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.

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.

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.

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.

Evolution of Anatomical Studies on the Arterial, Venous, and Lymphatic System in Plastic Surgery.

Anatomies of the vascular and lymphatic systems have been vital research topics in reconstructive surgery. Harvey was a pioneer who provided the earliest descriptions of the cutaneous vasculature in the 17th century. The concept of vascular territories of the skin was first described by Manchot. The radiographic injection method in cadavers was developed by Salman, who defined more than 80 vascular territories. The arterial system has been thoroughly investigated with the development of regional and free flaps. The concept of axial and random pattern flaps was introduced by McGregor and Morgan. Manchot's vascular territories were refined by Taylor and Palmer as the angiosome concept. Detailed information about the venous circulation is essential for reconstructive surgeries. The concept of intrinsic and extrinsic venocutaneous vascular systems was introduced by Nakajima and led to the development of the venoadipofascial flap. The importance of venous augmentation in flap survival was emphasized by Chang. The lymphatic system was discovered much later than the arterial and venous systems. Aselli was credited for discovering the lacteal vessels in the 17th century; mercury was popularly used as a contrast agent to distinguish lymphatic vessels for the next three centuries. A radiographic method in cadavers was developed by Suami. Lymphatic imaging devices are constantly upgrading, and photoacoustic imaging was recently introduced for three-dimensional visualization of architecture of superficial layers of the lymphatic and venous systems.

Use of fluorescence imaging during lymphatic surgery: A Delphi survey of experts worldwide.

BACKGROUND: Fluorescence imaging with indocyanine green is increasingly used during lymphedema patient management. However, to date, no guidelines exist on when it should and should not be used or how it should be performed. Our objective was to have an international panel of experts identify areas of consensus and nonconsensus in current attitudes and practices in fluorescence imaging with indocyanine green use during lymphedema surgery patient management. METHODS: A 2-round Delphi study was conducted involving 18 experts in the use of fluorescence imaging during lymphatic surgery, all asked to vote on 49 statements on patient preparation and contraindications (n = 7 statements), indocyanine green dosing and administration (n = 10), fluorescence imaging uses and potential advantages (n = 16), and potential disadvantages and training needs (n = 16). RESULTS: Consensus ultimately was reached on 40/49 statements, including consistent consensus regarding the value of fluorescence imaging with indocyanine green in almost all facets of lymphedema patient management, including early detection, assessing disease extent, preoperative work-up, surgical planning, intraoperative guidance, monitoring short- and longer-term outcomes, quality control, and resident training. All experts felt it was very safe, while 94% felt it should be part of routine care and that indocyanine green was superior to colored dyes and ultrasound. Nonetheless, there also was consensus that limited high-quality evidence remains a barrier to its widespread use and that patients should still be provided with specific information and asked to sign specific consent for both fluorescence imaging and indocyanine green. CONCLUSION: Fluorescence imaging with or without indocyanine green appears to have several roles in lymphedema prevention, diagnosis, assessment, and treatment.

A new indocyanine green fluorescence lymphography protocol for diagnostic assessment of lower limb lymphoedema.

INTRODUCTION: The lower limbs are a common body site affected by chronic edema. Imaging examination of the lymphatic system is useful to diagnose lymphoedema, identify structural changes in individuals, and guide interventional strategies. In this study, we used a protocol combining indocyanine green (ICG) lymphography and ICG-guided manual lymphatic drainage (MLD) for the diagnostic assessment of lower limb lymphoedema. MATERIALS AND METHODS: Patients with lower limb lymphoedema were divided into three groups by their medical history: primary, secondary cancer-related, or secondary non-cancer-related. ICG lymphography was conducted in three phases: initial observation, MLD to accelerate ICG dye transit and reduce imaging time, and imaging data collection. Lymphatic drainage regions were recorded, and the MD Anderson Cancer Center ICG staging was applied. We collected routine lymphoedema assessment data, including limb volume and bioimpedance spectroscopy measurements. RESULTS: Three hundred and twenty-six lower limbs that underwent ICG lymphography were analyzed. Eight drainage regions were identified. The ipsilateral inguinal and popliteal were recognized as the original regions, and the remaining six regions were considered compensatory regions that occur only in lymphoedema. More than half of the secondary cancer-related lower limb lymphoedema (57.6%) continued to drain to the ipsilateral inguinal region. The incidence of drainage to the ipsilateral inguinal region was even higher for the primary (82.8%) and secondary non-cancer-related (87.1%) groups. Significant associations were observed between cancer-related lymphoedema and the presence of compensatory drainage regions. CONCLUSIONS: We proposed a prospective ICG lymphography protocol for the diagnostic assessment of lower limb lymphoedema in combination with MLD. Eight drainage regions were identified, including two original and six compensatory regions.

