Breast lymphedema following breast-conserving treatment for breast cancer: current status and future directions.

PURPOSE: To examine the current evidence on breast lymphedema (BL) diagnosis and treatment after breast-conserving surgery, identify gaps in the literature, and propose future research directions. METHODS: A comprehensive literature review was conducted using Ovid, PubMed, and Cochrane, including studies published between 2000 and 2023. References were reviewed manually for eligible studies. Inclusion criteria were as follows: patients who underwent breast conserving treatment (surgery ± radiation) for breast cancer, goals of the paper included analyzing or reviewing BL measurement with ultrasound or tissue dielectric constant, or BL treatment. Twenty-seven manuscripts were included in the review. RESULTS: There is variation in incidence, time course, and risk factors for BL. Risk factors for BL included breast size, primary and axillary surgery extent, radiation, and chemotherapy but require further investigation. Diagnostic methods for BL currently rely on patient report and lack standardized criteria. Tissue dielectric constant (TDC) and ultrasound (US) emerged as promising ambulatory BL assessment tools; however, diagnostic thresholds and validation studies with ICG lymphography are needed to establish clinical utility. The evidence base for treatment of BL is weak, lacking high-quality studies. CONCLUSION: The natural history of BL is not well defined. TDC and US show promise as ambulatory assessment tools for BL; however, further validation with lymphatic imaging is required. BL treatment is not established in the literature. Longitudinal, prospective studies including pre-radiation measurements and validating with lymphatic imaging are required. These data will inform screening, diagnostic criteria, and evidence-based treatment parameters for patients with BL after breast-conserving surgery and radiation.

Assessing breast lymphoedema following breast cancer treatment using indocyanine green lymphography.

PURPOSE: Breast lymphoedema is a largely unrecognised survivorship issue for women following breast cancer treatment. While a few objective methods have previously been applied to assess breast lymphoedema, none are capable of imaging breast lymphatics or identifying lymphatic morphological changes indicative of breast lymphoedema. The purpose of this study was to determine if indocyanine green (ICG) lymphography, a validated assessment technique in breast cancer-related lymphoedema), can visualise breast lymphatics and identify breast lymphoedema. Additionally, ICG lymphography was utilised to investigate lymphatic drainage pathways of the affected breast following breast-conserving therapy. METHODS: Twenty female participants (10 breast lymphoedema and 10 healthy controls) were recruited for this pilot study. All underwent a medical history, physical breast assessment, tissue dielectric constant measures of breast water content, and ICG lymphography. RESULTS: ICG lymphography identified lymphatic morphological changes in all breast lymphoedema participants (dermal backflow patterns = 10, collateral lymphatic drainage = 9) and none in the control group. The dominant lymphatic drainage pathway to the ipsilateral axilla was observed in all control participants but in only four breast lymphoedema participants. Collateral drainage pathways in the breast lymphoedema group were to: parasternal (6/10); contralateral axilla (4/10); intercostal (3/10); and clavicular (2/10) regions. CONCLUSION: These findings suggest ICG lymphography, through the identification of morphological lymphatic changes, is a potential qualitative objective assessment technique for breast lymphoedema. Furthermore, in this group of breast lymphoedema patients it identified changes to the normal drainage pathway of the breast. Understanding these changes will have implications for clinical management.

Lower-Limb Lymphatic Drainage Pathways and Lymph Nodes: A CT Lymphangiography Cadaver Study.

Background Most lymphatic imaging examinations of the lower limb require intradermal or subcutaneous injection of tracer material into the foot to demonstrate the lymphatic vessels; however, no standard protocol exists, and single or multiple injections are applied at different sites. Purpose To determine the three-dimensional relationships between each lymphatic group of the lower limb and corresponding regional lymph nodes. Materials and Methods A total of 130 lower limbs (55 from men and 75 from women) from 83 fresh human cadavers were studied. Lymphatic vessels were first visualized by using indocyanine green fluorescent lymphography with 19 injection sites in the foot, classified into four distinct lymphatic groups (anteromedial, anterolateral, posteromedial, and posterolateral); dilute oil-based contrast material was then injected. Next, specimens were scanned with CT and three-dimensional images were analyzed. Results The anteromedial and anterolateral lymphatic groups of the lower-leg lymphatic vessels were independent of each other and connected to different regional lymph nodes in the inguinal region. The posteromedial group and the anteromedial group in the lower leg drained to the same inguinal lymph nodes. Only the posterolateral group of lymphatic vessels in the lower leg drained to the popliteal lymph nodes. Leg lymphatic drainage pathways were independent of genital pathways. Conclusion Standard injection sites at the web spaces between the toes did not help visualize some lymph nodes of the lower leg. Additional injection sites in the medial, lateral, and posterior aspect of the foot would be better for evaluating the whole lymphatic pathways and regional lymph nodes and for improving understanding of leg lymphedema. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Weiss and Liddel in this issue.

