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Granoff MD, Pardo J, Shillue K, Fleishman A, Teller P, Lee BT, James T, Singhal D.
Abstract
Background: The lateral upper arm channel is an accessory lymphatic pathway that drains the upper extremity by means of the deltopectoral groove and supraclavicular nodes, thereby bypassing the axilla. Its variable connectivity to the forearm has not been studied in vivo.
Methods: Indocyanine green (ICG) lymphography was performed preoperatively to map the superficial and functional arm lymphatics in breast cancer patients without clinical or objective evidence of lymphedema. A retrospective review was performed to extract demographic, ICG imaging, and surgical data.
Results: Sixty patients underwent ICG lymphography before axillary lymph node dissection between June of 2019 and October of 2020. In 59%, the lateral upper arm lymphatic channel was contiguous with the forearm (long bundle). In 38%, the lateral upper arm lymphatic channel was present but not contiguous with the forearm (short bundle). In 3%, the lateral upper arm pathway was entirely absent. Seven patients developed at least one sign of lymphedema during postoperative surveillance, of which 71% demonstrated the short bundle variant.
Conclusion: Although the lateral upper arm pathway is most often present, its connections to the forearm are frequently absent (short bundle), which, in this pilot report, appears to represent a potential risk factor for the development of lymphedema.
Clinical question/level of evidence: Risk, V.
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Kinney JR, Babapour S, Kim E, Friedman R, Singhal D, Lee BT, Tsai LL.
Abstract
Background and Objectives: One of the surgical treatments for breast cancer-related lymphedema (BCRL) is debulking lipectomy. The aim of this study is to investigate whether dermal thickness could be utilized as an objective indicator of post-operative changes following debulking.
Materials and Methods: A retrospective review of BCRL patients who underwent debulking lipectomy was conducted. MRI-based dermal thickness was measured by two separate trained readers at 16 regions of the upper extremity. Pre- and post-operative reduction in dermal thickness was compared across the affected and unaffected (control) arms for each patient. The Wilcoxon rank sum test was used to assess for significant change. Univariate linear regression was used to assess the relationship between dermal thickness reduction and changes to LYMPH-Q scores, L-Dex scores, and relative volume change.
Results: Seventeen patients were included in our analysis. There was significant reduction in dermal thickness at 5/16 regions in the affected arm. Dermal thickness change was significantly correlated with LYMPH-Q scores, L-Dex scores, and relative volume change in 2/16 limb compartments. There was predominant dermal thickening in the dorsal compartment of the upper arm and in the ventral and ulnar compartments of the forearm.
Conclusions: Dermal thickness shows promising utility in tracking post-operative debulking procedures for breast cancer-related lymphedema. Further studies with larger patient populations and a variety of imaging modalities are required to continue to develop a clinically objective and reproducible method of post-surgical lymphedema staging and monitoring.
Non-Linear Lymphatic Anatomy in Breast Cancer Patients Prior to Axillary Lymph Node Dissection: A Risk Factor For Lymphedema Development
Kinney JR, Friedman R, Kim E, Tillotson E, Shillue K, Lee BT, Singhal D.
Abstract
Immediate lymphatic reconstruction (ILR) at the time of axillary lymph node dissection (ALND) has become increasingly utilized for the prevention of breast cancer related lymphedema. Preoperative indocyanine green (ICG) lymphography is routinely performed prior to an ILR procedure to characterize baseline lymphatic anatomy of the upper extremity. While most patients have linear lymphatic channels visualized on ICG, representing a non-diseased state, some patients demonstrate non-linear patterns.
This study aims to determine potential inciting factors that help explain why some patients have non-linear patterns, and what these patterns represent regarding the relative risk of developing postoperative breast cancer related lymphedema in this population. A retrospective review was conducted to identify breast cancer patients who underwent successful ILR with preoperative ICG at our institution from November 2017-June 2022. Among the 248 patients who were identified, 13 (5%) had preoperative non-linear lymphatic anatomy. A history of trauma or surgery of the affected limb and an increasing number of sentinel lymph nodes removed prior to ALND appeared to be risk factors for non-linear lymphatic anatomy. Furthermore, non-linear anatomy in the limb of interest was associated with an increased risk of postoperative lymphedema development.
