postoperatively
in most cases. All studies reported positive outcomes based on improvement in the
limb circumference and volume, lymphatic function, or clinical symptoms. Ito et al,[38] Koshima et al,[62] and Lee et al[63] have reported the largest reduction rates at 63.8, 55.6, and 51.1%, respectively.
Regarding outcomes, Gloviczki and collegues[41] reported improvement in only two of eight patients, while four patients reported
worsening of lymphedema. Mihara et al[34] compared LVA outcomes in the following two groups of patients: those in whom noncontact
vein visualizing system was used to detect subcutaneous veins (control group) versus
those in whom venous echography was used (echo group). Lymphedema exacerbation was
reported in 23.8% of the patients from the control group, while only 5.9% from the
echo group experienced lymphedema deterioration.[34] In patients with lymphedema onset before 11 years of age, Hara et al[58] reported aggravation of their condition. Positive outcomes were seen more often
in those with onset after 11 years of age.[58]
The largest number of patients included in a study was reported by Olszewski.[28] Over the course of 45 years, the author performed LVAs on 216 patients, with an
average postoperative follow-up of 60 months. Major improvement was observed in patients
with early stages of lymphedema, regardless of the etiology. The lymphovenous shunt
operation was ineffective in patients with stage-II idiopathic and stage-III postinflammatory
types of lymphedema. Hence, Olszewski suggested performing the surgery at an early
stage (I and II) of postinflammatory, postsurgical, or hyperplastic types, with at
least one thigh lymphatic and inguinal or iliac lymph node visible on stress lymphoscintigraphy.
Similarly, Demirtas et al[60] reported a greater decrease in limb volume in patients with a lower volume of edema.
However, Mihara et al[30] described contradicting results, with significant volume reductions in advanced
stages of lymphedema. They recorded a volume decline in 73.9% of patients with stage
III compared with 56.7% with stage I.
Thirteen studies assessed the relationship between lymphedema and episodes of cellulitis
or lymphangitis.[1]
[24]
[27]
[29]
[30]
[34]
[38]
[56]
[60]
[61]
[63]
[64]
[65] All, except one chart review by Lee et al,[63] reported significant reductions in infection incidence.
Discussion
The possibility of creating an anastomosis between lymphatic vessels and veins to
diverge the lymphatic fluid into the venous system was mentioned for the first time
in 1962.[66] Subsequently, several others attempted to perform LVA in canine models.[67]
[68]
[69] However, the field of lymphatic microsurgery did not experience a major breakthrough
until O’Brien et al[70] presented a clinical report establishing the clinical effectiveness of this method
in human patients. Lymphatic vessels with a diameter of 0.5 to 1.0 mm and veins with
a diameter of 2.0 to 3.0 mm were required for anastomosis under general anesthesia.[70] Thereafter, the introduction of supermicrosurgery, which enabled anastomosis of
vessels with a caliber of 0.3 to 0.8 mm, increased the reliability of LVA.[62]
[71] LVA using lymphatics with diameter between 0.5 to 0.7 mm and subdermal veins between
0.7 to 1.0 mm of diameter demonstrated positive outcomes with reduction rates from
30 to 78% and reduction of episodes of cellulitis from a mean of 1.6 to 0.2.[38] Currently, the operation can be performed under local anesthesia in the dermal layer
of the skin via a 2- to 3-cm skin incision, making it safe for high-risk patients,
including the elderly and those with cardiopulmonary disease or terminal cancer.[62] Mihara et al[72] was able to report favorable outcomes of LVA performed through a 2-mm skin incision
under guidance of the AccuVein system (AccuVein Inc.) and ICG-L in patients with early
and latent stage lymphedema. This was possible because of the absence of subcutaneous
tissue fibrosis in these patients.
LVA is indicated in cases where there has been insufficient lymphedema reduction by
complex physical therapy (less than 50%), worsening limb function, recurrent episodes
of cellulitis, and intractable pain. In addition, patients not satisfied with the
result obtained by conservative methods can be given the option to proceed with a
surgical alternative.[73] LVA can also be performed as prophylactic treatment in patients with subclinical
lymphedema.[72]
[74]
Many surgeons agree that it is desirable to perform microlymphatic surgery at an early
stage of edema because lymphatics get permanently damaged from increased pressure
and recurrent infections, and preserved smooth muscle function is required to effectively
pump the lymphatic fluid into the venous system.[32]
[35]
[38]
[53]
[60]
[61]
[65]
[71]
[75]
[76]
[77] Thus, advanced disease, where lymphatic vessels are usually sclerotic, is a relative
contraindication.