Retrograde lymph flow in the lymphatic vessels in limb lymphedema.

OBJECTIVE: Retrograde movement of lymph owing to damaged and/or incompetent valves in the lymphatic vessels has been considered a pathological feature of lymphedema. This study aimed to determine the prevalence of retrograde lymph flow and the characteristics of patients with this condition using indocyanine green (ICG) lymphography. METHODS: An audit of 679 patients with upper or lower limb swelling who underwent ICG lymphography was undertaken over a 4-year period. Harvey's technique was applied to identify retrograde flow in the lymph collecting vessel during ICG lymphography. The characteristics of patients with retrograde lymph flow were recorded. RESULTS: Twenty-one patients (3.7%; lower limb, n = 19; upper limb, n = 2) were identified as having retrograde flow in lymph collecting vessels out of 566 confirmed lymphedema patients (lower limb, n = 275; upper limb, n = 291). Of the two patients with upper limb lymphedema (ULLE), one had a short segment of retrograde lymph flow in the forearm. The other patient with ULLE and one patient with lower limb lymphedema (LLLE) were previously diagnosed with lymphedema-distichiasis syndrome. Of the remaining 18 patients with LLLE and retrograde lymph flow, nine had initiating insect bites with lymphangitis and three had palpable benign enlarged inguinal lymph nodes evident before lower limb swelling onset. None had cancer-related LLLE. CONCLUSIONS: Retrograde lymph flow with valve incompetence in the lymph-collecting vessels was a rare finding in ULLE and a relatively uncommon finding in LLLE, contradicting the conventional understanding of pathological changes in lymphedema. ICG lymphography identified anticipated retrograde lymph flow in two patients with lymphedema distichiasis. In the remaining patients, retrograde lymph flow may have resulted from toxic or asymptomatic lymphangitis but there was no association with secondary cancer-related lymphedema. These findings have implication for conservative management as well as lymphovenous anastomosis surgery where both ends of a transected lymph collecting vessel would be potential targets for anastomoses.

Personalizing Conservative Lymphedema Management Using Indocyanine Green-Guided Manual Lymphatic Drainage.

Background: The Australian Lymphoedema Education, Research and Treatment Program (ALERT) at Macquarie University in Sydney, Australia is one of the flagship programs of Australia's first fully integrated academic health sciences centre, MQ Health. The aim of this study was to describe our findings of compensatory drainage demonstrated by indocyanine green (ICG) lymphography in cancer-related upper and lower limb lymphedema and how this may be translated into clinical practice. Methods and Results: Retrospective data from 339 patients aged between 18 and 90 years with secondary cancer-related unilateral or bilateral lymphedema of the upper or lower limb who underwent ICG lymphography assessment at the ALERT clinic between February 2017 and March 2020 were analyzed. In patients with upper limb lymphedema, the ipsilateral axilla was the most frequent drainage region (74.9%), followed by clavicular (41.8%) and parasternal (11.3%). For patients with mild upper limb lymphedema, 94.4% drained to the ipsilateral axilla. No patients drained to the ipsilateral inguinal region. For lower limb lymphedema, drainage to the ipsilateral inguinal was most common (52.3%), followed by contralateral inguinal (30.7%), popliteal (26.1%), and gluteal (21.6%) regions. Three main patterns of superficial lymphatic compensation were identified based on which anatomical structure carried lymph fluid. Manual lymphatic drainage (MLD) was used to facilitate movement of the dye. A light/effleurage technique was sufficient to move the dye through patent lymphatic vessels; a slow and firmer technique was required to move the dye through areas of bridging dermal backflow. Conclusion: The introduction of ICG lymphography to our program and its use in guiding personalized conservative management plans, including facilitative MLD techniques, has translated into clinical practice and changed research and educational priorities within the ALERT program.

Real-Time Visualization of the Mascagni-Sappey Pathway Utilizing ICG Lymphography.

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. 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. 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%. 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.

Anatomical Theories of the Pathophysiology of Cancer-Related Lymphoedema.