Overall, non-linear lymphatic anatomy on pre-operative ICG lymphography appears to be a risk factor for developing ipsilateral breast cancer-related lymphedema. Guided by the study's findings, when breast cancer patients present with baseline non-linear lymphatic anatomy, our institution has implemented a protocol of prophylactically prescribing compression sleeves immediately following ALND.
Friedman R, Lee C, Kinney JR, Salehi BP, Kim G, Singhal D, Tsai LL.
Abstract
Introduction: Magnetic resonance imaging (MRI) stage 1 (early stage) upper extremity lymphedema is characterized by fluid infiltration in the subcutaneous tissues that does not exceed 50% of the extremity circumference at any level. The spatial fluid distribution in these cases has not been detailed and may be important to help determine the presence and location of compensatory lymphatic channels. The aim of this study is to determine whether there was a pattern of distribution of fluid infiltration in patients with early-stage lymphedema that could correspond to known lymphatic pathways in the upper extremity.
Methods: A retrospective review identified all patients with MRI stage 1 upper extremity lymphedema who were evaluated at a single lymphatic center. Using a standardized scoring system, a radiologist graded the severity of fluid infiltration at 18 anatomical locations. A cumulative spatial histogram was then created to map out regions where fluid accumulation occurred most and least frequently.
Results: Eleven patients with MRI stage 1 upper extremity lymphedema were identified between January 2017 and January 2022. The mean age was 58 years and the mean BMI was 30 m/kg2. One patient had primary lymphedema and the remaining 10 had secondary lymphedema. The forearm was affected in nine cases, and fluid infiltration was predominantly concentrated along the ulnar aspect, followed by the volar aspect, while the radial aspect was completely spared. Within the upper arm, fluid was primarily concentrated distally and posteriorly, and occasionally medially.
Conclusions: In patients with early-stage lymphedema, fluid infiltration is concentrated along the ulnar forearm and the posterior distal upper arm, which aligns with the tricipital lymphatic pathway. There is also sparing of fluid accumulation along the radial forearm in these patients, suggesting a more robust lymphatic drainage along this region, possibly due to a connection to the lateral upper arm pathway.
MRI of Lymphedema
Salehi BP, Sibley RC, Friedman R, Kim G, Singhal D, Loening AM, Tsai LL.
Abstract
Lymphedema is a devastating disease that has no cure. Management of lymphedema has evolved rapidly over the past two decades with the advent of surgeries that can ameliorate symptoms. MRI has played an increasingly important role in the diagnosis and evaluation of lymphedema, as it provides high spatial resolution of the distribution and severity of soft tissue edema, characterizes diseased lymphatic channels, and assesses secondary effects such as fat hypertrophy. Many different MR techniques have been developed for the evaluation of lymphedema, and the modality can be tailored to suit the needs of a lymphatic clinic. In this review article we provide an overview of lymphedema, current management options, and the current role of MRI in lymphedema diagnosis and management. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 5.
Singhal D, Börner K, Chaikof EL, Detmar M, Hollmén M, Iliff JJ, Itkin M, Makinen T, Oliver G, Padera TP, Quardokus EM, Radtke AJ, Suami H, Weber GM, Rovira II, Muratoglu SC, Galis ZS.
Abstract
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.
Friedman R, Bustos VP, Pardo J, Tillotson E, Donohoe K, Chatterjee A, Ciucci JL, Singhal D.
Abstract
Purpose: The tricipital, or Caplan's, lymphatic pathway has been previously identified in cadavers and described as a potential compensatory pathway for lymphatic drainage of the upper extremity, as it may drain lymphatic fluid directly to the scapular lymph nodes, avoiding the axillary lymph node groups. The aim of this study was to map the anatomy of the tricipital pathway in vivo in patients without lymphatic disease.
Methods: A retrospective review was performed to identify patients with unilateral breast cancer undergoing preoperative Indocyanine green (ICG) lymphography prior to axillary lymph node dissection from May 2021 through January 2022. Exclusion criteria were evidence or known history of upper extremity lymphedema or non-linear channels visualized on ICG. Demographic, oncologic, and ICG imaging data were extracted from a Lymphatic Surgery Database. The primary outcome of this study was the presence and absence of the tricipital pathway. The secondary outcome was major anatomical variations among those with a tricipital pathway.
