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.

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.

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.

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.

There is a lack of large epidemiological studies focusing on the prevalence of lymphedema. Vital registration data from the United States (US) (1999-2020) and Veneto, Italy (2008-2021) were analyzed. Lymphedema-related deaths were identified using disease-specific ICD-10 codes and served to estimate the burden of disease in the general population. We studied (i) the lymphedema-specific proportionate mortality as a proxy of the disease-specific prevalence, (ii) the prevalence of lymphedema in key patient subgroups, and (iii) age and sex-specific mortality rates. The prevalence of lymphedema increased over the last two decades with marked sex-specific differences: in the US, the estimated prevalence of lymphedema was 2.7 per 10,000 deaths for women and 1.5 per 10,000 deaths for men. In Veneto, the prevalence was 3.0 per 10,000 deaths for women and 1.1 per 10,000 deaths for men. The prevalence of lymphedema was 2- to 20-times in specific subgroups of patients, including those with obesity, skin infections, hypertension, diabetes mellitus, breast/gynecological cancers, and venous thromboembolism. The estimated prevalence of lymphedema is 2- to 3-times higher than previously thought and has been increasing for the past two decades. These results will serve as a reference for future research in this field.

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.

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).

Liposuction for treatment of lymphedema is an effective and time-tested treatment. However, as there is a fear regarding further lymphatic damage caused by liposuction, we objectively compared lymphatic function pre- and post-liposuction. All patients with solid-predominant lymphedema who were treated during the study period of June 2014 and November 2018 were included. Patients were assessed using patient-reported baselines/outcomes, lymphedema- specific quality of life scale (LYMQOL), limb circumference/volume measurements, and indocyanine green lymphography (ICGL) preoperatively and at predefined postoperative time intervals. Fifty-seven limbs from 41 patients were included. Mean lipoaspirate volumes were 2035 mL, 5385 mL, and 3106 mL for the arm, thigh, and leg, respectively with a mean adipose fraction of the lipoaspirate of 71%. All patients underwent redundant skin excision with the "flying squirrel" technique. The mean follow-up was 10.7 months (range 3 - 48 months) with a mean limb volume reduction of 32.2% and all patients reporting satisfactory relief of symptoms. All showed statistically significant improvement in LYMQOL in symptoms, appearance, and function. On ICGL, none showed worsened lymphatic drainage, rather, all showed improved lymph drainage. Furthermore, the improved lymph drainage was found to be progressive during the study period in all patients. Our study results demonstrate that treating extremity lymphedema with liposuction does not worsen lymphatic function and in fact, paradoxically, it induces progressive improvement in lymph drainage.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The proposed term "oncolymphology" encompasses the intimate relationship between cancer growth and the immune responses.

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.

Lipedema is usually thought of as a dis-ease of women. Potentially diagnostic comparative data is needed between patients with lip-edema and those with lower limb lymphedema (LLL). Since there is no gold standard to diagnose lipedema, some promising modalities such as Tissue Dielectric Constant (TDC) need to be investigated among patients with lipedema and lymphedema. This study was completed with a total of 26 patients (14 lipedema, 12 LLL). Local tissue water was assessed with Moisture MeterD compact (DelfinTech, Kuopio, Finland) according to the TDC method at 300 MHz within a 2.5 mm tissue penetration depth via the following reference points: Thigh, calf (20 cm upper and lower point of knee level, respectively), and malleoli (5 cm upper point of medial malleolus). Patients with LLL showed significantly higher TDC values and interlimb TDC ratios in all affected points and unaffected malleolus points compared to patients with lipedema. No significant difference was achieved between genders with LLL in all reference points. The area under the curve (AUC) for thigh, calf, and malleolus reference points were found as 0.851 (95%CI .678-1.00), 0.801 (95% CI 0.612-0.989) and 0.786 (95%CI 0.596-0.976), respectively. Patients with LLL showed significantly higher TDC values compared to patients with lipedema, these differences should be carefully interpreted in patients with bilateral LLL and those with lipo-lymphedema.

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.