LYMPHOLOGY

Pulmonary Lymphatics History, Anatomy, and Pathophysiology: Emerging Knowledge and a Look to the Future
Kelly B and Daley S
Central lymphatic disorders of the lung have not received intense investigation. Lymphatic system physiology is presented in the context of historical developments and basic lung lymphatic anatomy is reviewed followed by emerging characteristics of primary and secondary pathophysiological disturbances of lymphatic involvement in a number of pulmonary diseases including Gorham-Stout disease, pulmonary edema and infections and inflammatory conditions including lymphangioleiomyomatosis (LAM). The future includes potential molecular targeting of lymphangiogenesis or lymphatic vessels for interventional occlusion. This article is an amalgamation of presentations at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease and as part of a Special Symposium on the Lymphatic system of the Heart and Lung in Health and Disease at the 26th International Congress of Lymphology meeting held in Barcelona, Spain, September 2017, which has been updated to 2024.
Physiology and Functional Pathology of the Lymphatic System with Implications for the Fontan Patient
Hjortdal V
Contractile function of the collecting lymphatic vessels depend on smooth muscle cells, one-way valves, surrounding tissues, and regulation by the autonomic nervous system. The potentially deleterious effects of the Fontan procedure and elevated central venous pressure on lymphatic function leading to life-threatening complications are described. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease.
Looking Backward and Looking Forward: Revisiting "Clinical Usefulness of Thoracic Duct Cannulation"
Witte MH
Over the past decade, there has been a resurgence of interest in the thoracic duct and central lymphatic system and its disorders, stimulated by advances in interventional magnetic resonance imaging techniques and urgent challenges in the clinical management of lymphatic malformations and lymphatic complications from congenital heart disease. The following chapter reprinted here written shortly after the formal founding of the discipline of lymphology and the International Society of Lymphology, describes early efforts, and also suggests future directions now being revisited and others yet to be explored (1).
Brain Lymphatics: Rediscovery and New Insights into Lymphatic Involvement in Diseases of Human Brains
Bartlett MJ, Erickson RP, Hutchinson EB, Witte RS and Witte MH
The brain's lymphatic system is comprised of a glymphatic-meningeal-cervical lymphatic vessel pathway. The study of its mechanism and pathophysiology in neurodegenerative disease has been one of the most exciting topics in basic and translational neuroscience of the last decade. However, while there has been some debate about when the meningeal lymphatics were discovered, it cannot be denied that studies in preclinical models and humans in this century represent a monumental step forward in our understanding of how the brain removes metabolic waste, the role this system plays in neurodegenerative disease, and, most importantly, its potential as a novel therapeutic target. This is a summary of the history, functional anatomy, and role of the brain's lymphatics in neurodegenerative disease.
Can Acupuncture be a Part of the Treatment for Breast Cancer-Related Lymphedema? A Systematic Review of the Safety and Proposed Model for Care
Kim JK, Loo C, Kim JS, Pranskevich C and Gordon OK
Acupuncture is a potential therapy for breast cancer-related lymphedema (BCRL). Despite a recent meta-analysis on efficacy, data on acupuncture safety in BCRL are lacking. Current clinical guidelines recommend avoiding needling in the upper extremity affected by lymph node dissection. We undertook a systematic review focusing on acupuncture safety and treatment protocols in clinical trials for BCRL. Literature searches were conducted in PubMed, Ovid, CINAHL, and Cochrane library. Eight clinical trials on acupuncture for BCRL were analyzed. The Standards of Acupuncture intervention (STRICTA 2010) and Cochrane risk of bias (RoB2 2019) were applied to assess methods for acupuncture interventions within Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Quantity and severity of adverse events (AE) were reviewed. A total of 189 subjects participated in 8 clinical trials with 2965 acupuncture treatments. No serious adverse events (SAE) were reported regardless of treatment laterality or protocol, with only a single grade 2 skin infection in 2,965 total treatments (0.034%), including 1,165 bilateral and 225 ipsilateral treatments. Our comprehensive review of clinical trials of acupuncture for BCRL demonstrated no significant adverse events in 2,965 treatments, including 1,390 in the affected limb. An approach for routine integration of acupuncture into BCRL maintenance therapy is proposed.