Other procedures used to treat lower limb lymphedema include vascularized lymph node
transfer (VLNT), as well as VLNT in combination with lipoaspiration.[78] Although, VLNT is also preferred in early stages of the disease as LVA, LVA is better
suited in patients with available lymphatic vessels.[78]
[79]
[80] In addition, LVA has the advantage of not having any morbidity risk associated with
the donor site as in VLNT.[79] On the other hand, combined procedures have shown better outcomes in more advanced
stages of lymphedema.[78]
Previously, it was believed that primary lymphedema was also a relative contraindication
for LVA due to the hypoplastic nature of lymphatic vessels.[75] However, encouraging results have been reported for select patients with primary
lymphedema in the recent years.[58]
[81] Congenital lymph node fibrosclerosis and the lower number of functional lymphatic
collectors can account for the decreased volume reduction observed in primary lymphedema
as compared with secondary.[32]
[81] Since extensive lymphatic abnormalities are associated with early onset of disease,
LVA is advised in cases of primary lymphedema with no dermal backflow and disease
onset after 11 years of age.[58]
Regarding the surgical technique, subdermal venules with intact valves are recommended
for anastomosis due to their small diameter and lower intravenous pressures. The smaller
diameter allows caliber-matching, and lower intravenous pressure with a functioning
valve reduces the chance of thrombosis due to minimal backflow.[82]
Constant lymphatic vessels are easier to locate at the dorsal foot, ankle, and groin
region for the lower extremity.[29] However, Seki et al[83] described a method to locate easily between three to five superficial large lymphatic
vessels when a 2.5-cm transverse incision is made in the intersection of a transverse
line at the superior edge of the patella and a longitudinal line along the medial
axis of the distal thigh. Preoperative identification of functional lymphatic vessels
and veins can substantially shorten operative time and improve surgical outcomes.[84] For this purpose, ICG-L and lymphoscintigraphy can be used to locate patent lymphatic
vessels and assess the severity of lymphedema before surgery.[55]
[56]
[72]
[85]
[86]
[87] Although, our systematic review observed different classifications used to assess
severity of lymphedema, the most widely used classification was the one stated by
International Society of Lymphology. Ultrasound is a noninvasive tool that can also
facilitate lymphatic channel visualization in regions masked by dermal backflow pattern
or in patients allergic to iodine.[55]
[57] It has a sensitivity and specificity of 88.2 and 92.7%, respectively.[57] Postoperative patency and efficacy of the anastomosis can also be determined via
lymphoscintigraphy[41] and ICG-L.[42] Lee et al[63] published a chart review in which they suggested that once LVA is conducted properly
and becomes functional in the early postoperative period, it might remain effective
for up to 4 years following surgery.
Performing as many LVAs as possible is desirable, given that treatment efficacy was
found to be proportional to the number of anastomoses created.[38]
[46]
[65]
[82]
[86] However, there is still a topic open for investigation regarding the number of anastomoses
that result in significant reductions. Chen[88] in his operative technique that routinely they perform between 7 to 12 per limb.
