Lymphedema is a common, chronic, and debilitating condition affecting approximately 1 in 30 people worldwide.1–3 In developing countries, secondary lymphedema most frequently arises because of filariasis, a parasitic infection that leads to lymphedema of the lower extremities by direct lymphatic obstruction.1 In the Western world, lymphedema is predominantly iatrogenic secondary to lymphadenectomy for the treatment of cancer, in particular, breast4,5 and gynecologic cancers,6,7 with risk increased by adjuvant radiotherapy, especially regional nodal irradiation.5 Primary lymphedema is rare, with identifiable genetic mutations found in approximately 30 percent of patients, many involving the signaling pathway for vascular endothelial growth factor (VEGF)-C.8,9
Lymphedema results from developmental or acquired dysfunction of the lymphatic system, characterized by lymphatic vessel ectasia and valve dysfunction, followed by reflux of lymphatic fluid into the interstitial space. Lymphatic fluid stasis leads to a localized chronic inflammatory process, resulting in extracellular matrix remodeling and fibrosis, adipose tissue differentiation, and progressive fibrosis/sclerosis, with eventual obliteration of the lymphatic vessel lumen.10–13 The inflammatory cell accumulation around the lymphatic vessels leads to up-regulation of inducible nitric oxide synthase expression, resulting in increased nitric oxide levels that disrupt the intrinsic nitric oxide gradient and decrease collecting lymphatic contractility and lymphatic fluid transport.14 In addition, the chronic T-helper 2 cell–biased inflammatory response with expression of cytokines—including interleukin-4, interleukin-13, interferon-gamma, and transforming growth factor-β1—leads to decreased collateral lymphatic vessel formation by hindering lymphatic endothelial cell proliferation and tubule formation, migration, and function.15,16 Obesity, an independent risk factor for lymphedema development, results in reversible lymphatic dysfunction regulated by perilymphatic inducible nitric oxide synthase expression and accumulation of T cells and macrophages, mediated by T-cell inflammatory responses.17,18
Advances in our understanding of the anatomophysiology of the lymphatic system, and the pathogenesis underlying lymphedema, have led to the development of effective surgical techniques to ameliorate the symptoms and disability of patients with lymphedema and reduce the risk of future episodes of cellulitis. Physiologic procedures, including lymphovenous bypass and vascularized lymph node transplant procedures, aim to restore lymphatic fluid drainage within the affected area.19–23 Vascularized lymph node flaps may be harvested from within the axillary, inguinal, or cervical lymph node basins, or from intraabdominal donor sites. Once established, the chronic lymphedema phenotype is characterized by hypertrophy of fibroadipose soft tissues, which can only be removed directed by suction-assisted lipectomy or excisional procedures to restore function and appearance.24
DIAGNOSIS AND STAGING
The presence of dermal backflow on contrast-enhanced imaging of the lymphatic system is diagnostic for lymphedema, and the severity and distribution of this backflow correlate closely with the pathologic condition of the lymphatic vessels.25–27 Magnetic resonance lymphography enables global detailed visualization of individual lymphatic vessels and lymph nodes and enables both diagnosis of lymphedema and surgical planning.28 Radioisotope lymphoscintigraphy allows for the global serial assessment of lymphatic physiologic function, and of the draining lymph nodes29,30; it can be combined with computed tomography (single-photon emission computed tomography/computed tomography) for three-dimensional localization of lymph nodes for reverse lymphatic mapping for vascularized lymph node transplantation31,32 (Fig. 1). Indocyanine green fluorescent lymphography enables detailed dynamic functional evaluation of the superficial lymphatic system,33 and can also be used for intraoperative lymph node mapping for vascularized lymph node transplantation. Several clinical staging systems for lymphedema derived from these imaging modalities have been reported,25,26,30,34–39 which may aid in informing treatment algorithms. Staging systems using indocyanine green lymphography are used most commonly, evaluating the lymphatic transport, presence of functional lymphatic vessels, and pattern and distribution of dermal backflow25,26,38,40,41 (Fig. 2).