The All but Forgotten Mascagni-Sappey Pathway: Learning from Immediate Lymphatic Reconstruction.

BACKGROUND: Upper extremity lymphedema occurs in 25 to 40% of patients after axillary lymph node dissection (ALND). Immediate lymphatic reconstruction (ILR) or the lymphatic micro- surgical preventative healing approach has demonstrated a significant decrease in postoperative rates of lymphedema (LE) from 4 to 12%. Our objective was to map the Mascagni -Sappey pathway, the lateral upper arm draining lymphatics, in patients undergoing ILR to better characterize the drainage pattern of this lymphosome to the axilla. METHODS: A retrospective review of our institutional lymphatic database was conducted and consecutive breast cancer patients undergoing ILR were identified from November 2017 through June 2018. Patient demographics, clinical characteristics, and intraoperative records were retrieved and analyzed. RESULTS: Twenty-nine consecutive breast cancer patients who underwent ILR after ALND were identified. Patients had a mean age of 54.6years and body mass index (BMI) of 26.6 kg/m2. Fluorescein isothiocyanate (FITC) was injected at the medial upper arm and isosulfan blue was injected at the cephalic vein, or lateral upper arm, prior to ALND. After ALND, an average 2.5 divided lymphatics were identified, and a mean 1.2 lymphatics were bypassed. In all patients, divided FITC lymphatics were identified. However, in only three patients (10%), divided blue lymphatics were identified after ALND. CONCLUSION: In this study, variable drainage of the lateral upper arm to the axillary bed was noted. This study is the first to provide a description of intraoperative findings, demonstrating variable drainage patterns of upper extremity lymphatics to the axilla. Moreover, we noted that the lateral- and medial-upper arm lymphosomes have mutually exclusive pathways draining to the axilla. Further study of lymphatic anatomy variability may elucidate the pathophysiology of lymphedema development and influence approaches to immediate lymphatic reconstruction.

A new indocyanine green fluorescence lymphography protocol for identification of the lymphatic drainage pathway for patients with breast cancer-related lymphoedema.

BACKGROUND: Breast cancer related lymphoedema (BCRL) is a common side effect of cancer treatment. Recently indocyanine green (ICG) fluorescent lymphography has become a popular method for imaging the lymphatics, however there are no standard protocols nor imaging criteria. We have developed a prospective protocol to aid in the diagnosis and therapeutic management of BCRL. METHODS: Lymphatic imaging procedures were conducted in three phases. Following initial observation of spontaneous movement of ICG in phase one, manual lymphatic drainage (MLD) massage was applied to facilitate ICG transit via the lymphatics in phase two. All imaging data was collected in phase three. Continuous lymphatic imaging of the upper limb was conducted for approximately an hour and lymphatic drainage pathways were determined. Correlations between the drainage pathway and MD Anderson Cancer Centre (MDACC) ICG lymphoedema stage were investigated. RESULTS: One hundred and three upper limbs with BCRL were assessed with this new protocol. Despite most of the patients having undergone axillary node dissection, the ipsilateral axilla drainage pathway was the most common (67% of upper limbs). We found drainage to the ipsilateral axilla decreased as MDACC stage increased. Our results suggest that the axillary pathway remained patent for over two-thirds of patients, rather than completely obstructed as conventionally thought to be the case for BCRL. CONCLUSIONS: We developed a new ICG lymphography protocol for diagnosing BCRL focusing on identification of an individual patient's lymphatic drainage pathway after lymph node surgery. The new ICG lymphography protocol will allow a personalised approach to manual lymphatic drainage massage and potentially surgery.

Multimodal imaging of the tumor microenvironment and biological responses to immune therapy.