Koshima et al[53] believe that a large number of LVAs is not required, and only two to three anastomoses
are enough to provide a satisfactory volume reduction. Seki and colleagues, on the
other hand, commented that one functional LVA can be sufficient.[83]
The basic types of LVA include E-E, E-S, S-E, and S-S.[46]
[47]
[52]
[89]
[90]
[91] Controversy still exists regarding the type of anastomosis that should be performed
but each type has its own advantages and disadvantages. E-E LVA seems to be inferior
to E-S and S-S LVA as it drains only distal lymph in LEL and requires a higher number
of anastomoses in more proximal sites.[92] Moreover, lymphedema is characterized to have a retrograde and antegrade lymph flow,
therefore, LVA should try to bypass both directions of lymph flows.[92] S-E LVA is the most technically challenging and recommended, and is efficient to
divert bidirectional lymph flow via one anastomosis.[38] Similarly, S-S anastomosis can divert both antegrade and retrograde lymph flows,
but it takes a longer time compared with S-E anastomosis and eventually results in
venous backflow, which may cause anastomotic site thrombosis. However unlike S-E LVA,
S-S LVA does not require supermicrosurgical technique when the diameter of the lymphatic
vessel is smaller than 0.5 mm, can be performed when the vein is much larger than
the lymphatic vessel, and can use a vein distal to the anastomotic site.[37]
[46]
[47]
[86]
[90]
Due to the small caliber of microvessels and the transparent nature of lymphatic vessels,
the procedure of LVA is technically challenging. Yamamoto et al[90] proposed the method of temporary lymphatic expansion during S-E anastomosis, whereby
the lymphatic vessels are clamped and manually massaged. Although temporary, this
maneuver can dilate the vessels by approximately 0.12 mm, making the creation of a
lateral window much easier. Another way to facilitate the anastomosis is by inserting
an IVaS, a piece of nylon suture that allows identification of the lumen of lymph
channels and stabilizes vessels while guiding the needle.[46]
[91]
[93] Building on this approach, Yoshida et al[54] illustrated the mechanical dilatation technique, in which a larger nylon monofilament
was inserted after the IVaS to dilate the vessel lumen. According to their data, even
a vessel with a diameter of less than 0.1 mm can be dilated to more than 0.2 mm using
this method, with 100% immediate patency rate.[54] These techniques can aid in the creation of safe and secure LVAs in a shorter amount
of time, thus increasing the number of successful LVAs that can be performed.
Supportive use of complex decongestive physical therapy should not be ignored after
surgery.[75]
[81] It consists only of compression therapy with the help of bandaging and elastic stockings
but also of manual lymph drainage and massage, therapeutic exercise, and careful skin
care.[29] Superior outcomes have been observed in patients who underwent a combination of
LVA and compression bandaging compared with those who underwent surgery alone.[43] Compression therapy should be initiated one month postsurgery and patients should
be follow up each 3 months postoperatively to assess volume reduction until maintenance
of limb size is achieved with daytime therapy for 3 consecutive months.[94]
Our systematic review found that the largest reduction rates achieved after LVA for
LEL ranged between 51.1 and 63.8%, with better results presented in early stages of
lymphedema, and that almost all studies reported a decrease in episodes of infection.
Patients’ satisfaction after LVA has been also evaluated. Chung et al[45] found moderate scores of satisfaccion after treatment. Moreover, improvement in
the quality of life has been demonstrated after LVA during the first postoperative
months.[1]
[42] Although, most of the patients who underwent LVA for LEL have been reported to have
positive surgical outcomes, limb size reduction can be variable. This may be related
with the severity of the lymphedema and the number and type of anastomoses performed
along with the risk factors associated with lymphedema presented in the patients included
in the studies. Several studies have reported inferior outcomes for patients who have
undergone LVA for LEL compared with upper extremity lymphedema.[38] The effects of ambulation, the large size, the dependent position, and the higher
venous pressure of the lower extremities may account for this finding.[29] When a volumetric decrease of the edema was not achieved, it constitutes a failure.
In those cases, options such as VLNT, lipoaspiration or combined procedures could
be considered.
Limitations
As with all systematic reviews, this study has several limitations. Due to the general
lack of large volume studies addressing LVA in the lower extremity, we were restricted
to a limited range of reported data, and hence, a thorough statistical analysis was
not possible. Considerable heterogeneity exists among the reported outcomes in each
study, and therefore, there is a potential for bias in interpreting data, as it is
possible that not all studies captured reliable comorbidity data or outcomes over
a long-period of time. A risk of selective reporting bias can also be encountered
when documentation of subjective patient symptoms is involved. Larger, randomized,
multicenter studies are warranted to validate the results found from this systematic
review of the literature.
Conclusion
The results of this systematic review of the literature on LVA for LEL demonstrated
considerable improvements in objective and subjective findings in the majority of
patients. More importantly, the effectiveness of this treatment modality was maintained
in the long-term follow-up, suggesting great efficacy of LVA in cases of LEL.