Current Role of Pneumatic Compression Therapy in Lymphedema Care: A Scoping Review of Persistent Debates and New Applications
Pandy SK, Ozmen BB, Morkuzu S, Xiong Y, Kemp E and Chen WF
Access to trained lymphedema care providers remains limited making patient-driven management solutions essential. One such option, sequential intermittent pneumatic compression (IPC), has gained traction as a supportive tool for lymphedema management. While newer IPC devices and innovative applications are being introduced to the market, questions regarding the safety and efficacy of this technology persist. This underscores the importance of reviewing current literature to understand IPC's evolving role in lymphedema care and to identify existing knowledge gaps. A scoping review of literature was conducted across various databases using PRISMA-ScR guidelines. The eligibility criteria included articles published in English language from database's inception to June 2023, discussing IPC's safety, and/or efficacy, and/or optimal modes and settings for lymphedema management. Review articles and case reports and original studies with unclear outcome measures were excluded. The review identified 49 eligible studies from an initial pool of 614 articles, consisting of 12 randomized controlled trials, 25 cohort studies, and 12 experimental studies. Most studies (44) focused on limb lymphedema, while five examined non-limb regions. Sample sizes varied widely, ranging from 10 to 718 participants, reflecting differences in studies' power. Minor adverse events were reported in six studies, including transient skin irritation, paresthesia, and rare cases of genital edema. Efficacy data indicated that IPC, whether used with or without manual lymphatic drainage (MLD), improved limb volume, quality of life, and reduced infection rates, although results varied according to treatment protocols and limb type. The addition of IPC improved compliance of decongestive therapy and increased patient satisfaction. IPC sessions ranged from 45 to 120 minutes per day, conducted 3 to 7 days per week, with pressures set at 60 to 120 mmHg for lower limbs and 25 to 60 mmHg for upper limbs. Higher pressures were associated with more significant limb volume reduction in the lower limbs. A cost analysis indicated that IPC could potentially lead to healthcare savings by reducing infections and hospital admissions. IPC application also showed promising results in head and neck lymphedema, though results for trunk lymphedema were equivocal. Future research should aim to refine IPC protocols in different regions of the body and ascertain its long-term benefits.
Classification of Breast Lymphedema in a Racially Diverse Cohort
Chen JG, Perez CB, Coogan A, Kim T, Sanchez-Johnsen L, Ohara K, Nelson C, Rizzo DM, Matt J, Watson EJ, Sowden MM and Ahern TP
Breast lymphedema is a common sequela of breast conservation that delays healing and reduces quality of life. No rigorous classification system exists for this condition. We explored approaches for classifying breast lymph-edema based on breast ultrasound, physical exam, and patient-reported outcomes. We enrolled 80 patients from two institutions. Each site enrolled 30 invasive breast cancer patients treated with breast conservation and radiotherapy, and 10 control patients evaluated for benign breast complaints. All patients underwent bilateral breast ultrasound to measure dermal thickness and were assessed for physical signs of breast lymphedema. Patients reported quality of life impacts on standard questionnaires. We derived breast lymphedema classifiers using (1) a simple ultrasound-based metric of dermal thickness difference, and (2) a multiparameter machine learning classifier based on dermal thickness difference, physical exam, and patient-reported impacts. Ultrasound-defined breast lymphedema was present in 72% (95% CI: 59 to 82%) of invasive breast cancer patients. The multiparameter classifier identified three distinct patient groups: one with little evidence of breast lymph-edema, and two with increasingly severe breast lymphedema. A simple ultrasound-based measure and a novel multiparameter classifier both show promise for rigorous classification of breast lymphedema and warrant further development in larger patient cohorts.
Lymphatic Imaging and Intervention in Central Lymphatic Disorders
Dori Y
Advances in lymphatic imaging for both diagnosis and intervention are reviewed, and specific examples given for protein-losing enteropathy, multi compartment lymphatic failure, congestive heart failure. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease.
Letter: BioBridge Collagen Matrix for Lymphedema Therapy
Paukshto M and King G
Letter in response to article: Witt, M, A Ring: Handley's Thread Lymphangioplasty Vs. BioBridge Collagen Matrix for Lymphedema Therapy-Old Wine in New Bottles? Lymphology 56 (2023) 110-120.