Beyond heterogeneous cancer cells, the tumor microenvironment includes stromal and immune cells, blood vessels, extracellular matrix and biologically active molecules. Abnormal signaling, uncontrolled proliferation and high interstitial pressure all contribute to a chaotic, non-hierarchical vascular organization. Using an immune competent 4T1 breast adenocarcinoma murine model, this study fully characterizes the architecture and immunocyte milieu of the tumor microenvironment. Heterogeneous vessel distribution, chaotic connectivity, limited perfusion, cancer cell density, immune phenotype, and biological responses to immune therapy are presented. Cancer cell density mirrored the distribution of large, perfusable vessels, both predominately in the tumor periphery. Intratumoral administration of the proinflammatory cytokine IL-12 led to an increase in CD45+ leukocytes, with a specific increase in CD4+ and CD8+ T cells, and a decrease in the percentage of Gr-llo myeloid-derived suppressor cells. Concomitantly, serum G-CSF, IL-10 and VEGF decreased, while CXCR9 and interferon gamma increased. The distribution pattern of infiltrating monocytes/macrophages, visualized using a fluorescent perfluorocarbon emulsion, indicated that macrophages predominately localize in the vicinity of large blood vessels. Electron microscopy supports the presence of dense tumor cell masses throughout the tumor, with the largest vessels present in the surrounding mammary fat pad. Overall, large vessels in the 4T1 tumor periphery support high, localized vascular perfusion and myeloid accumulation. The pro-inflammatory cytokine IL-12 stimulated a transition towards T helper 1 cytokines in serum, supporting suppression of tumor growth and angiostatic conditions.

Interview Scores Correlate with Fellow Microsurgical Skill and Performance.

BACKGROUND: The interview process for surgical trainees aims to select those individuals who will perform best during training and have the greatest potential as future surgeons. The objective of this study was to evaluate the relationship between criteria assessed at interview, technical skills, and performance, for the first time, to optimize the selection process for a Microsurgery fellowship. METHODS: Twenty microsurgery fellows in three consecutive annual cohorts at a single academic center were prospectively evaluated. At interview, subjects were scored for multiple standardized domains. At the start and at end of the fellowship, microsurgical technical skill was assessed both in the laboratory and operating room (OR) using a validated assessment tool. At the end of the fellowship, there was a final evaluation of performance. RESULTS: At the start, microsurgical skill significantly correlated with almost all domains evaluated at interview, most closely with prior plastic surgery training experience. At the end of the fellowship, skill level improved in all trainees, with the greatest improvement made by the lowest ranked and skilled trainees. The highest ranked trainees, however, made the greatest improvement in speed. CONCLUSIONS: The results of this study, for the first time, validate the current interview process to correctly select the highest performing and most skilled candidates and support the effectiveness of a 1-year microsurgical fellowship in improving microsurgical skill in all trainees, irrespective of their initial ability. The importance of valuing the relative quality of prior training and experience at selection is also highlighted.

Lymphosome concept: Anatomical study of the lymphatic system.

The gross anatomical study of the lymphatic system in humans and animals has been suspended for almost 100 years. This article introduces the author's technique for investigating the lymphatic system using the concept of the lymphosome. In revisiting the anatomical study of the lymphatic system, our updated knowledge can potentially be utilized either to reassure surgeons about their current procedures in the surgical management of cancers and lymphedema or assist them to refine them. J. Surg. Oncol. 2017;115:13-17. © 2016 Wiley Periodicals, Inc.

Long-term outcomes of the minimally invasive free vascularized omental lymphatic flap for the treatment of lymphedema.

BACKGROUND: The free vascularized omental lymphatic flap provides an option without the risk for iatrogenic donor site lymphedema that plagues alternative lymph node transfer donor sites. The omental flap has been associated with significant morbidity in the past; however, with modern techniques and advanced in technology, a minimally invasive approach to flap harvest is feasible. We present the long-term outcomes of the minimally invasive free vascularized omental lymphatic flap for the treatment of lymphedema. METHODS: All consecutive patients with advanced lymphedema undergoing minimally invasive free vascularized omental lymphatic flap transfer were included. Perioperative evaluation included qualitative assessments, lymphoscintigraphy, and volumetric measurements. RESULTS: Overall, 42 patients underwent a free omental lymphatic flap and had a mean follow-up of 14 (3-32) months. Subjective improvements were noted in 83% of patients. Mean volumetric improvement was 22%. Complications occurred in 16% (n = 7) of patients; this included one episode of pancreatitis and one flap loss. Postoperative imaging revealed viable lymphatic transfers. Cellulitis history was present in 74% (n = 31) patients with post-operative cellulitis occurring in 5% (n = 2) patients. CONCLUSIONS: The minimally invasive free vascularized omental lymphatic flap provides a safe donor site, a durable and versatile flap, and an efficacious therapy against lymphedema and lymphedema-related cellulitis. J. Surg. Oncol. 2017;115:84-89. © 2016 Wiley Periodicals, Inc.

