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BACKGROUND: Lymphedema is primarily treated conservatively using complex physical decongestion treatment (CDT). Lymphovenous anastomosis (LVA), vascularized lymph node transplantation (VLNT) and liposuction are available as surgical treatment methods; however, reimbursement in the diagnosis-related groups (DRG) system is sometimes inadequate or only possible following an individual application. The costs of these relatively new surgical procedures have not yet been set in relation to those of CDT. METHOD: The costs of conservative treatment were determined in accordance with the guidelines. The costs for LVA, VLNT and liposuction of the upper and lower extremities were estimated on the basis of the DRG reimbursement per case and the expected reduction in conservative measures according to current knowledge. The annual treatment costs were then compared. RESULTS: The annual treatment costs of LVA and VLNT are already lower than conservative treatment alone in the second postoperative year. Liposuction reaches this point in the 6th (upper extremity) or 47th postoperative year (lower extremity). CONCLUSION: The evidence for the positive effects of lymphatic surgery is still limited; however, it is recognizable that the curative surgical approach can significantly reduce the treatment costs and improve the quality of life of lymphedema patients; however, there is a lack of adequate reflection of the surgical effort in the reimbursement.

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Lymphadenectomy is a surgical procedure in which lymph nodes are surgically resected. It is usually carried out for oncological surgical treatment of various malignant diseases. These include carcinomas of the breast, penis, vulva and anus as well as malignant melanomas and the broad field of sarcomas. A distinction is made between the removal of regional lymph nodes, the sentinel lymph node and the radical removal of lymph nodes in a body region. Cervical, axillary, inguinal and iliac lymph nodes are clinically relevant. The strategy of sentinel lymph node dissection, in which the first lymph node in the drainage system is resected and histopathologically examined for malignant tissue, has brought decisive advantages for the patients, as radical lymphadenectomy with its severe morbidities is utilized in fewer cases. This can improve the patient's quality of life by sparing the lymphatic drainage pathways and reducing lymphedema, inflammation and wound healing disorders. In addition, a lymphadenectomy may be indicated as part of palliative interventions. Another form of lymph node removal is the vascularized lymph node transplantation, which is used for reconstructive purposes in lymphedema. Therefore lymph node grafts are transferred to the site where lymph nodes were previously removed. This review presents the current status of lymphadenectomy in accordance with the German guidelines, anatomical knowledge and specific indications for axillary, inguinal and iliac lymphadenectomy. In addition, an overview of vascularized lymph node transfer is given.

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Background: Despite the lymphatic system being so important and extensive, the field of lymphatic diseases, research is still very young. Lymphedema is a progressively debilitating condition with no known "cure." Specific pathologies that could benefit from improved lymphatic drainage by advanced super surgical techniques or engineered tissue transfer are being sought. Microsurgical techniques like lymphovenous bypass and anastomosis have spurred interest as they tend to physiologically restore the damaged lymphatic channels and may be a key to permanent cure. The latest in the field is vascularized lymph node transfer (VLNT), indicated in post mastectomy or other post operative settings producing disruption of regional lymphatic channels and draining lymph nodes. Autologous healthy lymph nodes are transferred along with surrounding fat and vascular pedicle to the affected limb in a bid to promote lymphangiogenesis. Lymphoscintigraphy (LS) is a simple, noninvasive nuclear technique used in identifying upper or lower limb lymphatic dysfunction and obstruction with a high degree of sensitivity. Quantitative LS is extremely useful in follow-up assessment of lymphedema postmanual lymphatic drainage (MLD) or other forms of medical management. Aim: We hypothesize that LS can document perinodal lymphangiogenesis post VLNT. Material and Methods: Three cases of acquired lymphedema (suspected filariasis and postmastectomy conditions) who underwent VLNT in our institute were prospectively studied with LS. The imaging findings highlight the subtle lymphatic regeneration along with the vascularized graft in all three patients during the early postoperative period. Conclusion: This is the first (pilot) study documenting early spontaneous perinodal lymphangiogenesis after VLNT in human subjects.99mTc Nanocolloid LS has been found to be incremental in demonstrating early lymphangiogenesis.