Lymphoedema is a well-known concern for cancer survivors. A crucial issue in lymphoedema is that we cannot predict who will be affected, and onset can occur many years after initial cancer treatment. The variability of time between cancer treatment and lymphoedema onset is an unexplained mystery. Retrospective cohort studies have investigated the risk factors for lymphoedema development, with extensive surgery and the combination of radiation and surgery identified as common high-risk factors. However, these studies could not predict lymphoedema risk in each individual patient in the early stages, nor could they explain the timing of onset. The study of anatomy is one promising tool to help shed light on the pathophysiology of lymphoedema. While the lymphatic system is the area least investigated in the field of anatomical science, some studies have described anatomical changes in the lymphatic system after lymph node dissection. Clinical imaging studies in lymphangiography, lymphoscintigraphy and indocyanine green (ICG) fluorescent lymphography have reported post-operative anatomical changes in the lymphatic system, including dermal backflow, lymphangiogenesis and creation of alternative pathways via the deep and torso lymphatics, demonstrating that such dynamic anatomical changes contribute to the maintenance of lymphatic drainage pathways. This article presents a descriptive review of the anatomical and imaging studies of the lymphatic system in the normal and post-operative conditions and attempts to answer the questions of why some people develop lymphoedema after cancer and some do not, and what causes the variability in lymphoedema onset timing.

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.

Optimizing Quality of Life for Patients with Breast Cancer-Related Lymphedema: A Prospective Study Combining DIEP Flap Breast Reconstruction and Lymphedema Surgery.

BACKGROUND: Patients with breast cancer-related lymphedema can be treated with a simultaneous deep inferior epigastric perforator (DIEP) flap, vascularized inguinal lymph node transfer, and lymphovenous anastomosis for aesthetic breast reconstruction and lymphedema in one operation. METHODS: The authors performed a comparison of prospectively followed patients who underwent free flap breast reconstruction with vascularized inguinal lymph node transfer and anastomosis to a retrospective cohort of patients who underwent free flap breast reconstruction with vascularized inguinal lymph node transfer alone. RESULTS: Thirty-three patients underwent DIEP flap reconstruction with vascularized inguinal lymph node transfer and lymphovenous anastomosis, and 21 received a free flap with lymph node transfer alone. There were no significant differences in demographics, adjuvant chemotherapy, or radiation therapy. The average number of nodes removed was also equivalent (21.2 versus 21.4 nodes). Two anastomoses per patient, on average, were performed (range, one to four) in the combined cohort, and all patients (100 percent) reported a subjective improvement in symptoms, compared with 81.0 percent of patients undergoing only lymph node transfer (p = 0.019). Perometer measurements demonstrated a significant reduction between the groups at early time points [3 months, 40.7 percent versus 20.0 percent (p = 0.037); 6 months, 57.0 percent versus 44.5 percent (p = 0.043)]; however, the difference was not statistically significant at 12 months (60.4 percent versus 57.8 percent; p = 0.43). CONCLUSION: This is the first prospective study demonstrating the safety and efficacy of a combined DIEP flap with vascularized inguinal lymph node transfer and lymphovenous anastomosis, which may be superior to lymph node transfer alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Vascularized Lymph Node Transfer for Patients with Breast Cancer-Related Lymphedema Can Potentially Reduce the Burden of Ongoing Conservative Management.

Background: Vascularized lymph node transfer (VLNT) microsurgery is conducted in selected specialist lymphatic programs as a surgical treatment option for breast cancer-related lymphedema (BCRL) with variation in treatment outcomes. Methods and Results: Ten patients with BCRL underwent VLNT from 2012 to 2015. Donor sites were the inguinal (n = 6) or supraclavicular fossa/neck (n = 4) regions and recipient sites were the axilla (n = 6) or elbow regions (n = 4). Outcomes included changes in limb volume and extracellular fluid ratios, postoperative garment use, number of cellulitis episodes, and self-reported symptom improvement. At a mean follow-up of 46 months from surgery (range: 28-66 months), the excess volume in the affected arm had reduced (n = 4) or remained stable (n = 1) for 5 of 10 patients (50%) (mean change: -106.4 mL, range: -515.5 to +69.6 mL). Four of these five patients had also reduced (n = 3) or discontinued (n = 1) wearing compression garments and three reported a reduction in episodes of cellulitis. The remaining five patients had an increase of over 100 mL in postoperative excess volume (mean change: 295.8 mL, range: 142.1-382.8 mL). Three of these five patients reported noncompliance with compression garments. Despite the increase in limb volume, some patients reported softness in swelling (n = 3) and better response to conservative treatment (n = 1). Conclusion: Our results warrant continuation of VLNT as a surgical treatment option for patients with BCRL and show that the burden of conservative management such as wearing garments can be reduced over time for some patients. Longer term follow-up with standardized measures across all centers is required to further investigate VLNT.

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.