Interaction between vascularized lymph node transfer and recipient lymphatics after lymph node dissection-a pilot study in a canine model.

BACKGROUND: Vascularized lymph node transfer (VLNT) has become more widespread for surgical treatment of lymphedema. However, interaction between a transferred lymph node and the recipient lymphatic system in relieving lymphedema has not been identified. The aims of this study were to investigate anatomic changes in the lymphatic system in the forelimb of a canine after lymph node dissection and irradiation and to clarify the interaction between the transferred lymph node and recipient lymphatics. MATERIALS AND METHODS: Two adult female mongrel canines were used for this exploratory study. The unilateral axillary and lower neck node dissections were performed, and 15-Gy irradiation was applied on postoperative day 3. After 1 y, a VLNT flap was harvested from the lower abdominal region and inset in the axilla with vascular anastomoses. The girth of each forelimb was determined with a tape measure at different time points. Indocyanine green fluorescence lymphography and lymphangiography were performed before and after each surgery to evaluate morphologic changes in the lymphatics. RESULTS: Both canines revealed identical changes in the lymphatic system, but only one canine developed lymphedema. After lymph node dissection, a collateral lymphatic pathway formed a connection to the contralateral cervical node. After VLNT, an additional collateral pathway formed a connection to the internal mammary node via the transferred node in the axilla. CONCLUSIONS: The findings suggest that the lymphatic system has a homing mechanism, which allows the severed lymphatic vessels to detect and connect to adjacent lymph nodes. VLNT may create new collateral pathways to relieve lymphedema.

An algorithmic approach to simultaneous vascularized lymph node transfer with microvascular breast reconstruction.

BACKGROUND: Lymphedema is a common, progressive, and often debilitating condition that can occur after breast cancer treatment. Preliminary reports on vascularized lymph node transfer (VLNT) have been promising. We propose an algorithmic approach to simultaneous VLNT with microvascular breast reconstruction (MBR) and provide early results. METHODS: All patients who underwent simultaneous VLNT with MBR were included. Postoperative evaluation was performed at standardized time points and included qualitative assessment and quantitative volumetric analysis. RESULTS: Between 2011 and 2013, 29 consecutive patients with refractory lymphedema secondary to breast cancer treatment underwent simultaneous VLNT with MBR. Mean follow-up was 11 months. On average, patients had experienced 3.3 years of lymphedema symptoms with 21 % increased volume in the affected arm compared with the unaffected arm. Using our algorithmic approach, all patients underwent successful breast reconstruction. There were no flap losses, and no patients developed donor site lymphedema. Six patients (21 %) experienced donor site wound complications that resolved with conservative measures; 23 patients (79 %) reported sustained symptomatic improvement after reconstruction. The mean volume differential volumes improved to 20, 19, 14, and 10 % at 1, 3, 6, and 12 months after reconstruction, respectively. CONCLUSIONS: Our algorithm provides a reliable approach to optimizing simultaneous abdominal free flap breast reconstruction and VLNT and demonstrates promising results. Long-term studies are warranted to further delineate and improve the safety and efficacy of lymph node transfers.

Cadaveric dissection and clinical experience with 20 consecutive tunneled pedicled superficial temporal artery perforator (STAP) flaps for ear reconstruction.

INTRODUCTION: Reconstruction of anterior ear defects is poorly described, but using "like" tissue provides the optimal reconstruction. We present a cadaveric dissection and our experience with the pedicled superficial temporal artery perforator (STAP) flap for reconstruction of partial ear defects. MATERIALS AND METHODS: Two cadavers were dissected bilaterally (n = 4) following injection of latex and barium sulfate. A retrospective review of 20 consecutive patients undergoing reconstruction with the STAP flap from 2009 to 2012 was performed. Twenty patients underwent reconstruction of anterior ear defects following resection for non-melanoma skin malignancies using a tunneled pedicled STAP flap (scapha: 5, triangular fossa: 2, scapha and triangular fossa: 13). RESULTS: Two perforators were identified in all dissections with one perforator at the level of the tragus, and the second perforator within 1 cm cephalad to the tragus. Thirteen patients underwent reconstruction following basal cell carcinoma excision and seven patients were reconstructed following excision of squamous cell carcinoma. There were no flap losses, but four flaps (20%) developed congestion at the tip of the flap that resolved without need for flap delay, leeching, or vasodilators. No patients developed complications with the donor site, and no patients underwent revisions. With a mean follow-up of 27.3 months (range: 19-38 months), all patients were pleased with their aesthetic outcomes and alive without recurrent disease. CONCLUSION: The STAP flap is a pedicled perforator flap providing local "like" tissue that can be utilized for resurfacing of defects involving the anterior upper external ear with minimal donor site morbidity.