PATIENT SELECTION FOR SURGICAL INTERVENTION
Patient selection for surgery for lymphedema varies across institutions. For patients presenting soon after developing lymphedema, where their lymphedema is at an early stage, a trial of complete decongestive therapy for 3 to 6 months is typically instituted42–47; surgical intervention is indicated for those with persistent lymphedema following this, especially with recurrent bouts of cellulitis.42,43,48 For patients presenting at an advanced stage with significant pitting edema, preoperative prehabilitation using reductive complete decongestive therapy can be beneficial to optimize conditions for surgery by transitioning toward the maintenance phase.37,49 Patients with recurrent episodes of cellulitis may benefit from prophylactic antibiotics.
Surgery is contraindicated in patients with active cellulitis. Those with untreated or uncontrolled primary cancer or locoregional recurrence, or those medically unfit to undergo surgery safely, are better served by nonsurgical management.
LYMPHOVENOUS BYPASS PROCEDURE
The lymphovenous bypass procedure is indicated in early lymphedema.27,38,44,50 Although it is less effective alone in advanced-stage lymphedema, there may be synergistic benefits when performed synchronously with vascularized lymph node transplantation.51,52 Intrinsic venous hypertension in the extremity may result from postirradiation fibrosis reducing the compliance of the proximal veins, and from perivascular postsurgical scarring.53–55 Selection of venules without reflux secondary to venous hypertension and lymphatic vessels without sclerosis, and meticulous surgical technique, are determinants for successful long-term anastomotic patency.56–59
Using a fluorescent lymphography imaging system, intradermal injection of indocyanine green into the web spaces of the affected extremity allows the lymphatic vessels to be mapped, and discrete lymphatic vessels distal to areas of dermal backflow are targeted for supermicrosurgical anastomosis to adjacent small venules.25,26,33,60,61 Crossing veins can be seen as shadows over the fluoresced lymphatic vessels, and a vein imager is a useful adjunct to identify adjacent venules without reflux.59
Anastomotic techniques are selected depending on the relative calibers of the lymphatic vessels and venules62–65 (Fig. 3). [See Figure, Supplemental Digital Content 1, which shows end-to-end lymphovenous bypass; passage of lymphatic fluid into the venule is seen without venous reflux, http://links.lww.com/PRS/D654. See Figure, Supplemental Digital Content 2, which shows end-to-side lymphovenous bypass into a larger vein; the lymphatic vessel is stented open and the flow characteristics are favorable toward flow of lymphatic fluid into the vein, http://links.lww.com/PRS/D655. See Figure, Supplemental Digital Content 3, which shows indocyanine green fluorescent lymphography of the end-to-side lymphovenous bypass in Supplemental Digital Content 2; the lymphatic fluid is visualized flowing into the vein, http://links.lww.com/PRS/D656. See Figure, Supplemental Digital Content 4, which shows end-to-end anastomosis of a large lymphatic using a 1.0-mm-diameter venous coupler (Synovis Micro Companies Alliance, Birmingham, Ala.); the coupler permanently stents open the anastomosis to reduce the risk of technical failure, http://links.lww.com/PRS/D657. See Figure, Supplemental Digital Content 5, which shows side-to-end lymphovenous bypass; the continuity of the lymphatic vessel is preserved and the combined lymphatic flow pressure from anterograde and retrograde flow overcomes venous reflux, http://links.lww.com/PRS/D658. See Figure, Supplemental Digital Content 6, which shows double-barreled end-to-end lymphovenous bypass into a side branch of a vein; the thicker vein wall maintains patency, and the combined lymphatic fluid flow pressure overcomes the higher venous back-pressure, http://links.lww.com/PRS/D659.] Incisions 1 to 2 cm in length are made over the selected site, and a high-power specialist microscope is necessary for accurate visualization; 6-0 monofilament suture may used for intraluminal stenting to ensure patency.66 In addition, 11-0 nylon sutures are typically used in interrupted fashion; in the rare circumstance that the internal lymphatic vessel diameter is 1.0 mm or more in diameter, a venous coupler system may be used for end-to-end anastomosis. Immediate bypass of the lymphatic vessels severed at the time of axillary or inguinal lymphadenectomy into adjacent veins within the surgical field (lymphatic microsurgical preventing healing approach technique) has demonstrated efficacy at reducing the risk of subsequent lymphedema development, and is an area of ongoing investigation.67–69
