[Research progress of combined surgical treatment of lymphedema based on vascularized lymph node transfer].

Objective: To summarize the research progress of combined surgical treatment of lymphedema based on vascularized lymph node transfer (VLNT), and to provide systematic information for combined surgical treatment of lymphedema. Methods: Literature on VLNT in recent years was extensively reviewed, and the history, treatment mechanism, and clinical application of VLNT were summarized, with emphasis on the research progress of VLNT combined with other surgical methods. Results: VLNT is a physiological operation to restore lymphatic drainage. Multiple lymph node donor sites have been developed clinically, and two hypotheses have been proposed to explain its mechanism for the treatment of lymphedema. But it has some inadequacies such as slow effect and limb volume reduction rate less than 60%. To address these inadequacies, VLNT combined with other surgical methods for lymphedema has become a trend. VLNT can be used in combination with lymphovenous anastomosis (LVA), liposuction, debulking operation, breast reconstruction, and tissue engineered material, which have been shown to reduce the volume of affected limbs, reduce the incidence of cellulitis, and improve patients' quality of life. Conclusion: Current evidence shows that VLNT is safe and feasible in combination with LVA, liposuction, debulking operation, breast reconstruction, and tissue engineered material. However, many issues need to be solved, including the sequence of two surgeries, the interval between two surgeries, and the effectiveness compared with surgery alone. Rigorous standardized clinical studies need to be designed to confirm the efficacy of VLNT alone or in combination, and to further discuss the subsistent issues in the use of combination therapy.

Post-traumatic lymphedema treatment with superficial circumflex iliac artery perforator lymphatic free flap: A case report.

Post-traumatic lymphedema is poorly understood. It is rarely considered in limb reconstruction decision-making approach. We report a case of a 41-year-old female who presented with right upper extremity lymphedema after degloving injury and split thickness skin graft, successfully treated with a superficial circumflex iliac artery perforator (SCIP) free flap restoring the lymphatic drainage. Right upper extremity had an excess of 258.7 mL or an excess volume of 27.86% compared to the healthy contralateral limb. A SCIP free flap including lymphatic vessels (SCIP-L) was performed to replace the skin graft in order to restore the lymphatic flow. Flap size was 19 × 8 cm and pedicle length was 4 cm. No lymph nodes were included and no lymphatic or lymphovenous anastomoses were performed. The surgery was uneventful, and there were no postoperative complications. Fourteen days after free tissue transfer, lymphedema showed clear improvement. At a 4-month follow-up, 55.6% reduction of excess volume was obtained. Indocyanine green lymphography performed at that time showed a restitution of lymph flow through the flap. Lymphedema improvements persisted at a 6-month follow-up. A successful treatment of post-traumatic lymphedema can be performed by using the SCIP-L free flap for soft tissue reconstruction of critical lymphatic drainage areas.

Surgical interventions for the prevention or treatment of lymphoedema after breast cancer treatment.