Lymphatic drainage in renal cell carcinoma: back to the basics.

Lymphatic drainage in renal cell carcinoma (RCC) is unpredictable, however, basic patterns can be observed in cadaveric and sentinel lymph node mapping studies in patients with RCC. The existence of peripheral lymphovenous communications at the level of the renal vein has been shown in mammals but remains unknown in humans. The sentinel lymph node biopsy technique can be safely applied to map lymphatic drainage patterns in patients with RCC. Further standardisation of sentinel node biopsy techniques is required to improve the clinical significance of mapping studies. Understanding lymphatic drainage in RCC may lead to an evidence-based consensus on the surgical management of retroperitoneal lymph nodes.

Near-infrared lymphography as a minimally invasive modality for imaging lymphatic reconstitution in a rat orthotopic hind limb transplantation model.

Wider application of vascularized composite allotransplantation (VCA) is limited by the need for chronic immunosuppression. Recent data suggest that the lymphatic system plays an important role in mediating rejection. This study used near-infrared (NIR) lymphography to describe lymphatic reconstitution in a rat VCA model. Syngeneic (Lewis-Lewis) and allogeneic (Brown Norway-Lewis) rat orthotopic hind limb transplants were performed without immunosuppression. Animals were imaged pre- and postoperatively using indocyanine green (ICG) lymphography. Images were collected using an NIR imaging system. Co-localization was achieved through use of an acrylic paint/hydrogen peroxide mixture. In all transplants, ICG first crossed graft suture lines on postoperative day (POD) 5. Clinical signs of rejection also appeared on POD 5 in allogeneic transplants, with most exhibiting Grade 3 rejection by POD 6. Injection of an acrylic paint/hydrogen peroxide mixture on POD 5 confirmed the existence of continuous lymphatic vessels crossing the suture line and draining into the inguinal lymph node. NIR lymphography is a minimally invasive imaging modality that can be used to study lymphatic vessels in a rat VCA model. In allogeneic transplants, lymphatic reconstitution correlated with clinical rejection. Lymphatic reconstitution may represent an early target for immunomodulation.

Three-dimensional demonstration of the lymphatic system in the lower extremities with multi-detector-row computed tomography: a study in a cadaver model.

Sentinel lymph node biopsy (SLNB) has had a great impact on the staging and treatment of cancer. The purpose of this study was to study the lymphatic anatomy of the lower extremities by constructing three-dimensional images using multi-detector-row computed tomography (MDCT). To select appropriate contrast media for MDCT lymphatic imaging in a cadaver, we tested four kinds of contrast media by injecting them into fresh swine kidneys. After the suitable contrast medium was selected, 10 lower extremities from 5 fresh cadavers were studied. After injection of the contrast medium, each lower extremity was scanned with high-spatial-resolution MDCT. The zinc oxide mixture was found to be the most appropriate contrast formula for MDCT imaging of cadaver lymphatics in terms of CT value and no extravasation. The high-resolution MDCT imaging revealed two different superficial lymphatic pathways in the legs. One lymphatic pathway accompanying the great saphenous vein had a constant course and was connected to the superficial inguinal lymph nodes. However, another pathway, along the small saphenous vein, was variable. Some of the deep lymphatic vessels bypassed the inguinal lymph nodes. Using a new protocol, we were able to construct three-dimensional images of the lower extremity lymphatics in a cadaver model. MDCT imaging provided novel information about two different superficial lymphatic pathways in the lower extremities.

The Prevalence of the Axillo-Inguinal Lymphatic Pathway in Lymphedema of the Extremities and Potential Therapeutic Implications.