Results: Thirty patients underwent preoperative ICG lymphography in the study period. The tricipital pathway was visualized in the posterior upper arm in 90% of patients. In 63% of patients, the pathway had a functional connection to the forearm (long bundle variant) and in 27%, the pathway was isolated to the upper arm without a connection to the forearm (short bundle variant). In those with a long bundle, the contribution was predominantly from the posterior ulnar lymphosome. Anatomic destinations of the tricipital pathway included the deltotricipital groove and the medial upper arm channel, which drains to the axilla.
Conclusion: When present, the tricipital pathway coursed along the posterior upper arm with variability in its connections to the forearm distally, and the torso proximally. Long-term follow-up studies will help determine the significance of these anatomic variations in terms of individual risk of lymphedema after axillary nodal dissection
Friedman R, Suami H, Tsai LL, Singhal D.
Abstract
No abstract available.
Granoff, Melisa D. BA; Pardo, Jaime MD; Johnson, Anna Rose MD, MPH2; Fleishman, Aaron MPH; Tillotson, Elizabeth NP-C; Thomson, Sarah RN; Lee, Bernard T. MD, MBA, MPH; Singhal, Dhruv MD.
Abstract
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Background: Knowledge of detailed lymphatic anatomy in humans is limited as the small size of lymphatic channels makes it difficult to image. Most current knowledge of the superficial lymphatic system has been obtained from cadaveric dissections.
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Methods: Indocyanine green (ICG) lymphography was performed pre-operatively to map the functional arm lymphatics in breast cancer patients without clinical or objective evidence of lymphedema. A retrospective review was performed to extract demographic, ICG imaging, and surgical data.
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Results: Three main functional forearm channels with variable connections to two upper arm pathways were identified. The median forearm channel predominantly courses in the volar forearm (99%). The ulnar forearm channel courses in the volar forearm in the majority of patients (66%). The radial forearm channel courses in the dorsal forearm in the majority of patients (92%). Median (100%), radial (91%), and ulnar (96%) channels almost universally connect to the medial upper arm channel. In contrast, connections to the lateral upper arm channel occur less frequently from the radial (40%) and ulnar (31%) channels.
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Conclusions: This study details the anatomy of three forearm lymphatic channels and their connections to the upper arm in living adults without lymphatic disease. Knowledge of these pathways and variations is relevant to any individual performing procedures on the upper extremities as injury to the superficial lymphatic system can predispose patients to the development of lymphedema.
​Anna Rose Johnson, Marc-André Tétrault, Miguel G Bravo, Vincent Girouard, Rita Laurence, Bernard T Lee, Hak Soo Choi, Dhruv Singhal.
Abstract
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Background: The real-time quantification of lymphatic flow remains elusive. Efforts to provide a metric of direct lymphatic function are not clinically translatable and lack reproducibility. Early reports demonstrate the promise of immediate lymphatic reconstruction (immediate lymphovenous bypass after lymphadenectomy) to reduce the risk of lymphedema development. However, there remains a heightened need to appraise this technique in a clinically translatable large-animal model. The aim of the authors’ experiment was to evaluate the role of molecular imaging in the quantification of real-time lymphatic flow after lymphadenectomy, and lymphadenectomy with lymphovenous bypass using novel fluorophores in a swine model.
Methods: A lymphadenectomy or lymphadenectomy with subsequent lymphovenous bypass was performed in 10 female swine. After subdermal fluorophore injection, near-infrared molecular imaging of blood samples was used to evaluate change in lymphatic flow after lymphadenectomy versus after lymphadenectomy with lymphovenous bypass. Continuous imaging evaluating fluorescence of the superficial epigastric vein in the torso and adjacent skin was performed throughout all experiments. Findings between modalities were correlated.
Results: The near-infrared dye signal in central and peripheral blood samples was often difficult to separate from background and proved challenging for reliable quantification. Venous and skin near-infrared imaging demonstrated a lymphatic clearance rate decrease of 70 percent after lymphadenectomy versus a decrease by only 30 percent after lymphadenectomy with immediate lymphovenous bypass.