Postoperative Management for Lymphovenous Bypass
Perioperative antibiotics may be indicated in those experiencing recurrent infections. Following surgery, patients elevate the operated extremity; compression garments are typically recommenced at 4 weeks after surgery for approximately 6 months.70
VASCULARIZED LYMPH NODE TRANSPLANTATION PROCEDURE
Vascularized lymph node transplantation is indicated in established lymphedema to provide new physiologic function. The presence of significant segmental dermal backflow with few or no functioning lymphatic vessels on imaging is an indication for vascularized lymph node transplantation, and its distribution may help in deciding between proximal anatomical (orthotopic) or distal nonanatomical (heterotopic) lymph node flap placement. Where there are patent lymphatic channels, performing lymphovenous bypass and vascularized lymph node transplantation synchronously may provide a synergistic benefit.51,52
Vascularized lymph node transplantation is most commonly performed to treat upper extremity breast cancer–related lymphedema. In patients undergoing postmastectomy breast reconstruction, this may be performed by transferring a deep inferior epigastric artery perforator (DIEP) flap with a chimeric groin vascularized lymph node flap placed in the axilla.71–74 For patients that have undergone breast-conserving surgery, in those for whom a DIEP flap is contraindicated, or for those with lymphedema affecting the lower extremity, several other vascularized lymph node flap options are available (Table 1).1–152 These include the groin,48,75 supraclavicular,45,52,76,77 submental,78 and lateral thoracic32,79–81 vascularized lymph node flaps. For patients wishing to avoid any risk of iatrogenic donor extremity lymphedema or visible donor-site scars, intraabdominal lymph node flap options are increasingly being performed, including the omental (gastroepiploic) flap,43,83 which may be harvested laparoscopically, and the jejunal mesenteric flap.84,85 The role of prophylactic vascularized lymph node transplantation in those at high risk of developing lymphedema is yet to be determined.86
Table 1. -
Vascularized Lymph Node Flap Options and Characteristics
||Lymph Node Group
||Mean No. of Lymph Nodes ± SD
|Groin lymph node flap48,71–75,103
||Superficial inguinal lymph nodes
||Superficial circumflex iliac artery and vein
||3.3 ± 1.6
||•Ability to combine flap with free abdominal tissue transfer for postmastectomy breast reconstruction
•Inconspicuous donor-site scar
|•Risk of causing iatrogenic lower extremity lymphedema
•Need for reverse mapping
•Short vascular pedicle
|Supraclavicular lymph node flap45,52,76,77
||Cervical level Vb lymph nodes
||Supraclavicular branch of the transverse cervical vessels and branches of the external jugular vein
||3.3 ± 1.5
||•Minimal risk of upper extremity lymphedema
||•Risk of injury to surrounding vital structures [thoracic duct (left), right lymphatic duct, phrenic nerve] and supraclavicular nerve (paresthesia of upper anterior chest)
|Submental lymph node flap78,106–108
||Cervical level Ia/Ib lymph nodes
||Submental artery (branch of the facial artery)
||3 ± 0.6
||•Minimal risk of donor-site lymphedema
||•Risk of injuring the marginal mandibular nerve (temporary paralysis)
•Potentially conspicuous donor-site scar
|Lateral thoracic lymph node flap79–81
||Axillary level I lymph node
||Lateral thoracic artery and vein (or thoracodorsal artery and vein if absent)
||13.40 ± 3.13
||•Flap size may be tailored to recipient-site requirements
||•Potential to cause upper extremity donor-site lymphedema
•Need for reverse mapping
•Potential need to divide terminal branches of the thoracodorsal nerve
|Greater omental/gastroepiploic lymph node flap43,82,83,115–117
||Area of omentum adjacent to the gastroepiploic vascular arcade
||Right (or left) gastroepiploic artery and vein
||Right gastroepiploic: 6.4 ± 7.3; left gastroepiploic: 8.3 ± 7.9
||•Possibility for laparoscopic harvest
•Minimal risk of intraabdominal lymphedema
•Flap size may be tailored to recipient-site requirements