Background: The axillo-inguinal (or inguino-axillary) is a compensatory lymphatic drainage pathway regularly utilized by lymphedema therapists when applying manual lymphatic drainage (MLD) for upper and lower extremity lymphedema. However, there is limited evidence of the frequency of this pathway and the characteristics of patients with lymphedema in which this pathway is present. Indocyanine green (ICG) lymphography is an imaging technique that has the capability to identify lymphatic drainage pathways in lymphedema when combined with MLD. In this study, we used ICG lymphography in patients with upper and lower extremity lymphedema to investigate the presence of this pathway and its clinical characteristics. Methods and Results: A retrospective cohort audit of 563 patients with lymphedema (285 with upper extremity and 278 with lower extremity) who underwent ICG lymphography was conducted in combination with MLD. Compensatory lymphatic drainage was investigated. Patients demonstrating the axillo-inguinal pathway were identified, and their clinical characteristics were recorded. The axillo-inguinal pathway was not demonstrated in any patient with upper extremity and only five patients with lower extremity lymphedema. Of these five patients, all were female with a history of secondary cancer-related lymphedema following gynecological cancer. The majority (four) had bilateral lymphedema extending to the lower abdomen and presented with a greater severity of lymphedema. Conclusions: These findings suggest that the axillo-inguinal pathway is an infrequent compensatory drainage pathway in lower extremity lymphedema and rare in upper extremity lymphedema. Our findings have clinical implications for lymphedema management, in particular, the sequence in which MLD is applied.

Differentiation of lipoedema from bilateral lower limb lymphoedema by imaging assessment of indocyanine green lymphography.

Lipoedema is characterized by disproportionate painful fat accumulation mostly in the lower limbs. The presence of lymphoedema in lipoedema remains controversial. This study aimed to assess the presence or absence of lymphoedema in the lower limbs of women with lipoedema using indocyanine green (ICG) lymphography. A cross-sectional retrospective study was undertaken in women with a clinical diagnosis of lipoedema whose lower limbs were examined with ICG lymphography. MD Anderson Cancer Center (MDACC) ICG staging was used to determine lymphoedema presence and severity. Patient characteristics, ICG lymphography findings, Stemmer sign, body mass index, waist-to-hip ratio, limb volume and bioimpedance spectroscopy measures were recorded. Forty women with lipoedema underwent ICG lymphography for the lower limbs from January 2018 to July 2022. Thirty-four women (85.0%) were determined by ICG lymphography as MDACC ICG Stage 0 representing normal lymphatics. Of the six women who demonstrated dermal backflow on ICG lymphography, all were determined as ICG Stage 1, four had localized traumatic dermal backflow area at their ankles, one had previously diagnosed with primary lymphoedema and one was classified as lipoedema stage 4. ICG lymphography findings suggested the absence of lymphoedema in a clear majority of women with lower limb lipoedema.

Toward Development of a Portable System for 3D Fluorescence Lymphography.

Lymphoedema is a debilitating disease that results in chronic swelling of a body region due to a dysfunctional lymphatic system. Since a cure is yet to be identified for this disease, management is currently the best option for preventing disease progression and improving patient outcomes. Fluorescence lymphography is a popular approach for mapping the lymphatic vessels to provide information about the underlying lymphatic dysfunction. However, current clinical fluorescence lymphography tools do not enable the creation of comprehensive 3D maps of lymphatics throughout affected limbs. This work presents the development toward multi-camera 3D reconstruction with fluorescence imaging to overcome the current limitations in clinical tools. Pilot studies have been performed that identify suitable instrumentation for this multi-camera approach and techniques for creating a 3D fluorescence lymphography device are discussed.Clinical Relevance- This paper presents development toward new low-cost and portable clinical tools for lymphoedema diagnosis and to facilitate personalised treatment and self-management of this disease.

Mapping the lymphatic system across body scales and expertise domains: A report from the 2021 National Heart, Lung, and Blood Institute workshop at the Boston Lymphatic Symposium.

Enhancing our understanding of lymphatic anatomy from the microscopic to the anatomical scale is essential to discern how the structure and function of the lymphatic system interacts with different tissues and organs within the body and contributes to health and disease. The knowledge of molecular aspects of the lymphatic network is fundamental to understand the mechanisms of disease progression and prevention. Recent advances in mapping components of the lymphatic system using state of the art single cell technologies, the identification of novel biomarkers, new clinical imaging efforts, and computational tools which attempt to identify connections between these diverse technologies hold the potential to catalyze new strategies to address lymphatic diseases such as lymphedema and lipedema. This manuscript summarizes current knowledge of the lymphatic system and identifies prevailing challenges and opportunities to advance the field of lymphatic research as discussed by the experts in the workshop.