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Background: Transplantation of lymph nodes (LNs) is an increasingly popular option for treating lymphedema. Increasing evidence indicates an intrinsic correlation between estrogen signaling and the lymphatic system. We explored the effects of 17ß estradiol and antiestrogen treatment (tamoxifen) on the survival and functional restoration of transplanted popliteal lymph nodes (PLNs). Methods: A total of forty-eight ovariectomized mice were divided into three groups of 16: OVX + E2 (treated with 17ß-estradiol), OVX + TMX (treated with tamoxifen), and OVX (control; treated with olive oil as a solvent). After 2 weeks, PLNs were transplanted. Then, reconnections of lymphatic vessels were observed, and the morphology and survival of transplanted PLNs were evaluated 4 weeks after transplantation. T cells, B cells, lymphatic vessels, and high endothelial venules (HEVs) were subjected to immunofluorescence staining or immunohistochemical staining and quantified. Results: The percentage of lymphatic reconnections was 93.75% in the OVX + E2 group, 68.75% in the OVX + TMX group, and 75% in the OVX group. Surviving PLNs were observed in 16 of 16 in the OVX + E2 group, seven of 16 in the OVX + TMX group, and 13 of 16 in the OVX group. The mean size of PLNs in the largest cross section of the OVX + TMX group was significantly lower than that in the other groups. The distributions of B cells and T cells in surviving PLNs were similar to those in normal LNs. The ratio of dilated HEVs/total HEVs and density of lymphatic vessels in the OVX + E2 group were the highest among the three groups, whereas the lowest ratio and density were observed in the OVX + TMX group. Conclusion: Tamoxifen treatment might lead to cellular loss of transplanted LNs and interfere with the structural reconstruction and functional restoration, thereby inhibiting the survival of transplanted PLNs. Estrogen treatment facilitated the maintenance and regeneration of functional HEVs as well as lymphangiogenesis.

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BACKGROUND: Secondary lymphoedema is a challenging pandemic. This condition may arise after oncologic resection of tumor-draining lymph nodes and/or radiation. Plastic-surgical procedures for lymphoedema comprise transplantation of vascularized lymph node flaps, which are, however, technically challenging and difficult to implement on a global level due to the scarcity of microsurgery facilities in some countries. To improve this situation, comparative research in valid animal models is needed. METHODS: A total of 33 minipigs were subjected to lymphatic resection in the hind limbs. This large animal model was used in a first phase to compare different lymph node fragmentation methods and assess lymphatic regeneration after avascular transplantation. In a second phase, several stimulants were tested for their effect on lymphatic regeneration after fragment transplantation. In a third phase, animals additionally received irradiation of the groin. In this novel animal model, autologous avascular lymph node fragment transplantation was complemented by peripheral injections of vascular endothelial growth factor-C (VEGF-C). Finally, regeneration rates were quantified in relative numbers (percentage) in the irradiated tissue. RESULTS: In the first phase, transversal lymph node fragmentation under preservation of the nodal capsule showed the best percentage of regeneration (62.5%). Peripheral intradermal administration of VEGF-C enhanced lymph node fragment regeneration (70.8%) better than injections of tetanus toxoid (41.6%) or Streptococcus suis (62.5%). Lymph node fragment regeneration also occurred in an irradiated porcine model of lymphadenectomy under VEGF-C administration (66.6%). CONCLUSIONS: The present findings provide a pre-clinical proof-of-concept for a possible simplification strategy for current operative procedures of autologous lymph node transplantation.Level of evidence : Not gradable.

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The progress in the treatment of gynecological malignant tumours has prolonged the survival time of postoperative patients, but lower limb lymphedema as a complication has seriously affected the health and quality of life of postoperative patients. In recent years, secondary lymphedema of lower extremities after radical resection of gynecological malignant tumours has attracted more and more attention. This paper reviews the progress of surgical treatment, introduces the application, indications, existing issues and matters that requir attentions and various surgical methods, and to puts forward a possible development direction in the future.

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Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.