|•Risk of causing abdominal complications (incisional hernia, peritonitis, gastric ischemia, pancreatitis, injury to intraabdominal organs including bowel, bowel obstruction)
•No skin paddle
•Short vascular pedicle
|Jejunal mesenteric lymph node flap84
||Third part of the jejunal mesentery
||Second, third, or fourth mesenteric branch of superior mesenteric artery and vein
||Proximal jejunal segment: 10.4 ± 3.6 at periphery; 8.8 ± 5.2 at root
||•Minimal risk of donor-site lymphedema
||•Risk of causing abdominal complications (incisional hernia, peritonitis, gastric ischemia, pancreatitis, injury to intraabdominal organs including bowel, bowel obstruction)
•No skin paddle
•Short vascular pedicle
Mechanism of Action
Although the precise mechanism of vascularized lymph node transplant action is incompletely understood, two main mechanisms have been demonstrated in experimental and clinical settings87–94: lymphangiogenesis with new afferent and efferent lymphatic collateral pathways connecting the transplanted lymph nodes with lymphatic vessels in the recipient site to restore outflow (“bridging” mechanism), mediated by lymphangiogenic growth factor secretion from the transplanted lymph nodes, in particular, VEGF-C87,95,96; and neolymphangiogenesis, establishing new lymphaticovenous drainage within the transplanted lymph nodes, driven by perfusion gradients between the arterial inflow and venous outflow (“pumping” mechanism).88,91,92,94 These mechanisms support the clinical efficacy of both orthotopic and heterotopic placement of the vascularized lymph nodes within an extremity. Lymphaticolymphatic anastomoses are unnecessary, as neolymphatic connections develop by means of homing lymphatic growth factor mechanisms.89 The number of lymph nodes transferred may proportionally relate to outcome.97,98
Groin Lymph Node Flap
Detailed knowledge of the lymphovascular anatomies and variability of the inguinal donor site is essential to avoid the risk of iatrogenic donor-site lower extremity lymphedema and ensure viability of the lymph nodes.99 The superficial inguinal lymph node basin that drains the lower abdomen and is supplied by the superficial circumflex iliac artery (SCIA) and vein (SCIV) is the target for lymph node flap harvest from this region, separated by distinct fascial boundaries from the deep lymph node basins adjacent to the femoral vessels that drain the lower extremity.48,71,75 Dissection medial to the lateral border of femoral artery, caudal to the groin crease, and deep to the fascia of the thigh, is avoided48,99–101; because of the variability of the lymphatic drainage patterns,102 reverse lymphatic mapping is essential for intraoperative guidance32 (Fig. 1). Limitations include variable vascular anatomy with short pedicle length and small arterial caliber,103 and potential bulkiness when used for distal extremity placement.
Deep Inferior Epigastric Artery Perforator Flap with Chimeric Groin Lymph Node Flap
For chimeric DIEP-groin lymph node flap transfer,71–74,104 the lymph node flap is harvested deep to the suprafascial (Scarpa) plane with a broad pedicle to ensure perfusion105 (Fig. 4); adequate perfusion can be assessed by fluorescent perfusion clearance imaging (Fig. 5, left). Where the lymph node flap is located on the hemiabdomen ipsilateral to the perforators supplying the flap, additional anastomosis of the SCIV is typically required to adequately drain the lymph nodes (Fig. 5, right). Where the lymph node flap is located on the contralateral hemiabdomen to the perforators, additional anastomosis of both the SCIA and SCIV to branches of the subscapular system within the axilla is necessary to perfuse the lymph node flap.
Submental Lymph Node Flap
The submental lymph node flap includes submental (cervical level Ia) and submandibular (cervical level Ib) lymph nodes perfused by the submental artery.78 The incision is placed parallel to the inferior border of the mandible over the submental artery, and a skin paddle may be raised on perforators arising from this artery (Fig. 6, left). The arterial pedicle length is short and of small caliber, and there may be anatomical variability of the facial artery and vein.106,107 Care should be taken to preserve branches of the marginal mandibular nerve.108 The flap is low volume, making it suitable for distal extremity placement, and there is very low risk of donor-site lymphedema. The resultant scar, however, may be visible in the submandibular area (Fig. 6, right).
