Surgical Prevention of Breast Cancer-Related Lymphedema: Delayed Distal Lymphaticovenicular Anastomosis– An Alternative to the Classic LYMPHA Technique

Breast cancer-related lymphedema (BCRL) is a devastating potential complication of axillary lymphadenectomy and radiotherapy. Several effective surgical treatment measures now exist, including lymphaticovenicular anastomosis (LVA), vascularized lymph node transplant (VLNT), and vascularized lymph vessel transplant (VLVT) for fluid-predominant disease, and liposuction and radical excision for solid-predominant disease. Super-microsurgical LVA is of particular interest, owing to its minimally invasive nature and highly favorable outcomes in the hands of experienced supermicrosurgeons. As LVA techniques are refined and improved, interest is rising in utilizing it to prevent the manifestation of disease in the first place. Lymphatic microsurgical preventive healing approach (LYMPHA), also known as immediate lymphatic reconstruction (ILR), is the most widely used approach. It involves performing axillary LVA immediately following axillary lymphadenectomy. While preliminary results are favorable, the high-pressure proximal axillary venous branches used in ILR and the site’s vulnerability to damage from radiotherapy endanger the long-term patency of these anastomoses. Moreover, a theoretical oncologic concern exists regarding creating a direct conduit for the remaining malignant cells in the axilla into the circulation. Finally, coordinating ILR with axillary lymphadenectomy creates significant logistical challenges. Delayed, distally-based LVA (DD-LVA) has emerged as an alternative method that avoids these issues. This article presents an overview of the development of preemptive lymphatic reconstruction, and the senior author’s approach to the novel technique of DD-LVA.

Vegfr3-tdTomato, a reporter mouse for microscopic visualization of lymphatic vessel by multiple modalities

Lymphatic vessels are indispensable for tissue fluid homeostasis, transport of solutes and dietary lipids and immune cell trafficking. In contrast to blood vessels, which are easily visible by their erythrocyte cargo, lymphatic vessels are not readily detected in the tissue context. Their invisibility interferes with the analysis of the three-dimensional lymph vessel structure in large tissue volumes and hampers dynamic intravital studies on lymphatic function and pathofunction. An approach to overcome these limitations are mouse models, which express transgenic fluorescent proteins under the control of tissue-specific promotor elements. We introduce here the BAC-transgenic mouse reporter strain Vegfr3-tdTomato that expresses a membrane-tagged version of tdTomato under control of Flt4 regulatory elements. Vegfr3-tdTomato mice inherited the reporter in a mendelian fashion and showed selective and stable fluorescence in the lymphatic vessels of multiple organs tested, including lung, kidney, heart, diaphragm, intestine, mesentery, liver and dermis. In this model, tdTomato expression was sufficient for direct visualisation of lymphatic vessels by epifluorescence microscopy. Furthermore, lymph vessels were readily visualized using a number of microscopic modalities including confocal laser scanning, light sheet fluorescence and two-photon microscopy. Due to the early onset of VEGFR-3 expression in venous embryonic vessels and the short maturation time of tdTomato, this reporter offers an interesting alternative to Prox1-promoter driven lymphatic reporter mice for instance to study the developmental differentiation of venous to lymphatic endothelial cells.

Using Computed Tomography Lymphography for Mapping of Sentinel Lymph Nodes in Patients with Breast Cancer

Objectives: In breast cancer surgery, the combined use of the dye method and radioisotope (RI) method is recommended for identifying sentinel lymph nodes. However, the RI method is difficult to license, expensive, and difficult to introduce. Thus, we introduced computed tomography lymphography (CTLG) and investigated the characteristics and usefulness of CTLG. Material and Methods: Among breast cancer patients who underwent surgery during a 6-year period from January 2013 to December 2018, CTLG was performed on 141 patients with clinically negative lymph node metastasis. These cases were then retrospectively investigated. The number and location of lymph vessel, true sentinel lymph nodes, and the positional relationships with surrounding muscles and blood vessels were confirmed from the constructed 3D images. The actual surgeries were then performed using a dye method with indigo carmine based on images obtained using CTLG. Results: CTLG was able to identify lymph vessels and true sentinel lymph nodes in 131 of the 141 cases (92.91%). There were 97 patients in whom the first true sentinel lymph node reached from the breast was one node, 30 with two nodes, and 4 with three nodes. Moreover, there were three cases in which sentinel lymph nodes were present at Level II. During surgery, sentinel lymph nodes were identified in 131 patients (92.91%) using dye. Conclusion: CTLG has a high identification rate in sentinel lymph nodes, and it is considered a convenient and useful examination method because a lot of information, such as the number and position of sentinel lymph nodes, can be obtained.