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Introduction Scarring and volume reduction of the axillary space resulting in persistent lymphedema is a side effect of axillary treatment in breast cancer patients. The aim of this paper is to describe the reduction of lymphedema achieved with a turnover flap. Materials and Methods Between October 2016 and May 2018, five patients with grade 2 lymphedema following breast cancer therapy underwent reconstructive surgery with a turnover flap. Complete excision of the symptomatic axillary scar tissue followed by re-augmentation using a turnover flap was performed. Subsequently, all patients underwent breast reconstruction using a distant flap reconnected to the thoracodorsal vessels. The circumference of both arms, quality of life and pain were measured before and after surgery. Results An average reduction in pain in the ipsilateral arm from 6 to 1 on the numerical scale as well as an improvement in quality of life (2.8 vs. 7.0) was observed. A decrease in lymphedema especially in the upper arm was identified. No complications such as secondary bleeding, infections or flap loss were observed. Conclusion Complete removal of the axillary scar tissue after breast cancer treatment and re-augmentation of the axilla with a turnover flap results in a reduction in ipsilateral lymphedema and an improvement in pain and quality of life. We interpret these findings as a result of the physiological re-alignment of the lymphatic vessels combined with a lymph node-containing local transposition flap. Therefore, re-augmentation with a turnover flap could be an effective non-microsurgical alternative to lymph node transplantation.

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BACKGROUND AND OBJECTIVES: Development of vascularized submental lymph node (VSLN) flap has encountered dilemmas; (a) whether to include skin paddle, (b) how to reduce the harvest area while gaining most lymph nodes. To answer, these structures were studied; submental perforator, lymph nodes in neck-level I and anterior belly of digastric muscle (ABDM). METHODS: Forty VSLN flaps were harvested from 23 cadavers. The lymph nodes and arterial supply were studied macro- and microscopically. The nodes were classified by arterial supplies, location along the longitudinal axis and relationship with ABDM. RESULTS: VSLN flap had 4.4 lymph nodes by average (range 1-8) predominantly located in the posterior three-quarter of the flap. Half of the submental perforators were originated deep to ABDM. they circumvent the muscle, supplied much of the nodes in neck sublevel Ia before reaching the skin. While sublevel Ib located the most surgically accessible submental nodes. Most of their arterial supply was branched from submental perforator lateral to ABDM, not directly from the submental artery. CONCLUSION: The flap could be reduced to the posterior three-quarter of the original area. Skin paddle should be included to serve as an indirect lymph node monitor. If Ia lymph nodes are to be included, ABDM should be sacrified.

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BACKGROUND: A physiological and minimal invasive form of surgery with minimal risk to treat lymphedemas is the so-called supermicrosurgical lymphovenous anastomosis (LVA) where a lymph vessel is connected with a venule. METHODS: 30 patients (between 2018 and 2019) with secondary upper extremity lymphedema refractory to conservative therapy (manual lymph drainage and compression therapy were operated using the "simplified lymphovenous anastomosis" method). For the assessment of lymphatic supermicrosurgery, an operating microscope in which a near-infrared illumination system is integrated (Leica M530 OHX with glow technology ULT530, Leica Microsystems) and the IC-FlowTM Imaging System(Diagnostic Green)/Visionsense System (Medtronic) together with a ZEISS S8 microscope was used. Augmented reality intraoperative indocyanin green (ICG) lymphography-navigated modified "simplified lymphovenous anastomosis" were performed on the Leica microscope. All patients were informed about Off-label-use of ICG lymphography. RESULTS: 57 LVAs were performed with modified "simplified lymphovenous anastomosis" lymphography-guidance on 30 upper extremities. All patients showed good patency after lymphovenous anastomosis. CONCLUSIONS: Supermicrosurgery in the case of LVA is minimally invasive, highly effective, and shows a very low complication rate. The surgeon/equipment-related factors restrict the pratice of LVA, and its effectiveness limited by technical constraints.