Supraclavicular Lymph Node Flap
The supraclavicular lymph node flap is based on the transverse cervical vessels and includes cervical level Vb lymph nodes.45,52,76,77 It is a thin pliable flap suitable for distal extremity placement, and the resultant scar can be well-concealed by clothing. Injury to the supraclavicular nerve, however, may result in paresthesia of the upper anterior chest. Although the right side is typically preferred for harvest to avoid risk of injury to the thoracic duct, it contains fewer lymph nodes than the left side.77
Lateral Thoracic Lymph Node Flap
The lateral thoracic lymph node flap incorporates axillary level I lymph nodes.79–81 Sentinel lymph node drainage of the thorax and upper extremity is discretely organized109–111; the sentinel lymph nodes to the upper extremity are typically located cephalad to the second intercostal brachial nerve and lateral to the lateral thoracic vein. Dissection medial to the lateral border of the pectoralis minor and cephalad to the second intercostal brachial nerve is avoided, and the use of reverse lymphatic mapping is essential to reduce the risk of donor-site lymphedema.32
Although the lateral thoracic lymph nodes are typically perfused by the lateral thoracic or accessory lateral thoracic vessels, where these are absent, the thoracodorsal pedicle is the dominant blood supply; perforators from these vessels variably supply the overlying skin paddle. The flap has a long vascular pedicle and contains many lymph nodes80; there is freedom of design of the skin paddle and thus the resultant donor-site scar (Fig. 7, above). Versatility in flap design makes it suitable for both orthotopic and heterotopic flap placement81,112,113 (Fig. 7, below).
Gastroepiploic (Greater Omental) Lymph Node Flap
The omental flap has recently been revisited as a vascularized lymph node flap using microsurgical transfer, negating the many limitations of the pedicled flap.114 Within the omentum, several lymph nodes are clustered around the gastroepiploic vessels, allowing for bilateral or dual-level transfer on the right and left sides of the pedicle43,82,83,115–117 (Fig. 8). There is a low risk of causing abdominal complications, and there is no risk of donor-site lymphedema. Flap size can be tailored to the donor-site requirements, and limiting harvest to the right gastroepiploic lymph node packet reduces unwanted bulk and gastric morbidity43,85,118 (Fig. 9). Skin grafting may be required for distal extremity placement. Flap harvest is by means of a minilaparotomy or abdominoplasty approach, resulting in well-hidden scars, or by using laparoscopic techniques to reduce donor-site morbidity.
Jejunal Mesenteric Lymph Node Flap
The jejunal mesenteric lymph node flap has been described as both a flap harvested from the periphery of the mesentery,84 and from closer to the root of the mesentery85; the latter approach avoids the risk of disruption to the vascular supply to the adjacent bowel segment and subsequent ischemic bowel complications (Fig. 10, above), and a flow-through design is favored. The low flap bulk makes it suitable for distal extremity placement (Fig. 10, below); however, remote monitoring is typically required. Harvest is by means of a minilaparotomy or abdominoplasty approach.
Selection of Recipient Site
Decisions regarding vascularized lymph node flap selection relative to recipient-site location are individualized to the patient, taking into account the results of imaging, clinical examination findings, body habitus, and availability and quality of flap donor sites, in addition to patient and surgeon preferences. Following prior axillary lymphadenectomy, orthotopic vascularized lymph node transplant to the axilla allows for radical scar release and decompression of the subclavian vein, and the resultant scar and flap bulk are well-concealed within the axilla (Fig. 11); dead space is obliterated to prevent scar recurrence.74 In the setting of postmastectomy breast reconstruction, and when lymphedema predominantly affects the upper arm, this is typically achieved using a DIEP flap with chimeric groin vascularized lymph node transplant using the internal mammary recipient vessels. Alternative proximal recipient sites include the upper medial arm for the upper extremity and the medial thigh or inguinal region for the lower extremity.113
Whereas advanced-stage lymphedema predominantly affects the distal extremity, as lymphatic fluid transport is severely impaired, heterotopic nonanatomical lymph node placement allows for the fluid to be absorbed from the most gravity-dependent position of the limb.48,78,89,91,92 For the upper extremity, placement of the flap in the volar forearm conceals the flap bulk well. For the lower extremity, placement of the flap in the medial calf area achieves distal placement with acceptable cosmetic appearance.81 Localized debulking of fibroadipose soft tissues and the typically thickened deep fascia provides a pocket for the lymph node flap and may allow tension-free primary skin closure. Meticulous excision of perivascular scarring around the recipient veins is necessary to avoid venous hypertension. Low-volume flaps may achieve improved cosmesis in the setting of distal vascularized lymph node transplant, reducing the need for revision operations. Options for recipient-site selection relative to vascularized lymph node flap options to aid in decision-making are presented in Figure 12.
Where the entire extremity is affected, dual-level transfer may improve clinical outcomes by enhancing the lymphatic drainage throughout the affected limb; the intraabdominal donor site is well-suited for this requirement.43,84,119 For these more complex reconstructions, a two-team approach is preferable to reduce ischemic and operative time.