BACKGROUND: Breast cancer is the most common type of cancer amongst women worldwide, and one distressing complication of breast cancer treatment is breast and upper-limb lymphoedema. There is uncertainty regarding the effectiveness of surgical interventions in both the prevention and management of lymphoedema affecting the arm after breast cancer treatment. OBJECTIVES: 1. To assess and compare the efficacy of surgical interventions for the prevention of the development of lymphoedema (LE) in the arm after breast cancer treatment.2. To assess and compare the efficacy of surgical interventions for the treatment of established LE in the arm after breast cancer treatment. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for all prospectively registered and ongoing trials on 2 November 2017. Reference lists of included studies were also handsearched by three review authors for additional eligible trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing a surgical intervention for the prevention or treatment of lymphoedema of the arm after breast cancer treatment to either standard intervention, placebo intervention, or another surgical intervention were included. Patients of both sexes and all ages who have had treatment for their breast cancer were considered. No limits were applied to language or study location. Three authors independently determined the eligibility of each study. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data for each included study using a pre-designed data extraction pro forma and used Cochrane's 'risk of bias' tool for assessing risk of bias. Dichotomous variables were analysed using the Mantel-Haenszel method to estimate risk ratios (RRs). Differences in continuous variables were expressed as mean differences (MDs). GRADE was used to assess the certainty of the evidence provided by the included studies. MAIN RESULTS: Two studies involving 95 participants examined surgical interventions for preventing breast cancer-related lymphoedema. Both studies evaluated the efficacy of the lymphaticovenular anastomosis technique as part of a preventative management protocol. Both studies were deemed to be at unclear risk of bias overall. Statistical variation between the studies was low, which increases the reliability of the evidence. However, the two studies were conducted in the same centre. Lymphaticovenular anastomosis appears to result in a reduction in the incidence of lymphoedema compared to nonoperative management with a risk ratio of 0.20 (95% CI 0.06 to 0.63, P = 0.006; 95 participants; low-certainty evidence). The RCTs did not evaluate any of the secondary outcomes.One study involving 36 participants evaluated the effectiveness of vascularised lymph node transfer for treating breast cancer-related lymphoedema. The trial was deemed to be at unclear risk of bias. For participants suffering from stage 2 lymphoedema, the evidence suggested reductions in limb volume (MD -39.00%, 95% CI -47.37% to -30.63%, very low-certainty evidence), pain scores (MD -4.16, 95% CI -5.17 to -3.15, very low-certainty evidence), heaviness sensation (MD -4.27, 95% CI -5.74 to -2.80, very low-certainty evidence), mean number of infections/year (MD -1.22, 95% CI -2.00 to -0.44, very low-certainty evidence), and an improvement in overall function scores (MD -3.77, 95% CI -4.89 to -2.65, very low-certainty evidence) for those who had undergone vascularised lymph node transfer compared to those who had undergone no treatment. AUTHORS' CONCLUSIONS: There is low-certainty evidence that lymphaticovenular anastomosis is effective in preventing the development of lymphoedema after breast cancer treatment based on the findings from two studies. One study providing very low-certainty evidence found that vascularised lymph node transfer is an efficacious option in the treatment of established stage 2 lymphoedema related to breast cancer. Important secondary outcomes in this review were rarely reported in the included studies. More high-quality RCTs are required to further elucidate the effectiveness of surgical interventions in the prevention and treatment of lymphoedema after breast cancer treatment. At the time of this review, no ongoing trials on this topic were identified.

Outcomes in Vascularized Lymph Node Transplantation in Rabbits: A Reliable Model for Improving the Surgical Approach to Lymphedema.

Background: Conservative nonsurgical treatment has traditionally been applied to lymphedema. Early surgical procedures were invasive and disfiguring and their long-term success was often limited. In contrast, contemporary surgical techniques are much less invasive and have been shown to be effective in reducing excess limb volume, the risk of cellulitis, and the need for compression garments. Microsurgical procedures such as lymphovenous anastomosis and vascularized lymph node transfer can treat the excess fluid component of lymphedema and are gaining in popularity. In this study, we first evaluate the possibility of generating lymphedema in the hind limb of a rabbit and then describe its treatment with microsurgical lymph node transfer without lymph vessel transfer. Methods and Results: In experimental rabbit models, animals first underwent surgery in which the popliteal lymph node was removed to create lymphedema in the hind limb. After 15 days, another operation was performed to excise the contralateral popliteal lymph node and transfer it to the limb with lymphedema. Our model showed that lymph node transfer was able to reduce lymphedema in the rabbit's hind limb; intervened hind limb: basal volume (51.94 ± 11.23), volume day transfer (73.40 ± 26.47), and final volume (50.13 ± 12). Conclusion: We have developed a feasible model to microsurgically induce and treat lymphedema by lymph node transfer that shows promising results.

Transplantation of artificial human lymphatic vascular tissues fabricated using a cell-accumulation technique and their engraftment in mouse tissue with vascular remodelling.