The Relationship Between Disease Variables, Pain Coping, and Functional Status of Patients with Lower Extremity Lymphedema
Huseyinli L, Aydin AB, Altug D, Cakmak MA, Tuncer OB, Tuglu Y, Kenis-Coskun O and Sanal-Toprak C
The purpose of this study is to investigate the relationship between reported symptoms, functional outcomes, and pain coping mechanisms in participants with lower limb lymph-edema. This research has been designed as cross-sectional. Participants' age, sex, height, weight, pain, tightness, and stiffness levels reported by the participants were documented with a 10 cm visual analogue scale. The Pain Coping Inventory scale has been used to evaluate coping strategies. Functional status was measured with timed-up-and-go test (TUGT), six-minute walk test (6MWT), and quadriceps muscle strength measurement with a hand-held dynamometer. The functional outcomes were also measured in a healthy control group. The difference in muscle strength in both lower extremities was evaluated using the t-test, and the correlations were assessed using the Spearman correlation test. Twenty-eight participants with lymphedema (PWL) and 23 controls were included in the study. Twenty-three of the PWL were female (82%). The mean age of the PWL was 54.43 ± 14.12, and the mean body mass index was 33.84 ± 6.17. There were no significant differences between the PWL and healthy controls regarding age and sex. The mean muscle strength of the affected lower extremity was 4.21 ± 1.10 kgs and was significantly lower compared to the contralateral lower extremity (6.10 ± 2.98 kgs) and control group (10.92 ± 1.25 kgs) (p<0.05 and p=0.007 respectively). In functional outcomes, TUGT was significantly worse in PWL when compared to the control group (11.17 ± 3.28 seconds vs 9.04 ± 1.33 seconds, p=0.004). A significant correlation was observed between the TUGT result and the level of tightness felt by the PWL (r= 0.43, p=0.02). There were significant correlations between pain coping strategies and patient reported symptoms. No correlations were found between coping strategies and functional measurements. Lymphedema disrupts the functional status of the participants, and these functional disruptions may be related to symptoms reported by the participants. The correlation between pain coping strategies and patient reported tightness may indicate that tightness may be more influential on coping with pain, but further research is needed to determine a cause-and-effect relationship.
Author Response to Letter: BioBridge Collagen Matrix for Lymphedema Therapy
Witt M and Ring A
Author's response to letter concerning article: Witt, M, A Ring: Handley's Thread Lymphangioplasty Vs. BioBridge Collagen Matrix for Lymphedema Therapy-Old Wine in New Bottles? Lymphology 56 (2023) 110-120.
Validation of a New Measurement Device (Perikit®) For Perimetry and Volumetry of The Lower Limb: Metrological and Intra-Observer Comparative Study
Louys M, Mathieu M, Harnie S and Adriaenssens N
Accurate quantitative assessments are crucial to understanding development of diseases and their effective treatments. Various validated perimetry and volumetry measurement methods for patients with lymphedema exist and each has its own advantages and limitations and choosing the right instrument is essential. PeriKit® (PK) is a new measurement device that requires validation. This single-blind, cross-sectional study compared three assessment methods for perimetry and volumetry of the lower limb: conventional tape measure (CTM); optoelectronic infrared volumeter (Perometer®) (OS) as the gold standard); and PK. Correlation coefficients between measurements were "strong" to "very strong". The ICC of the lower limb was the highest for PK (0.995), followed by the CTM (0.986) and the OS (0.974). PK had the lowest dispersion of results for all segments. Despite its poor reliability, CTM is widely used because of its low cost and portability. The OS is simple, ergonomic, and doesn't require calibration, but suffers from imperfections such as the absence of distal extremities (i.e. feet, hands, fingers, etc.) as well as cost. PK has succeeded in reducing many of the problems associated with measurement thanks to its standardized methodology which offers high repeatability. PK can replace OS and CTM, but OS or CTM can't replace PeriKit® because they are more dispersed and less accurate.
The Added Effect of Artificial Intelligence in CT Assessment of Abdominal Lymphadenopathy
Meshref RA, Saleem IA, Salama AA, Darwish SH, El-Kholy SM and Mohame EI
Lymphadenopathy is associated with lymph node abnormal size or consistency due to many causes. We employed the deep convolutional neural network ResNet-34 to detect and classify CT images from patients with abdominal lymphadenopathy and healthy controls. We created a single database containing 1400 source CT images for patients with abdominal lymphadenopathy (n = 700) and healthy controls (n = 700). To train, test, and cross-validate the ResNet-34 classifier to detect specific lesions, we first resized and normalized all images. Then, we randomly divided the 1400 images into 88 groups of 16, and the classifier was trained to identify and label lesions using automatic volume delineation 3D reconstruction of target areas. The ResNet-34 had a diagnostic accuracy with receiver operating characteristic (ROC) curves of the true-positive rate versus the false-positive rate with the area under the curve (AUC) of 0.9957 and 1.00 for abdominal lymphadenopathy and healthy control CT images, respectively. This accuracy implied identical high sensitivity and specificity values of 99.57 % and 100% for the two groups. The added effect of ResNet-34 is a success rate of 99.57% and 100% for classifying random CT images of the two groups, with an overall accuracy of 99.79% in the testing subset for detecting and classifying lymph node lesions. Based on this high classification precision, we believe the output activation map of the final layer of the ResNet-34 is a powerful tool for the accurate diagnosis of lymph node lesions of abdominal lymphadenopathy from CT images.