Postoperative Management for Vascularized Lymph Node Transplant Procedure
Antibiotics are indicated postoperatively to avoid cellulitis. The extremity is elevated postoperatively; distal lower extremity flaps may require a postoperative dangling protocol. Postoperative compression therapy may be reinstituted at 4 weeks postoperatively for approximately 6 months.23,72,81,119 Suction-assisted lipectomy of residual soft-tissue excess may be performed in staged fashion.120–122
CLINICAL OUTCOMES OF LYMPHOVENOUS BYPASS/VASCULARIZED LYMPH NODE TRANSPLANTATION PROCEDURES
Observational case-control and cohort studies support the efficacy of lymphovenous bypass and vascularized lymph node transplantation for lymphedema in reduction of limb volume and episodes of cellulitis (Tables 2 and 3). The available literature supports favorable limb volume reduction outcomes for both orthotopic22,23,73,123 and heterotopic48,75,89,98,124 lymph node flap transfer in both the upper and lower extremities (Table 3). Long-term outcomes data from recently described flaps and for dual-level (orthotopic and heterotopic) lymph node flap transfer are awaited.43,82,116,119
Table 2. -
Observational Case-Control Study Data of Outcomes of Surgical Interventions for Lymphedema
||Primary or Secondary
|Comparison of CDT with LVB and/or VLNT
||Dionyssiou et al., 201623
||•RCT: 18 patients treated with groin LN flap (to axilla)
•18 patients received 6 mo of CDT alone
|•Limb volume reduction greater in VLNT (57%) group than in CDT (18%) group
•Infective episodes significantly reduced in VLNT compared with CDT group
||Cheng et al., 201348
||•10 patients underwent groin LN flap (to wrist or elbow) (mean follow-up, 39.1 ± 15.7 mo)
•10 patients underwent CDT only
|•Mean circumferential measurement reduction rate significantly greater (40.4 ± 16.1%) in VLNT compared with CDT group (8.3 ± 34.7%; p = 0.02)
||Akita et al., 201444
||•29 patients underwent LVB surgery (mean follow-up, 12.0 ± 4.9 mo)
•24 patients underwent CDT alone (mean follow-up, 12.5 ± 7.7 mo)
|•In LVB group, LEL index of limb circumference significantly improved; ICG imaging improved in 17 patients; CDT discontinued in 13 and decreased in 4
•In CDT group, LEL index was similar; 15 had stable ICG imaging and 9 had deterioration, 4 of which increased compression therapy requirements
|Comparison of LVB with VLNT
||Engel et al., 2017124
||•37 patients underwent MBR (mean follow-up, 12.7 ± 1.8 mo
•87 patients did not undergo MBR (mean follow-up, 25.5 ± 8.9 mo)
•Outcomes of CDT alone, LVB, and VLNT compared (submental LN flap, n = 27; groin LN flap, n = 18; all transferred to wrist or elbow)
|•In both groups, mean circumferential reduction rates significantly greater with VLNT than with LVB or CDT
•CDT alone, 9.8 ± 2.5% (n = 30); LVB alone, 17.3 ± 6.0% (n = 23); VLNT alone, 34.0 ± 6.9% (n = 34)
•MBR plus CDT, 6.5 ± 2.7% (n = 22); MBR plus LVB, 10.7 ± 8.9% (n = 4); MBR plus VLNT, 24.4 ± 8.8% (n = 11)
•Iatrogenic LE lymphedema occurred in one patient
||Akita et al., 201545
||•13 patients underwent supraclavicular VLNT (to distal thigh or lower leg)
•43 patients underwent LVB
|•Improvement in circumference reduction rate using LEL index seen in both groups; however, significantly better in VLNT group
•ICG lymphography or lymphoscintigraphy improved in significantly more patients following VLNT (n = 7) than LVB (n = 10)
|Comparison of different VLN flaps
||Ciudad et al., 201743
||UE and LE
||Primary and secondary
||•Comparative outcomes between groin LN, supraclavicular LN, and gastroepiploic LN flaps with ISL stage II and III lymphedema (2-yr follow-up)
||•Similar good outcomes for patients with stage II disease [groin LN, 28.5 ± 7.8% (n = 10); supraclavicular LN, 26.2 ± 9.8% (n = 10); and gastroepiploic LN flap, 30.4 ± 7.3% (n = 25)]
