Publications

PURPOSE: Regional nodal irradiation (RNI) increases breast cancer-related lymphedema (BCRL) following axillary lymph node dissection despite immediate lymphatic reconstruction (ILR). This study examines the relationship between radiation (RT) dose to the ILR anastomosis and BCRL.

METHODS AND MATERIALS: This prospective study included 23 patients with invasive breast cancer who underwent axillary lymph node dissection/ILR followed by RNI. The anastomosis was indicated by a twirl clip, allowing for ILR contouring. The median RNI dose was 4000 cGy in 16 fractions. Lymphedema was defined as an increase in arm volume (10% dominant, 7% nondominant) in the affected extremity or a 10-point increase in Lymphedema Index plus patient-reported symptoms >6 months after RT completion. Dosimetric parameters included mean and maximum doses, V35, V40, Dmin<36.8Gy at the ILR site, ILR + 5 mm, and ILR + 2 cm expansion volumes.

RESULTS: Median follow-up was 25.9 months (interquartile range, 22.8-33.9). Fourteen patients met criteria for lymphedema at >1 time point, but only 4 (17.4%) met criteria for BCRL at their last follow-up. Patients who developed lymphedema had higher mean dose (4135 cGy vs 1410 cGy; P = .006), V35 (89% vs 20%; P = .005), and V40 (84% vs 17%; P = .012) at the ILR + 2 cm volume compared with those who did not. These parameters remained significant after controlling for BMI and the number of nodes removed. Threshold doses for lymphedema risk were found for the ILR + 2 cm volume: mean dose, 3074 cGy (AUC = 0.86), with rates of lymphedema above and below the threshold at 92% versus 30%, P = .006; V35, 56% (AUC = 0.87), 92% versus 22%, P = .001; and V40, 50% (AUC = 0.83), 92% versus 30%, P = .006.

CONCLUSIONS: Increasing RT doses to the ILR anastomosis site and the surrounding area increased lymphedema risk. Future studies will assess whether limiting the dose below these thresholds can lower BCRL rates while maintaining disease control.

Immediate lymphatic reconstruction (ILR), originally described as the lymphatic microsurgical preventative healing approach (LYMPHA), reduces the risk of developing lymphedema secondary to breast cancer treatment. ILR involves the intussusception of arm lymphatic channels into a vein draining centrally. However, performing this technique in a deep surgical field is technically challenging. We introduce a technical modification to ILR by repurposing a pulmonary wire to facilitate the intussusception technique. Intraoperatively, fluorescein isothiocyanate (FITC) was injected into the first and forth webspaces on the dorsum of the hand and the volar wrist. A vein graft was harvested from the lower leg during the axillary lymph node dissection. The accessory branch of the axillary vein was isolated. Lymphatic channels were identified under a 560-nm filter in the axillary bed. The largest-diameter channel was selected and isolated. An anastomosis was performed between the vein graft and targeted lymphatic channel utilizing the intussusception technique. A mini-forceps was passed retrograde through the vein graft to grasp the lymphatic channel. The channel was then intussuscepted into the vein graft and released. The vein graft was sutured to the surrounding peri-lymphatic fat using 8-0 sutures. Lymphatic flow from the proximal end of the vein graft was confirmed with FITC imaging. The vein graft was then anastomosed to the accessory vein using a coupler device. Patency was confirmed by visualizing FITC dye crossing the anastomosis and filling the recipient vein. Use of mini-forceps in ILR improves lymphatic channel manipulation in a deep surgical field and eliminates the U-Stitch.

BACKGROUND: Lymphatic anatomy has primarily been described in cadaveric dissections. Mapping of the upper extremity superficial lymphatic system with indocyanine green (ICG) lymphography provides functional insights and detail to major anatomic variations.

METHODS: Healthy female volunteers underwent lymphatic mapping of the upper extremities with ICG lymphography. ICG was injected in six standard sites in the hand/wrist and upper arm. Major anatomic variations of four main forearm pathways and connectivity to four upper arm pathways were described.

RESULTS: 90 arms of 45 volunteers were included. The posterior radial channel predominantly courses in the dorsal forearm (98%). The posterior ulnar forearm pathway courses in the dorsal forearm in the majority of arms (70%). The anterior radial and anterior ulnar forearm channels exclusively course in the volar forearm (100%). The posterior radial pathway connects to the bicipital (80%), lateral (48%), medial (9%), and tricipital (7%) upper am pathways. The posterior ulnar pathway connects to the lateral (54%), tricipital (51%), medial (21%), and bicipital (14%) upper arm pathways. The anterior radial pathway connects to the medial (50%) and bicipital (60%) pathways. The anterior ulnar pathway connects to the medial (54%) and bicipital (59%) pathways.