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BACKGROUND: A new technique named "Selected Lymph Node" ("SeLyN") was evaluated, aiming to identify the most functional groin lymph nodes (LNs) for an effective LN transplantation. METHODS: Bilateral lower-limb SPECT-CT was performed in the upper-limb lymphedema patients, to select the most radioactive inguinal LN. Recorded data included demographics, stage, etiology of lymphedema, flap consistency in accordance to preoperative findings, flap size, number of LN, and harvesting time. Infection episodes per year and volume changes of the upper limbs were documented. Donor-site complications were recorded and lower-limb evaluation was performed through clinical examination, volume analysis, and lymphoscintigraphy. RESULTS: A total of 41 patients underwent a "SeLyN" transfer technique. The mean flap size was 28.34 cm2 containing a mean of 3.4 LNs. The mean time spent on flap harvest was 39 minutes. A mean 56.5% volume reduction (P < .001) and a mean 1.41 to 0.29 infection episodes per patient per year (P < .001) were recorded. Clinical evaluation and lymphography of the donor site advocated no major complications for a mean follow-up period of 42.5 months. CONCLUSIONS: "SeLyN" is a safe and effective technique in selecting the most suitable LNs, minimizing the donor-site morbidity, and decreasing the overall operating time.

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Lymph node (LN) transplantation is a recognized method for reconstruction of the lymphatic system and is used in the clinical setting to treat lymphedema. However, it is unclear whether transplanted LNs contribute to immune surveillance. In our study, we investigated whether a single transplanted non-vascularized LN, defined as a tumor-draining transplanted lymph node (TDTLN), could exert an immune-mediated antitumor effect. LN and lung metastases and primary tumor enlargement were evaluated in mice that were inoculated with B16-F10-luc2 melanoma cells in a hind limb footpad without (group 1) and with (group 2) popliteal lymph node (PLN) resection and in mice that underwent LN transplantation after PLN resection (group 3). The function of a TDTLN (group 3) and a tumor-draining popliteal lymph node (TDPLN; group 1) was evaluated in the context of cancer. LN and lung metastases were significantly aggravated by PLN resection but were significantly decreased by LN transplantation. Immunohistochemistry showed that the TDTLNs retained T-cells and B-cells and fluorescence-activated cell sorting analysis confirmed expansion of lymphocytes in these nodes; however, the degree of expansion in TDTLNs was different from that in TDPLNs. Expression of cytokines associated with immunostimulation was confirmed in the TDTLNs as well as in the TDPLNs. One of the differences in the immune-mediated antitumor effect of the TDPLNs and TDTLNs was ascribed to a difference in the site of lymphocyte homing to peripheral LNs through high endothelial venules. Non-vascularized LN transplantation had an immune-mediated antitumor effect.

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BACKGROUND: Lymph node transplantation is being increasingly recognized as a method of reconstruction of the lymphatic system for the treatment of lymphedema. However, the mechanisms regulating the connections between the lymphatic vessels and the lymph nodes remain poorly understood. The objective of this study was to examine whether removal of a popliteal lymph node (PLN) could result in rerouting of lymph flow and whether a single transplanted nonvascularized lymph node could reconnect with a lymphatic vessel and restore lymph flow. METHODS AND RESULTS: Thirty-six mice were allocated to undergo resection of a PLN alone (group 1) or a transplanted lymph node after resection of a PLN (group 2). Changes in lymph flow were observed using indocyanine green dye. The ability of the transplanted lymph node to reconnect with the lymphatic vessels was examined by fluorescein isothiocyanate (FITC)-dextran and immunohistochemical staining. In group 1, the flow of lymph was redirected to an inguinal lymph node (ILN) in 8 of 18 mice and continued to drain to the PLN in 10 mice. In group 2, the lymph continued to drain normally after removal of the PLN, and was also directed to an ILN in two mice. FITC-dextran demonstrated continuity of the transplanted PLN and the lymphatic vessels. Immunohistochemical staining showed that T cell and B cell populations in the transplanted lymph node were preserved. CONCLUSION: Lymphatic flow was rerouted after lymph node resection. A transplanted lymph node can be made viable with normal lymph flow by reconnecting the transplanted lymph node to a lymphatic vessel.