Conclusions: In this article, the authors describe a noninvasive, swine, large-animal model to quantify lymphatic clearance using skin imaging. The authors’ findings were consistent with results yielded from real-time imaging of the vein. The authors believe this model may have important implications for eventual direct translation to the clinical setting.
​Kim Geunwon, Anna Rose Johnson, Ryoko Hamaguchi, Michael Adondakis, Leo L. Tsai, Dhruv Singhal
Abstract
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Background: A distinct pattern of edema distribution is seen in breast cancer-related lymphedema. The area of edema sparing has not been characterized in relation to anatomy. Specifically, alternate lymphatic pathways are known to travel adjacent to the cephalic vein. Our study aims to define the location of edema sparing in the arm relative to the cephalic vein.
Methods: A retrospective review of patients who underwent magnetic resonance imaging (MRI) between March 2017 and September 2018 was performed. Variables including patient demographics, arm volumes, and MRI data were extracted. MRIs were reviewed to define the amount of sparing, or angle of sparing, and the deviation between the center of sparing and the cephalic vein, or angle of deviation.
Results: A total of 34 consecutive patients were included in the analysis. Five patients demonstrated circumferential edema (no sparing) and 29 patients demonstrated areas of edema sparing. Advanced age (69.7 vs. 57.6 years) and greater excess arm volume (40.4 vs. 20.8%) correlated with having circumferential edema without sparing (p = 0.003). In 29 patients with areas of edema sparing, the upper arm demonstrated the greatest angle of sparing (183.2 degrees) and the narrowest in the forearm (99.9 degrees; p = 0.0032). The mean angle of deviation to the cephalic vein measured 3.2, –0.1, and –5.2 degrees at the upper arm, elbow, and forearm, respectively.
Conclusion: Our study found that the area of edema sparing, when present, is centered around the cephalic vein. This may be explained by the presence of the Mascagni-Sappey (M-S) pathway as it is located alongside the cephalic vein. Our findings represent a key springboard for additional research to better elucidate any trends between the presence of the M-S pathway, areas of sparing, and severity of lymphedema.
Abstract
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Background: Anatomic variations in lymphatic drainage pathways of the upper arm may have an important role in the pathophysiology of lymphedema development. The Mascagni-Sappey (M-S) pathway, initially described in 1787 by Mascagni and then again in 1874 by Sappey, is a lymphatic drainage pathway of the upper arm that normally bypasses the axilla. Utilizing modern lymphatic imaging modalities, there is an opportunity to better visualize this pathway and its potential clinical implications.
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Methods: A retrospective review of preoperative indocyanine green (ICG) lymphangiograms of
consecutive node-positive breast cancer patients undergoing nodal resection was performed. Lymphography targeted the M-S pathway with an ICG injection over the cephalic vein in the lateral upper arm.
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Results: In our experience, the M-S pathway was not visualized in 22% (n = 5) of patients. In the 78% (n = 18) of patients where the pathway was visualized, the most frequent anatomic destination of the channel was the deltopectoral groove in 83% of patients and the axilla in the remaining 17%.
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Conclusion: Our study supports that ICG injections over the cephalic vein reliably visualizes the M-S pathway when present. Further study to characterize this pathway may help elucidate its potential role in the prevention or development of upper extremity lymphedema.
Abstract
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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.
Abstract
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Lymphedema arises from impaired lymphatic function. Quantification of lymphatic contractility has previously been shown using a custom-built near-infrared imaging system. However, to broaden the clinical use of functional lymphatic measurements, these measurements need to be performed using a standard-of-care, clinically available camera. The authors propose an objective, algorithmic, and clinically accessible approach to quantify lymphatic contractility using a 3-minute indocyanine green lymphangiograph recorded with a commercially available near-infrared camera. A retrospective review of the authors' indocyanine green lymphangiography video repository maintained in a Research Electronic Data Capture database was performed. All patients with a newly diagnosed unilateral breast cancer undergoing preoperative indocyanine green lymphangiography were included in the analysis. Patient medical records were then analyzed for patient demographics, and videos were analyzed for contractility. Seventeen consecutive patients with unilateral breast cancers underwent video processing to quantify lymphatic contractility of the ipsilateral extremity in contractions per minute. All patients were women, with an average age of 60.5 years (range, 38 to 84 years). The average lymphatic contractility rate was 1.13 contractions per minute (range, 0.67 to 2.5 contractions per minute). Using a clinically accessible standard-of-care device for indocyanine green lymphangiography, the authors were able to determine lymphatic contractility rates of a normal extremity. The authors' finding falls within the range of previously published data quantifying lymphatic contractility using a research device, suggesting that the authors' technique provides a clinically accessible, time-effective means of assessing lymphatic contractility. Potential future applications include both lymphedema surveillance and evaluation of nonsurgical and surgical interventions. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Diagnostic, IV.