•For stage III disease, results were modest, and nonsignificant for groin LN flap group [groin LN, 11.7 ± 10.2% (n = 3); supraclavicular LN, 18.9 ± 8.90% (n = 15); and gastroepiploic LN, 18.2 ± 11% (n = 17)]
•Complications: groin LN group, 30.8%; supraclavicular LN group, 28%; gastroepiploic LN flap group, 24%; no donor-site lymphedema
•In patients with prior cellulitis, no further episodes in 61.4%, and significant reduction in 27.7%
||Akita et al., 201774
||•13 patients underwent chimeric DIEP-groin LN flap (mean follow-up, 13.9 ± 6.5 mo)
•14 patients underwent groin LN flap alone (to axilla; mean follow-up, 13.2 ± 4.4 mo)
|•Mean circumference reduction rate using UEL index similar at 6 mo postoperatively: DIEP-groin group, 13.9 ± 4.1; groin LN group, 13.2 ± 1.5
•In DIEP-groin LN group, significant improvement using ICG lymphography in 6 patients; in groin LN flap–only group, significant improvement in 4 patients
•In DIEP-groin LN group, compression therapy discontinued in 6 patients, reduced in 4 patients; in groin LN flap–only group, compression therapy discontinued in 3 patients
RCT, randomized controlled trial; UE, upper extremity; LE, lower extremity; BCRL, breast cancer–related lymphedema; LVB, lymphovenous bypass; VLNT, vascularized lymph node transplant; CDT, complete decongestive therapy; LEL, lower extremity lymphedema; UEL, upper extremity lymphedema; MBR, microvascular breast reconstruction; ISL, International Society of Lymphology.
Table 3. -
Limb Volume Reduction Outcomes of Cohort Studies for Vascularized Lymph Node Flaps
||No. of Flaps
||Mean Limb Volume Reduction ± SD (%)
||Mean Follow-Up ± SD (mo)
|Gustafsson et al., 201898
||19.8 ± 9.2
|Gratzon et al., 201722
||Groin LN, n = 42; lateral thoracic LN, n = 5; supraclavicular LN, n = 3
|Dionyssiou et al., 201623
|Liu et al., 2018123
||47.1 ± 27.9
||22.1 ± 7.8
|Nguyen et al., 201573
||11 (range, 3–33)
|Lin et al., 200975
||50.5 ± 6.9
||56.3 ± 27.1
|Cheng et al., 201348
||Wrist, 8; elbow, 2
||40.4 ± 16.1
||39.1 ± 15.7
|Engel et al., 2017124
||Submental LN, n = 27; groin LN, n = 18
||Wrist, 31; elbow, 14
||Group I*, 34.0 ± 6.9; group II†, 24.9 ± 10.0
||19.1 ± 5.3
|Patel et al., 201536
||Groin LN, n = 13; submental LN, n = 2
||24.4 ± 14.7
||25.4 ± 8.4
|Patel et al., 201536
||35.2 ± 23.9
||16.1 ± 4
LN, lymph node; DIEP, deep inferior epigastric artery perforator; MS-TRAM, muscle-sparing transverse rectus abdominis myocutaneous.
*Thirty-four patients that received simultaneous microsurgical breast reconstruction.
†Eleven patients that underwent vascularized lymph node transplantation only.
SUCTION-ASSISTED LIPECTOMY DEBULKING PROCEDURE
The severe fibroadipose soft-tissue hypertrophy that occurs in chronic lymphedema can only be removed directly by lipectomy.24 Traditional excisional operations that result in unacceptable scarring and morbidity have been replaced except in severe cases by minimally invasive suction-assisted lipectomy125,126 (Fig. 13). Large-volume liposuction debulking provides only minimal physiologic improvement of the lymphatic system,127,128 and therefore patients need to wear compression garments lifelong to prevent recurrence. Selected patients may be candidates for staged physiologic surgery to reduce dependence on continuous compression garment use120,121 (Fig. 14).
Optimization with complete decongestive therapy is performed preoperatively until there is minimal or no pitting edema; then, custom compression garments are measured preoperatively (using the unaffected extremity as a template) and are applied intraoperatively. Tumescent liposuction is performed, and for large volumes, a tourniquet is used to reduce blood loss. Power-assisted devices are beneficial where the soft tissues are fibrous.
