Publications

Chronic lymphedema is a progressive, disfiguring disease that results from dysfunction of the lymphatic vasculature, causing distal accumulation of interstitial fluid, localized development of tissue edema, and expansion of subcutaneous adipose tissue (SAT). As the molecular mechanisms governing SAT remodeling in this disease are unclear, we performed single-nucleus RNA sequencing on paired control and affected SAT biopsies from patients with unilateral lymphedema. Lymphedema samples were characterized by expansion of SAA + adipocytes, pro-adipogenic stem cells, and proliferation of lymphatic capillaries. A GRIA1 + lymphedema-enriched stromal cell population expressing VEGFC , ADAMTS3 , and CCBE1 was identified, suggesting an enhanced axis of communication between adipose stem and progenitor cells (ASPCs) and lymphatic endothelial cells. Furthermore, lymphedema ASPC-conditioned media promoted lymphatic endothelial tube elongation in vitro . These findings indicate a critical role for ASPCs in regulating adipocyte differentiation and lymphatic vascular remodeling in lymphedema, and provide a valuable resource for better understanding this disease.

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.

Vascularized lymph node transplant (VLNT) is widely performed for chronic upper and lower extremity lymphedema. However, ideal recipient sites for the transplant are still under debate. The placement of VLNTs distally in an extremity can be challenging as the small cross-sectional area of the limb at this level does not allow for flap inset without gross contour deformity, which can adversely impact aesthetic outcomes and preclude fitting of an adequate compression garment. In this article, we introduce the Kager triangle as a potential distal lower extremity VLNT recipient site for the lower extremity. The Kager triangle is bordered by the Achilles tendon, the flexor hallucis longus, and the calcaneus, which accommodates the Kager fat pad, the largest adipose structure in the lower extremity. We transferred an omentum lymph node flap to the Kager triangle, and the posterior tibial artery and the anterior lateral malleolar artery were utilized as recipient vessels in a flow-through fashion. The incisions were directly closed with excellent cosmesis.

ObjectiveThe incidence of lipedema is poorly described due to its confusion with lymphedema. Patient education is crucial for treatment and prevention strategies but also for improving healthcare outcomes. This study assessed and compared the quality of English and Spanish online resources for patients suffering from lipedema using a multimetric approach.MethodsA deidentified Google search using the terms "lipedema" and "lipedema español" was conducted. The first 10 academic/organizational websites in each language were selected. Quality assessment was performed using the Patient Education and Materials Assessment Tool (PEMAT), Cultural Sensitivity Assessment Tool (CSAT), Simple Measure of Gobbledygook (SMOG), and facticity criteria to evaluate understandability and actionability, cultural sensitivity, readability, and factual quality, respectively.ResultsEnglish webpages scored 73.70% for understandability and 35.0% for actionability, while Spanish webpages scored 75.05% and 21.0%, respectively; no significant differences were found between languages in understandability (p = .970) and actionability (p = .895). A significantly higher proportion of Spanish resources was found to be culturally sensible than English resources (90% vs 70%; p < .001). However, no significant differences were found in the cultural sensitivity score (English 2.87 vs Spanish 3.01; p = .677). The grade reading level for Spanish materials was significantly lower compared to English materials (11.08 vs 13.45; p = .006). Factual quality was low across both languages according to the facticity framework, though English materials scored higher than Spanish (2.20 vs 1.00; p = .051).ConclusionOur results suggest that online English and Spanish materials on lipedema have inadequate actionability, facticity, and reading grade levels for patients. Nonetheless, the levels of understandability and cultural sensitivity are acceptable. Enhancing the quality of online health literature for lipedema patients presents an opportunity to alleviate psychosocial burdens and address misconceptions.