Transplantation of engineered tissues with microvascular structure is advancing towards therapeutic application to improve the flow of blood and/or lymphatic fluids. In lymphatic disorders, transplantation of tissue-engineered lymphatic grafts can be an ideal treatment for draining excessive lymphatic fluid. In this study, we examined the transplantation of 3-dimensional artificial human lymphatic network tissue (AHLT) fabricated by the cell accumulation technique into the subcutaneous tissue and fascia of mice. At 2 weeks after transplantation, the AHLT showed engraftment of artificial lymphatic vessels immunopositive for human CD31 and human podoplanin. Notably, we also observed the generation of blood vessel-like structure comprising endothelial cells immunopositive for human CD34 and mural-like cells immunopositive for human CD90 and αSMA, which were considered as myofibroblasts. In the fabrication of AHLT in vitro, the sporadic emergence of human CD34-positive/Prox-1-negative sites was observed, followed by the formation of blood vessel-like structure in the graft within 7 days after transplantation. The fine structure of engrafted AHLT observed by transmission electron microscopy showed that the engrafted artificial lymphatic vessels possess the specific structures of native lymphatic capillaries such as loose interendothelial connections and anchoring filaments. In contrast, blood vessel-like structure showed tight interendothelial connections, thick basement membranes, and layers of mural-like cells, which resemble small blood vessels. These results suggested the remodelling of artificial lymphatic network to form blood vessel-like structure associated with mural-like cells along with AHLT fabrication and engraftment.

The lymphatic superficial circumflex iliac vessels deep branch perforator flap: A new preventive approach to lower limb lymphedema after groin dissection-preliminary evidence.

OBJECTIVE: Groin dissection is the procedure with the highest risk of lower limb lymphedema.As lymph stasis causes irreversible alterations to the limb over time,therapies should be administered in early stages,or better yet, lymphatic drainage impairment should be prevented.We developed a new preventive approach to lymphedema after groin dissection, and we report our preliminary experience. PATIENTS AND METHODS: We enrolled 5 patients undergoing bilateral groin dissection for vulvar cancer. Preoperative study of lower limbs lymphatic function was obtained by lymphoscintigraphy, with lymphatic transport index, indocyanine green (ICG) lymphography, and volume measurement with lower extremity lymphedema (LEL) index calculation. At the end of lymphadenectomy, one groin was closed in the standard way. On the other side, a lymphatic flap pedicled on the distal perforator of the deep branch of the superficial circumflex iliac vessels, was transposed into the groin region. Lymphatic function examination of the limbs was repeated 6 months after surgery. RESULTS: Before surgery no patient showed lymphatic drainage impairment at lymphoscintigraphy or lymphography, LEL index was in every limb lower than 250 (mean: 217.3 ± 13.83). After surgery the limbs treated with the flap showed no pathological swelling, LEL-index < 250 (mean: 235.4 ± 13.069), linear pattern at lymphography, and normal lymphoscintigraphy. The untreated limbs showed from moderate to severe edema with 265 < LEL-index < 310 (mean: 283 ± 16.3), diffuse dermal backflow at lymphography and interruption of lymph flow, with dermal backflow, at lymphoscintigraphy. Mean difference between preoperative and postoperative volumes was 64.8 ± 25.1 in the untreated side and 19 ± 11.7 in the side with the flap. The difference between preoperative and postoperative volumes compared between the treated and untreated side was statistically significant (P < .01). CONCLUSION: Our preliminary evidence suggests that this flap can prevent lymphedema after groin dissection. Further studies are necessary to confirm these results.

Microsurgical Lymphatic Vessel Transplantation.

BACKGROUND: Lymphedema often arises after a regional interruption during cancer treatment, for example after lymph node resection the axilla or the groin. Lymphatic vessels as vascular grafts may overcome these lymphatic gaps. METHOD: Experiments in rats and dogs were performed for developing this method. Volume measurements, lymphoscintigraphies, proof of patency by MRI and radiology as well as quality of life studies were performed in patients. RESULTS: Long-term follow-up studies revealed significantly reduced volumes, significant improvement of lymphatic outflow shown by lymphoscintigraphy, long-term patency of the grafts for more than 10 years, and improved quality of life after surgery compared with the situation with conservative treatment before surgery. CONCLUSION: Vascular grafts using the patients own lymphatic vessels are able to successfully reconstruct a locally interrupted lymphatic pathway.

Modified lymph vessel flap transplantation for the treatment of refractory lymphedema: A case report.