Impact of Magnetic Resonance Lymphography on Lymphaticolvenular Anastomosis for Lower-Limb Lymphedema

Background Although several investigations have described the safety, utility, and precision of magnetic resonance lymphography (MRL) as a preoperative examination for lymphaticovenular anastomosis (LVA), it is unclear how much MRL assistance impacts LVA results. The present study aimed to clarify the outcome of MRL-assisted LVA for leg lymphedema using body water measurements obtained by bioelectrical impedance analysis. Methods The water reductive effect of MRL-assisted LVA in female secondary leg lymphedema patients was compared with that of non-MRL-assisted controls in this retrospective study. In the MRL-assisted group, all LVA candidates underwent MRL prior to surgery, and the lymphatic vessels to be anastomosed were primarily determined by MRL findings. The body water composition of the treated legs was assessed before LVA and at 6 months postoperatively using a multi-frequency bioelectrical impedance analyzer. Results Twenty-three patients in the MRL-assisted study group and an equal number in the non-MRL-assisted control group were analyzed. Although mean leg water volume before LVA, mean excess water volume of the affected leg before LVA, and number of anastomoses created were comparable between the groups, the water volume reduction (1.02 L versus 0.49 L; 95% confidence interval [CI]: 0.03–1.03, p < 0.05) and edema reduction rate (46.7% versus 27.2%; 95% CI: 3.7–35.5%, p < 0.05) in the MRL-assisted group were significantly greater than in controls. Conclusion Preoperative MRL-assisted lymph vessel visualization and selection appeared to significantly enhance the water reductive effect of LVA for International Society of Lymphology classification stage 2 leg lymphedema. MRL also helped to reliably identify lymphatic vessels for anastomosis. Without increasing the number of anastomoses, LVA could be performed more effectively by better detecting stagnant lymphatic vessels using MRL.

Microsurgical techniques in the treatment of breast cancer-related lymphedema: a systematic review of efficacy and patient outcomes

Introduction Secondary lymphedema is the abnormal collection of lymphatic fluid within subcutaneous structures. Patients with lymphedema suffer a low quality of life. In our study, we aim to provide a systematic review of the current data on patient outcomes regarding breast cancer-related lymphedema (BCRL), and the most prevalent reconstructive techniques. Methods A PubMed (MEDLINE) and Scopus literature search was performed in September 2020. Studies were screened based on inclusion/exclusion criteria. The protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO), and it was reported in line with the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results The search yielded 254 papers from 2010 to 2020. 67 were included in our study. Lymphaticovenous anastomosis (LVA)—a minimally invasive procedure diverting the lymph into the dermal venous drainage system—combined with postoperative bandaging and compression garments yields superior results with minimal donor site lymphedema morbidity. Vascularized lymph node transfer (VLNT)—another microsurgical technique, often combined with autologous free flap breast reconstruction—improves lymphedema and brachial plexus neuropathies, and reduces the risk of cellulitis. The combination of LVA and VLNT or with other methods maximizes their effectiveness. Vascularized lymph vessel transfer (VLVT) consists of harvesting certain lymph vessels, sparing the donor site’s lymph nodes. Conclusion Together with integrated lymphedema therapy, proper staging, and appropriate selection of procedure, safe and efficient surgical techniques can be beneficial to many patients with BCRL.

Unusual Left Periclavicular Cutaneous Lymphatic Fistula After Port Explantation Without Lymph Vessel Injury: Imaging and Interventional Treatment

Complex oncological treatment can be associated with lymphatic vascular injury that is burdened by considerable morbidity. Lymphatic imaging and interventional techniques offer new minimally invasive treatment options. We report the case of a 59-year-old woman with an unusual lympho-veno-cutaneous fistula, diagnosed by magnetic resonance lymphangiography and treated by minimally invasive embolization therapy and venous recanalization.

Vegfr3-tdTomato, a reporter mouse for microscopic visualization of lymphatic vessel by multiple modalities

Lymphatic vessels are indispensable for tissue fluid homeostasis, transport of solutes and dietary lipids and immune cell trafficking. In contrast to blood vessels, which are easily visible by their erythrocyte cargo, lymphatic vessels are not readily detected in the tissue context. Their invisibility interferes with the analysis of the three-dimensional lymph vessel structure in large tissue volumes and hampers dynamic intravital studies on lymphatic function and pathofunction. An approach to overcome these limitations are mouse models, which express transgenic fluorescent proteins under the control of tissue-specific promotor elements.We introduce here the BAC-transgenic mouse reporter strain Vegfr3-tdTomato that expresses a membrane-tagged version of tdTomato under control of Flt4 regulatory elements. Vegfr3-tdTomato mice inherited the reporter in a mendelian fashion and showed selective and stable fluorescence in the lymphatic vessels of multiple organs tested, including lung, kidney, heart, diaphragm, intestine, mesentery and dermis. In this model, tdTomato expression was sufficient for direct visualisation of lymphatic vessels by epifluorescence microscopy. Furthermore, lymph vessels were readily visualized using a number of microscopic modalities including confocal laser scanning, light sheet fluorescence and two-photon microscopy. Due to the early onset of VEGFR-3 expression in venous embryonic vessels and the short maturation time of tdTomato, this reporter offers an interesting alternative to Prox1-promoter driven lymphatic reporter mice for instance to study the developmental differentiation of venous to lymphatic endothelial cells.