CONCLUSIONS: Upper extremity lymphatic drainage to the lateral and tricipital pathways is enabled exclusively by the dorsal forearm channels suggesting their importance in BCRL risk. Variations of upper extremity lymphatic anatomy are relevant to the risk, prevention, and treatment of breast cancer-related lymphedema risk and warrant further study.

Despite major advancements in lymphatic care, there remains a lack of consensus across institutions regarding the evaluation and surgical management of lymphedema. The aim of this study is to describe the practices for diagnosis and surgical treatment of lymphedema across accredited Lymphatic Education & Research Network (LE&RN) comprehensive Centers of Excellence (COEs).A survey was distributed to directors of the 16 LE&RN comprehensive COEs in January 2023. Directors were queried on lymphatic surgeon training, evaluation of potential surgical patients, description of surgical operations offered at their center, surgical algorithms, and operative techniques for various procedures.Nine COEs completed the survey (56% response rate). Eight of nine centers reported having an interdisciplinary surgical evaluation program, including lymphatic surgery (100%, 8/8), certified lymphedema therapy (100%, 8/8), and lymphatic medicine (75%, 6/8). COEs use a variety of lymphatic imaging modalities, with indocyanine green lymphography (89%, 8/9) and lymphoscintigraphy (78%, 7/9) being the most common. While all COEs offered debulking procedures, 67% (6/9) offered physiologic procedures (lymphovenous bypass and vascularized lymph node transplant), and 56% (5/9) offered immediate lymphatic reconstruction. There was no consensus on surgical algorithms or operative approaches.LE&RN comprehensive COEs consistently use multidisciplinary care teams for medical and surgical evaluations, but there is significant variability in lymphatic imaging modalities used and lymphatic surgery types and techniques. These findings underscore the need for continued research and standardization of lymphatic surgery outcomes to develop consensus.

OBJECTIVE: To identify vulnerable upper extremity regions in native lymphatic anatomy that predispose women to the development of breast cancer-related lymphedema. Additionally, to identify currently available imaging technologies that could be repurposed for in-vivo lymphatic imaging of these anatomic regions and pathways.

BACKGROUND: Breast cancer-related lymphedema remains an incurable complication of breast cancer treatment, but improvements to knowledge of upper extremity lymphatic anatomy and imaging can unlock new techniques for prevention and treatment.

METHODS: "Bringing to Light the Invisible Lymphatic Anatomy of the Human Body" was a two day accelerator workshop held in May 2024 at the Harvard Radcliffe Institute attended by sixteen experts in lymphatic anatomy and imaging including four lymphatic anatomists, five imaging clinicians, three lymphatic scientists, and three program officers from the National Heart, Lung and Blood Institute (NHLBI) and Advanced Research Projects Agency for Health (ARPA-H).

RESULTS: Collateral pathways of the superficial lymphatic system, perforating lymphatic vessels, and the deep lymphatic system were implicated in preventing or reducing the severity of BCRL. Several strategies were proposed for repurposing existing imaging technology and developing new imaging technology that can improve understanding of the anatomy, function, and connectivity of lymphatic vessels in these three regions of the arm.

CONCLUSION: Advancements in lymphatic imaging are central to refining our knowledge of lymphatic anatomy. Key challenges to lymphatic imaging are visualization of the deep lymphatic system and perforating lymphatic vessels.

BACKGROUND: The lateral upper arm (LUA) pathway is a route of superficial lymphatic drainage that bypasses the axilla by draining to the deltopectoral, clavicular, and cervical lymph nodes. Despite the fact that anatomic variations of the LUA pathway have been implicated in breast cancer-related lymphedema (BCRL) risk after axillary lymph node dissection (ALND), the incidence of the LUA pathway variations in the healthy population has never been reported.

METHODS: Healthy female volunteers underwent bilateral lymphatic mapping of the upper extremities with indocyanine green (ICG) lymphography. ICG was injected in six standard sites in the hand/wrist and upper arm. Major anatomic variations of the LUA pathway were recorded including bundle phenotype (long, short, or absent), proximal visualization sites, and forearm pathway continuation to the long bundle phenotype.

RESULTS: 90 arms of 45 volunteers were included. The LUA pathway was present in 99% of arms and a long-versus-short bundle phenotype was observed in 71% versus 28% of arms. When the long bundle was present, it was formed by continuity with the forearm posterior radial channel alone (47%), posterior ulnar channel alone (34%), or both channels (19%). The LUA pathway was traced proximally to the deltopectoral groove in 89% of arms and to the axilla in 11% of arms.

CONCLUSIONS: We observed similar proportions of arms with long and short bundle phenotypes in comparison to our previous report of the LUA pathway in breast cancer patients with nodal disease. Defining the incidence of the LUA pathway with its variations in the general population is important as variations in this pathway may have implications for an individual's risk of developing BCRL.