Liver Lymphatic Anatomy and Its Role in Systemic Health and Disease
Smith C
Lymphatic anatomy of the abdomen is reviewed with focus on hepatic and mesenteric vessels in normal and pathologic conditions. Anatomy and pathophysiology is highlight using both specialized fluoroscopy and T2 Dynamic Contrast MR lymphangiography (DCMRL). Plastic bronchitis, chylothorax, protein losing enteropathy, and both cirrhosis and ascites due to hepatic lymphatics are highlighted. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease.
Toe-Brachial Index Rise in Lymphedema Patients with Multilayer Bandage
Trihan JE, Mestre S, Quere I, Laneelle D and Perez-Martin A
Multilayer compression bandaging (MLB) remains the primary treatment in lymphedema in association with manual lymphatic drainage. However, MLB can be contraindicated in patients with advanced lower extremity artery disease (LEAD). Presently, the prevalence of LEAD in lymphedema patients remains unknown. The goals of this study included i) to estimate the prevalence of LEAD, defined by toe-brachial index (TBI) less than 0.7, and ii) to measure the evolution of TBI after 30 min of MLB. A cross-sectional study was performed during a 3-month period on patients presenting with lower extremity lymphedema. Demographic data, basal TBI (T=0min) and TBI after 30 min of MLB at rest (T=30min) were recorded. Twenty-four patients with a total of 29 lymphedema limbs were included with a mean age of 62 years-old [Inter-quartile range (IQR) = 48 - 68] and 65.5% presenting with primary lymph-edema. Non-symptomatic LEAD, defined as TBI < 0.7, was found in 8 lymphedema limbs (27.6%). Advanced age, severe stages, and longer duration of lymphedema were associated with LEAD in univariate analysis. Median TBI increased significantly between T=0min and T=30min of MLB: 0.81 [IQR: 0.68 - 0.93] and 0.96 [IQR: 0.82 - 1.12] respectively (p= 0.004). Distal localization of lymphedema was associated with a decrease in TBI at T=30min in univariate analysis. Subclinical LEAD was found in over a quarter of lymphedema limbs and was more frequent in patients with advanced age, severe stages, and longer duration of lymphedema. Based on these findings, sub-clinical peripheral artery disease may be widely underestimated in lymphatic pathologies.
Imaging and Interventional Management of Lymphatic Disorders
Pinto E
Lymphatic flow disorders are reviewed, and a classification based on magnetic resonance lymphography findings outlined. Examples of successful interventional management based on this classification are provided. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease.
Retrograde Thoracic Duct Access for Embolization of Lymphatic Malformations in a Child with Congenital Heart Disease and a Plexiform Thoracic Duct Variant
Saferite A, Blair BJ, Price AM, Fox KA and Seckeler MD
The physiologic sequelae of the atypical vasculature in patients with congenital heart disease can result in potentially fatal lymphatic complications, especially after corrective cardiac surgery. Transcatheter embolization of the thoracic duct or lymphatic collaterals can reduce morbidity and mortality in these patients. While typically performed transabdominally via an antegrade approach, retrograde embolization may be preferable in cases where this is not feasible, including in rare variants of thoracic duct anatomy. We present a case of a child with severe chylothorax after congenital cardiac surgery who was found to have thoracic lymphatic malformations and a plexiform thoracic duct variant who underwent successful embolization of the malformations.
Returning the Central Lymphatic System to the Center of Lymphology
Witte MH
After the introduction of conventional oil contrast lymphography and the founding of the discipline of lymphology, great impetus was given to investigating central lymphatic system and its disorders along with lymphatic involvement and specifically lymphostasis in common diseases of major organs such as the liver (cirrhosis) and heart (heart failure). Gradually interest shifted to more peripheral disorders such as limb lymphedema and its treatment by physical and surgical measures. At the same time, basic lymphology turned to the study of isolate-ed ex vivo and in vitro, including lymphatic endothelial models and more recently, molecular lymphology focusing on lymphatic growth and modulating factors, genes and proteins under-lying primary lymphedema, and more potential biomarkers of lymphatic disease have gained prominence. However, it has been advances in lymphatic imaging, namely lymphoscintigraphy with SPECT-CT high resolution 3-D pictures and magnetic resonance imaging (contrast and non-contrast) of the peripheral and particularly central lymphatic system by more invasive means combined with endovascular interventional techniques to treat complex and life-threatening lymphatic disorders that has returned the central lymphatic system to the center of lymphology, where the journey began.