Lymph vessel flap transplantation (LFT), lymphaticovenous anastomosis (LVA), or lymph node flap transfer are sometimes used to treat lymphedema that is resistant to conservative treatment. LFT harvested from the contralateral limb has been reported for the treatment of lymphedema. Here we report the use of modified LFT from the abdominal wall for the treatment of refractory lymphedema. Our patient was a 57-year-old patient with secondary lower limb lymphedema was previously treated with conservative therapy and lymphaticovenous anastomosis. We first examined the lymphatic function of the lower abdominal region in the patient using indocyanine green (ICG) lymphography. After confirming the good lymphatic function in the right abdominal region, we harvested the pedicled abdominal adiposal flap containing multiple abdominal lymph vessels and transferred it to the left groin region. The flap (20 × 10 cm2 ) was based on the superficial circumflex iliac artery perforator. We anastomosed one lymph vessel in the flap to that in the recipient site. We also performed multiple fibrotripsy using a 3-mm-diameter stainless steel stick inserted into small incisions. The postoperative course was uneventful. The circumference measurement was decreased by 2.2-13.5 cm at 1 year after the operation. The lower abdominal region has many lymph vessel networks and is thought to be a less risky donor site in patients with lymphedema than the lower limbs. Thus, LFT may be an option for the treatment of chronic lymphedema. © 2015 Wiley Periodicals, Inc. Microsurgery 36:695-699, 2016.

[Microsurgical Autologous Lymph Vessel Transplantation: Does Harvesting Lymphatic Vessel Grafts Induce Lymphatic Transport Disturbances in the Donor Limb?]. / Mikrochirurgische autologe Lymphgefäß-Transplantation: Verursacht die Entnahme von Lymphgefäß-Transplantaten Lymphtransportstörungen an der Spenderextremität?

OBJECTIVE: The aim of this study was to determine whether the extirpation of lymphatic vessels induces lymphatic transport disturbances in the donor limb of patients following the harvest of lymph vessel grafts. PATIENTS, MATERIAL AND METHODS: A total of 19 consecutive patients (15 females, 4 males; mean age 51.5 years, range 21.8-72.3) were examined by lymphoscintigraphy before and after surgery. The patients had previously been diagnosed with upper or lower limb lymphoedema in accordance with the criteria of the International Society of Lymphology, and autologous lymph vessel transplantation had been intended for treatment. Since only patients with normal scintigraphic tests at the harvesting site were considered for treatment, all consecutive patients (n=19) had normal scintigraphic tests of the donor limb prior to surgery. In order to quantify the visual scintigraphic findings, a well established numeric transport index (TI) was used, which combined 5 visual parameters of transport kinetics. To that end, the following visually assessed criteria were evaluated: temporal and spatial kinetics, radiopharmaceutical distribution pattern, time to appearance of inguinal lymph nodes, qualitative visualisation of lymph nodes and lymph vessels. RESULTS: All patients underwent a preoperative scintigraphic baseline study and a postoperative scintigraphic follow-up after autologous lymphatic vessel grafting. The mean time period from the baseline study to the date of microsurgical lymph vessel transplantation was 3.5 months (median 2.5 months). The scintigraphic follow-up was performed 48.6 months (median 57.8 months) following transplantation. In all patients the postoperative TI was very close to the TI calculated in the preoperative baseline scintigraphy, and all TIs were within the normal range (TI<10). The absolute value of deviation of pre- vs. post-operative transport indices was calculated to be 0.2 on average (maximum 0.4). CONCLUSIONS: The results show that microsurgical transfer of lymph vessel grafts is possible without compromising lymphatic drainage of the donor limb if safety precautions are taken into account.

Modern surgical management of breast cancer therapy related upper limb and breast lymphoedema.