CLINICAL OUTCOMES OF SUCTION-ASSISTED LIPECTOMY DEBULKING PROCEDURE
Several studies have confirmed the efficacy and long-term stability of large-volume suction-assisted lipectomy debulking for reducing limb volume to that similar to the unaffected side for both the upper127,129,130 and lower128,131–133 extremities (Table 4). In addition, the incidence of cellulitis is reduced dramatically postoperatively.134
Table 4. -
Outcomes from Cohort Studies of the Suction-Assisted Lipectomy Debulking Procedure for Lymphedema
||No. of Patients
||Mean Limb Volume Reduction (%)
||Postoperative Time Interval (yr)
|Boyages et al., 2015127
||Upper, 15; lower, 6
||Upper, 90.2; lower, 88.2
|Damstra et al., 2009129
|Lamprou et al., 2017131
||Secondary, 101; primary, 79
|Stewart and Munnoch, 2017132
|Schaverien et al., 2012130
DIRECT EXCISIONAL DEBULKING PROCEDURES
For patients with large-volume advanced fibrotic disease, suction-assisted lipectomy is ineffective and excisional techniques are required. These include staged direct excision (modified Homan’s procedure) (Fig. 15),43,135,136 and, in extreme cases, excision and skin grafting (Charles procedure).137
ALGORITHMS FOR SURGICAL MANAGEMENT
Several algorithms have been described to aid in decision-making for surgical intervention for lymphedema,43,46,48,138 and treatment plans vary between institutions. Evidence supports that lymphovenous bypass is indicated for early-stage lymphedema, vascularized lymph node transplant for advanced lymphedema, and debulking procedures for excision of soft-tissue excess.34,37,38,43,46,48,138,139 The combination of de bulking, either before,140 synchronously with,43 or following120,121 vascularized lymph node transplant, extends indications for physiologic surgery to those with significant soft-tissue excess resulting from chronic lymphedema. In addition to previously published algorithms, an evidenced-based decision aid for patients presenting with symptoms of lymphedema is outlined in Figure 16.
ASSESSING OUTCOMES OF SURGICAL INTERVENTION
Outcome metrics for lymphatic surgery include limb volume, incidence of cellulitis, physiologic downstaging, and patient-reported outcomes. Change in limb volume is most commonly measured by limb circumferential measurements (including derived volumetric calculations) or by using a Perometer (Pero-System Messgeräte GmbH, Wuppertal, North Rhine-Westphalia, Germany). Bioimpedance spectroscopy can also be used to comparatively measure the extracellular fluid.141 Physiologic downstaging can be evaluated using either radioisotope lymphoscintigraphy or indocyanine green lymphography. The Lymphedema Quality of Life Tool, Upper Limb Lymphedema-27, and Lymphedema Life Impact Scale142 are validated tools for patient-reported outcomes in patients with lymphedema, and patient-reported functional disability can be measured using validated tools including the Disabilities of the Arm, Hand, and Shoulder questionnaire for the upper extremity, and the Lower Extremity Functional Scale for the lower extremity.
NEW AND EMERGING TREATMENTS
Several new and emerging therapies hold promise for the treatment of lymphedema.143 Mesenchymal stem cells can differentiate into functional lymphatic endothelial-like cells,144 and preliminary clinical research suggests that both bone marrow mesenchymal stem cells145,146 and adipose tissue–derived mesenchymal stem cells)147 may provide therapeutic benefit. Experimental studies using exogenous delivery of VEGF-C at supraphysiologic doses or gene therapy delivery with adenoviral vectors have demonstrated lymphangiogenesis and decreased lymphedema.148 Tacrolimus, which inhibits T-cell proliferation and differentiation, when applied topically, prevented the development of lymphedema in an experimental model.149 Leukotriene B4 levels are significantly elevated in postsurgical lymphedema,150 and antagonism by ketoprofen has demonstrated efficacy in experimental and clinical lymphedema.151,152 Specifically, Bestatin (Sigma-Aldrich, St. Louis, Mo.), an inhibitor of the biosynthetic enzyme for leukotriene B4, has demonstrated efficacy in experimental studies,150 and the results of clinical trials are awaited.
Surgical treatment is effective at alleviating the symptom burden, reducing the risk of cellulitis, and improving function and appearance in patients with lymphedema refractory to conservative treatment. Results from future comparative outcomes studies are awaited to better define surgical treatment algorithms, in particular for newer and combination therapies, and from clinical studies of novel surgical treatments and pharmaceutical therapeutics.
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