BACKGROUND: Axillary reverse mapping (ARM) identifies lymph vessels and nodes draining the arm to preserve them during axillary lymph node dissection (ALND) and thus reduce the risk of breast-cancer related lymphedema (BCRL). The ideal location for dye injections has not been previously studied. This study compared transected lymphatic vessels visualized for immediate lymphatic reconstruction (ILR) after ALND between patients who received fluorescein isothiocyanate (FITC) injections in the hand/wrist and those who received traditional medial upper-arm location.

METHODS: A retrospective review of ILR patients from September 2017 through May 2023 was performed. Dye injection site, number of channels visualized, channel distances from the axillary vein (cm), and channel diameters (mm) were collected. A chi-square test was used to compare the number of channels between injection sites. Mann-Whitney U tests were used to compare channel distances and channel diameters between injection sites.

RESULTS: Of 323 patients, 180 received hand/wrist injections, and 143 received medial upper-arm injections. Altogether, 755 channels were visualized. Fewer lymphatic channels were visualized in the hand/wrist injection group (p = 0.011). The median channel distance from the axillary vein was 2.3 cm after hand/wrist injections and 2.7 cm after medial upper-arm injections (p < 0.001). Channel diameters did not differ between injection-site groups (p = 0.066).

CONCLUSIONS: With the hand/wrist injections, fewer channels closer to the axillary vein were visualized. These findings corroborate prior anatomic and intraoperative studies identifying main lymphatic vessels of the arm as traveling closely along the axillary vein. Hand/wrist injections are more likely to identify main lymphatic channels draining the arm when ARM is performed.

BACKGROUND: The lateral upper arm lymphatic pathway is theorized as a route of superficial lymphatic drainage protective against breast cancer-related lymphedema (BCRL) after axillary lymph node dissection (ALND). This study describes lymph nodes draining the lateral upper arm pathway.

METHODS: Healthy female volunteers underwent bilateral ICG lymphography and nuclear lymphoscintigraphy. Nuclear tracer was injected over the cephalic vein in the upper arm. Lymph nodes with tracer uptake were recorded as deltopectoral, Station 1 (Axillary Levels I or II and Interpectoral), or Station 2 (Axillary Level III, Infraclavicular, Supraclavicular Levels IV or Vb, and Cervical Level Va).

RESULTS: 72 arms of 36 volunteers were included. Functional drainage to deltopectoral lymph nodes was observed in 38% (27/72) of arms. Drainage to Station 1, Station 2, and neither station was observed in 96% (69/72), 36% (26/72), and 3% (2/72) of arms, respectively. No differences were observed between arms with or without deltopectoral lymph nodes draining to Station 1 lymph nodes (93% vs 98%, p = 0.286) or neither station (4% vs 2%, p = 0.711), respectively. A significant difference was observed between arms with or without deltopectoral lymph nodes draining to Station 2 lymph nodes (52% vs 27%, p = 0.031).

CONCLUSIONS: Deltopectoral lymph node drainage is significantly correlated with Station 2 lymph node drainage. As Station 2 lymph nodes are preserved in an ALND, the presence of deltopectoral lymph node drainage represents an important potential protective biomarker for BCRL development.

BACKGROUND: Superficial to deep system rerouting of lymph protects against breast cancer-related lymphedema (BCRL). Humeral lymph nodes are a marker for deep lymphatic drainage. Epitrochlear lymph nodes are a site of superficial to deep collateralization based on cadaveric dissections. Functional connectivity between epitrochlear and humeral lymph nodes remains unexamined with in vivo imaging. We utilized lymphoscintigraphy to document epitrochlear and humeral lymph node drainage in healthy volunteers.

METHODS: Healthy female volunteers received four intradermal hand/wrist injections of 99-Tcm sulfur colloid to each upper extremity and were imaged with SPECT/CT at 2 h. Two nuclear medicine physicians independently reviewed the SPECT/CT scans to document lymph nodes with tracer uptake. A Chi-square test was performed to assess the correlation between functional epitrochlear and humeral lymph node drainage.

RESULTS: A total of 72 arms of 36 volunteers were included. Drainage to epitrochlear and humeral lymph nodes was observed in 57% (41/72) and 51% (37/72) of arms, respectively. Drainage to both epitrochlear and humeral lymph nodes was observed in 40% (29/72) of arms. Epitrochlear and humeral lymph node drainage were absent in 32% (27/72) of arms. The proportion of arms with humeral lymph node drainage was significantly greater in arms with (71%, 29/41) versus without (26%, 8/31) epitrochlear lymph node drainage [χ2 = 14.262 (1), p < 0.001].

CONCLUSIONS: Epitrochlear and humeral lymph node drainage are significantly correlated, suggesting a superficial to deep pathway may function at baseline in 40% of arms. The absence of epitrochlear and humeral lymph node drainage may represent a biomarker for BCRL risk.