Breast cancer is the commonest cancer in the UK. Advances in breast cancer treatment means that the sequelae of treatment are affecting more women and for a longer duration. Lymphoedema is one such sequela, with wide-ranging implications, from serious functional and psychological effects at the individual level to wider economic burdens to society. Breast cancer-related lymphoedema is principally managed by conservative therapy comprising compression garments and manual decongestive massage. This approach is effective for early stages of lymphoedema, but it is not curative and the effectiveness depends on patient compliance. Early surgical approaches were ablative, gave significant morbidity and hence, reserved for the most severe cases of refractory lymphoedema. However, recent non-ablative reconstructive surgical approaches have seen a revival of interest in the prevention or surgical management of breast cancer-related lymphoedema. This review examines the modern surgical techniques for the treatment of breast cancer-related lymphoedema. Liposuction reduces the volume and symptoms of lymphedema, but requires continual compressive therapy to avoid recurrence. Lymphatic reconstruction or bypass techniques including lymph node transfer (inguinal nodes are transferred to the affected limb), lymphatico-lymphatic bypass (lymphatics bypass the axilla using a lymph vessel graft reconstructing lymphatic flow from arm to neck) and lymphaticovenous anastomoses (lymphatics in the arm are joined to the venous system aiding lymph drainage) show promise in reducing lymphedema significantly. Further research is required, including into the role of primary lymphaticovenous anastomoses in the prevention of lymphedema at the time of axillary dissection.

Lymphedema of the upper limb: evaluation of the functional outcome by dynamic imaging of lymph kinetics after autologous lymph vessel transplantation.

PURPOSE: The aim of this study was to evaluate by lymphoscintigraphy the functional outcome after autologous lymph vessel transplantation (Tx) of the upper limb. METHODS: One hundred seventy-seven patients (172 female, 5 male; median age, 56 years; range, 12-84 years) presenting with Tx situs in an upper limb were included. For correlation of scintigraphic data versus reduction of volume (RV) surplus measurements, we examined at 4 different time points as follows: preoperatively (T0), within 2 weeks after Tx (T1), 6 to 12 months after Tx (T2), and 32 to 38 months after Tx (T3). An additional long-term follow-up after at least 8 years (T4) was available in some cases. RESULTS: The maximum individual postoperative observation period was 19 years. In 169 of 177 cases, lymphedema had been caused by treatment of breast cancer (mastectomy, n = 103/169; breast preserving, n = 66/169) and/or radiation therapy (n = 130/177), but 2 patients presented with primary lymphedema. The remaining 6 cases of lymphatic disorders were caused by treatment of malignant melanoma, Hodgkin lymphoma, axillary Ewing sarcoma, non-Hodgkin lymphoma, hemangioma, or abscess removal.At T1, the mean RV of the affected limb was 73%, and the mean improvement of transport index (TI) was 28%. At T2, the RV was 64% and the TI was 23%, and at T3, the RV was 63% and the TI was 25%. Long-term follow-up after at least 8 years (T4: range, 9-19.2; mean, 14.1 years) was available in 19 of 177 patients, in whom persistent improvement in the scintigraphic data (25% decrease in TI) was confirmed by a mean clinical RV of 68%. The mean overall correlation was by a factor of 2.64. CONCLUSIONS: Our findings in this large set of patients undergoing autologous lymph vessel Tx to an upper limb confirm that this microsurgical technique significantly and persistently improves lymph drainage in patients with lymphedema. The findings of lymphoscintigraphy correlated well with volume measurements at long-term follow-up.

Tissue-engineered lymphatic graft for the treatment of lymphedema.

BACKGROUND: Lymphedema is a chronic debilitating condition and curative treatment is yet to be found. Tissue engineering approach, which combines cellular components, scaffold, and molecular signals hold great potential in the treatment of secondary lymphedema with the advent of lymphatic graft to reconstruct damaged collecting lymphatic vessel. This review highlights the ideal characteristics of lymphatic graft, the limitation and challenges faced, and the approaches in developing tissue-engineered lymphatic graft. METHODS: Literature on tissue engineering of lymphatic system and lymphatic tissue biology was reviewed. RESULTS: The prime challenge in the design and manufacturing of this graft is producing endothelialized conduit with intraluminal valves. Suitable scaffold material is needed to ensure stability and functionality of the construct. Endothelialization of the construct can be enhanced via biofunctionalization and nanotopography, which mimics extracellular matrix. Nanocomposite polymers with improved performance over existing biomaterials are likely to benefit the development of lymphatic graft. CONCLUSIONS: With the in-depth understanding of tissue engineering, nanotechnology, and improved knowledge on the biology of lymphatic regeneration, the aspiration to develop successful lymphatic graft is well achievable.