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BACKGROUND: Free vascularized lymph node transfer (VLNT) is a relatively novel technique for treatment of lymphedema. The purpose of this systematic review was to evaluate the current evidence on VLNT and to determine if there is objective data concerning improved outcomes. METHODS: A literature search of PubMed, EMBASE and CENTRAL electronic databases was conducted to identify articles written in the English language on VLNT for treatment of lymphedema. Publications were selected according to inclusion criteria. Papers reporting adjunct techniques and those that did not describe outcomes were excluded. Data including patient demographics, surgical technique, complications and outcomes were extracted. A quality score was calculated for each article. RESULTS: Eighteen studies were included with an overall study population of 305 patients. Mean quality score of articles was 5.3 with levels of evidence range from II to IV. Among 182 patients who underwent limb circumference assessment, 165 (91%) showed postoperative improvement. Reduction of limb volume was noted in 98 of 114 (86%) patients. Ninety two patients underwent lymphoscintigraphy/lymphangiography and 55 (60%) demonstrated moderate or significant improvement of flow. Patient satisfaction was questioned in 105 patients and with exception of 7 patients, all reported a high satisfaction level with significant relief in symptoms and improved quality of life. Publications also reported a reduction in infectious episodes. CONCLUSION: VLNT appears to provide improvement in lymphedema. More studies with standardized methods for reporting outcomes and uniform patient selection are needed to evaluate this technique thoroughly.

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Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

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BACKGROUND: A limited number of lymph node flap models are available in rats, and none of them include a skin paddle. The aim of this study was to describe a new cervical lymph node-adipo-cutaneous flap model in the rat for future experimental studies. MATERIAL AND METHODS: Fifteen Wistar rats were used. In four, neck anatomy was investigated with special focus on cervical lymph nodes. In eleven rats, a lymph node flap with a skin paddle of 1.5 × 0.5 cm centered along the surface projection of the innominate septum was harvested and transferred to the inguinal region. The rats were followed-up for 7 d. At 30-d postoperatively, the lymphatic flow restoration with the recipient limb lymphatics was assessed with methylene blue, and histology was performed on excised flaps. RESULTS: According to the anatomic findings, the flap was based on an innominate septum which was a well-defined adipofascial structure containing glandular vessels to the surrounding tissues and located between submandibular-sublingual glandular complex and parotid gland. Flap's microvascular and lymph node anatomy (two to three lymph nodes) was constant. Donor-site morbidity was minimal, and all flaps survived. At 30-d postoperatively, the restoration of the lymphatic flow with the recipient limb lymphatics was observed, and histology revealed viable lymph nodes. CONCLUSIONS: The constant anatomy, the possibility to include a skin paddle and the minimal donor-site morbidity, make this flap a safe, reliable, and versatile lymph node flap supermicrosurgical model for autologous transplant in the rat for future experimental studies.

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BACKGROUND: Chronic secondary lymphedema is a well-known complication in oncologic surgery. Autologous lymph node transplantation, lymphovenous anastomosis, and other lymphatic surgeries have been developed in the last decades with rising clinical application. Animal models to explore the pathophysiology of lymphedema and microsurgical interventions have reached great popularity, although the induction of stable lymphedema in animals is still challenging. The aim of this review was to systematically assess lymphedema animal models and their potential use to study surgical interventions. MATERIALS AND METHODS: A systematic review according to the PRISMA guidelines was performed without time or language restriction. Studies describing new or partially new models were included in chronological order. Models for primary and secondary lymphedema were assessed, and their potential for surgical procedures was evaluated. RESULTS: The systematic search yielded 8590 discrete articles. Of 180 articles included on basis of title, 84 were excluded after abstract review. Ninety-six were included in the final analysis with 24 key articles. CONCLUSIONS: No animal model is perfect, and many models show spontaneous lymphedema resolution. The rodent limb appears to be the most eligible animal model for experimental reconstruction of the lymphatic function as it is well accessible for vascularized tissue transfer. There is a need for standardized parameters in experimental lymphedema quantification. Also, more permanent models to study the effect of free vascularized lymph node transfer are needed.

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Primary lower-limb lymphoedema is a chronic, progressive and debilitating condition with a difficult management, especially in advanced cases (elephantiasis). Recently, autologous lymph node transplantation (ALNT) appears to be a promising treatment for extremity lymphoedema. A case of a double ALNT for an advanced primary lower-limb lymphoedema is here reported: a contralateral inguinal lymph node flap was transferred to the knee and, in a second surgery, a thoracic lymph node flap was transplanted to the inguinal region. Clinical outcomes at 5 months postoperatively are very satisfactory with reduction in limb circumferences and improvement in skin quality and social impairment.

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