Staging System of Three-Dimensional Non-Contrast Magnetic Resonance Lymphography in Secondary Lower Extremity Lymphedema
Kageyama T, Shiko Y, Kawasaki Y, Miyazaki T, Sakai H, Tsukuura R and Yamamoto T
Non-contrast magnetic resonance lymphography (NMRL) has been reported to be efficient for the evaluation of lymphedema. However, its characteristic findings and grading system are yet fully clarified. We retrospectively examined 48 patients with secondary lower extremity lymphedema (LEL) who underwent NMRL and indocyanine green lymphography (ICG-L). The lower extremity was divided into 5 areas for NMRL evaluation, and the prevalence of characteristic NMRL findings (Mist, Spray, and Inky) and the 3D NMRL stage that we proposed were compared according to the ICG-L stage. All characteristic NMRL findings increased in prevalence with the progression of the ICG-L stage (Mist, Spray, and Inky: P < 0.001, < 0.001, and < 0.001, respectively) Pre-dominant findings in each segment changed significantly from Mist in the ICG-L stage 0-Ⅱ, to the Spray in ICG-L stage Ⅲ-Ⅳ, to the Inky in ICG-L stage Ⅴ (P < 0.001). 3D NMRL stage significantly advanced with the progression of the ICG-L stage (rs = 0.72; P < 0.001). We believe this severity grading system is useful for efficient evaluation of fluid accumulation in LEL patients.
Defocused and Radial Shock Wave Therapy, Mesotherapy, and Kinesio Taping Effects in Patients with Lipedema: A Pilot Study
Michelini S, Musa F, Vetrano M, Santoboni F, Nusca SM, Latini E, Trischitta D, Michelini S, Iosa M and Vulpiani MC
The aim of this pilot study was to investigate the effects of defocused and radial shock wave therapy, mesotherapy, and kinesio taping on pain, circumferences of lower limbs, echographic/ elastosonographic pattern of subcutaneous adipose tissue (SAT), and quality of life in patients with lipedema. Fifteen women affected by lower limb lipedema in stage II were treated with shock wave therapy, mesotherapy, and kinesio taping on thighs and legs (eight sessions, twice a week). The primary outcome was pain, as assessed by Numeric Rating Scale (NRS). Secondary outcomes included the limb circumferences measurements, the SF-12 Health Survey for quality of life, the International Classification of Functioning (ICF) for disability, and echographic/ elastosonographic changes of SAT. Significant reductions of pain and circumference measurements were seen in patients at each follow up. This was associated with significant reduction of thickness, echographic pattern improvement, and increased elasticity of SAT, with consequent positive impact on the quality of life and disability reported by the patients. The results demonstrate improved clinical and functional ultrasound findings in patients affected by lipedema in the early stages of lower limbs, and this combination therapy needs to be investigated in larger populations at multiple centers to confirm the findings.
Investigation of the Effect of Lymphedema Self-Care Patient School on Functionality, Quality of Life, Lymphedema Volume, and Body Value in Patients with Lower Extremity Lymphedema: A Quasi-Experimental Study
Eyigor S, Deveci Kocbilek Z, Ozgur Inbat M, Caliskan Kabayel S and Akgu BD
This study examined the effect of lymphedema self-care patient school education on patient functionality, quality of life, body value, and lymphedema volume in patients with lower extremity lymphedema. The study utilized a single-group quasi-experimental design. The study sample included 21 patients with primary and secondary lower extremity lymphedema. A multidisciplinary team created a face-to-face lymphedema self-care patient education program that lasted three weeks with four hours each week to enhance lymphedema self-care management. Data collected from participants prior to the program and then at third and sixth months via Lower Extremity Functional Scale (LEFS), Lymphedema Functionality, Disability and Quality of Life Scale in Lower Extremity Lymphedema (LYMPH-ICF-LL), Body Value Scale, and extremity volumes. The average age of the patients was 54.85±11.99 years and two-thirds had secondary lymphedema. A statistically significant difference was found in the mean scores of LEFS (p<0.001), LYMPH-ICF-LL total (p= 0.006) in the 3rd and 6th months after the completion of the program, and in the lymphedema volume change (p= 0.031) in the 6th month. It was found that the lymphedema self-care patient school improved functionality and quality of life in patients with lower extremity lymphedema and decreased lymphedema volume. This lymphedema self-care patient education pro-gram is a safe and effective educational method for self-care management in individuals with lower extremity lymphedema.