Microsurgical techniques for the treatment of breast cancer-related lymphedema: a systematic review.

BACKGROUND: Upper limb lymphedema is one of the most underestimated and debilitating complications of breast cancer treatment. The aim of this review is to summarize the recent literature for evidence of the effectiveness of lymphatic microsurgery for the treatment of breast cancer-related lymphedema (BCRL). METHODS: A search was conducted for articles published from January 2000 until January 2012. Only studies on secondary lymphedema after breast cancer treatment and those examining the effectiveness of microsurgery were included. RESULTS: No randomized clinical trials or comparative studies were available. Ten case-series met inclusion criteria: (composite) tissue transfer (n = 4), lymphatic vessel transfer (n = 2), and derivative microlymphatic surgery (n = 4). Limb volume/circumference reduction varied from 2 to 50% over a follow-up time ranging from 1 to 132 months. Postoperative discontinuation rates of conservative therapy were only reported after composite tissue transfer, ranging from 33 to 100% after 3 to 24 months. Clear selection criteria for lymphatic surgery and lymphatic flow assessment were absent in most studies. CONCLUSION: We identified important methodological shortcomings of the available literature. Evidence acquired through comparative studies with uniform patient selection is lacking. Consistent positive findings with regards to limb volume reduction and limited complications are reasons to further explore these techniques in methodologically superior studies.

[In search of the ideal surgical treatment for lymphedema. Report of 2nd European Conference on supermicrosurgery (Barcelona - March 2012)]. / À la recherche d'un traitement idéal du lymphœdème. Compte-rendu de la 2(e) Conférence européenne de supermicrochirurgie (Barcelone - Mars 2012).

Since more than 50 years, many surgeons all around the world try to find the perfect surgical technique to treat limb lymphedemas. Decongestive physiotherapy associated with the use of a compressive garment has been the primary choice for lymphedema treatment. Many different surgical techniques have been developed, however, to date, there is no consensus on surgical procedure. Most surgical experts of lymphedema met in the second European Conference on supermicrosurgery, organized on March 1st and 2nd 2012, in San Pau Hospital, Barcelona. Together they tried to clarify these different options and ideally a strategy for using these techniques.

Infrared fluorescence imaging of lymphatic regeneration in nonhuman primate facial vascularized composite allografts.

BACKGROUND: Clinical vascularized composite allografts (VCA), although performed with good success, have been characterized by rejection episodes and postoperative graft edema. We investigated lymphatic donor-recipient reconstitution and lymphatic regeneration in a nonhuman primate facial VCA model. METHODS: Heterotopic partial face (n = 9) VCAs were performed in cynomolgus macaques. Grafts were monitored for rejection episodes and response to immunosuppressive therapies as previously described. Donor and recipient lymphatic channels were evaluated using a near-infrared handheld dual-channel light-emitting diode camera system capable of detecting fluorescence from indocyanine green injections. Graft lymphatic channels were serially evaluated from postoperative day 0 to 364. RESULTS: Preoperative imaging demonstrated superficial lymphatic anatomy similar to human anatomy. Initial resolution of facial allograft swelling coincided with superficial donor-recipient lymphatic channel reconstitution. Reconstitution occurred despite early acute rejection episodes in 2 animals. However, lymphatic channels demonstrated persistent functional and anatomic pathology, and graft edema never fully resolved. No differences in lymphatic channels were noted between grafts that developed transplant vasculopathy (n = 3) and those that did not (n = 6). Dynamic changes in patterns of lymphatic drainage were noted in 4 animals following withdrawal of immunosuppression. CONCLUSIONS: Donor-recipient lymphatic channel regeneration following VCA did not result in resolution of edema. Technical causes of graft edema may be overcome with alternative surgical techniques, allowing for direct investigation of the immunologic relationship between VCA graft edema and rejection responses. Mechanisms and timing of dynamic donor-recipient lymphatic channel relationships can be evaluated using fluorescent imaging systems to better define the immunologic role of lymphatic channels in VCA engraftment and rejection responses, which may have direct clinical implications.