Christensen JM, Johnson AR, Fleishman A, Cauley R, Pardo J, Lee BT, Singhal D.
Abstract
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Lymphedema arises from impaired lymphatic function. Quantification of lymphatic contractility has previously been shown using a custom-built near-infrared imaging system. However, to broaden the clinical use of functional lymphatic measurements, these measurements need to be performed using a standard-of-care, clinically available camera. The authors propose an objective, algorithmic, and clinically accessible approach to quantify lymphatic contractility using a 3-minute indocyanine green lymphangiograph recorded with a commercially available near-infrared camera. A retrospective review of the authors' indocyanine green lymphangiography video repository maintained in a Research Electronic Data Capture database was performed. All patients with a newly diagnosed unilateral breast cancer undergoing preoperative indocyanine green lymphangiography were included in the analysis. Patient medical records were then analyzed for patient demographics, and videos were analyzed for contractility. Seventeen consecutive patients with unilateral breast cancers underwent video processing to quantify lymphatic contractility of the ipsilateral extremity in contractions per minute. All patients were women, with an average age of 60.5 years (range, 38 to 84 years). The average lymphatic contractility rate was 1.13 contractions per minute (range, 0.67 to 2.5 contractions per minute). Using a clinically accessible standard-of-care device for indocyanine green lymphangiography, the authors were able to determine lymphatic contractility rates of a normal extremity. The authors' finding falls within the range of previously published data quantifying lymphatic contractility using a research device, suggesting that the authors' technique provides a clinically accessible, time-effective means of assessing lymphatic contractility. Potential future applications include both lymphedema surveillance and evaluation of nonsurgical and surgical interventions. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Diagnostic, IV.
Abstract
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Background: Breast cancer-related lymphedema affects 700,000 breast cancer survivors in the United States. Although taxane-based chemotherapy regimens are commonly used in the treatment of breast cancer, the impact of taxanes on the lymphatic system remains poorly understood. This study aims to examine the influence of taxane-based chemotherapy on lymphatic function in breast cancer patients.
Methods: A retrospective review of a prospectively-maintained database was performed. Consecutive patients with node positive breast cancer who underwent preoperative indocyanine green (ICG) lymphangiograms were identified. Information including patient demographics, baseline measurements, cancer characteristics, and treatment information were retrieved. Preoperative ICG lymphangiography videos were analyzed and lymphatic contractility was quantified for each subject. Multiple regions of interest were selected on each lymphatic channel and signal intensity was recorded for 3 minutes to generate contractility curves. Each lymphatic contraction was identified using a novel, systematic, and algorithmic approach.
Results: Twenty-nine consecutive patients with unilateral node-positive breast cancer were included for analysis. Average patient age was 54.5 (13) years and mean BMI was 26.8 kg/m (4). The mean lymphatic contractility of patients who received taxane-based neoadjuvant chemotherapy was 0.7 contractions/minute (c/m) (n = 19) compared to 1.1 c/m in those who received no neoadjuvant therapy (n = 10), (P = 0.11). In subgroup analysis, patients who reported taxane induced neuropathy demonstrated significantly lower lymphatic contractility values than those who were asymptomatic or did not receive any chemotherapy (P = 0.018).
Conclusions: In this study, we used a novel method for quantifying and evaluating lymphatic contractility rates in routine ICG lymphangiograms. Diminished lymphatic contractility was noted in patients who received taxane-based neoadjuvant chemotherapy compared with those who did not. Taxane-based neoadjuvant chemotherapy may adversely affect the lymphatic system in the breast cancer population. A larger patient cohort with longer follow-up time is needed to validate this finding and evaluate any potential association with breast cancer-related lymphedema development.