Lymphatic Research and Biology

Generalized lymphatic anomalies (GLA) are complex vessel malformations that can impair lymphatic function. Potential GLA complications include lipid-rich lymph in the thoracic space or peritoneal cavity, respectively chylothorax and chylous ascites. To reduce the potential for chyle accumulation, GLA patients limit dietary fats. We hypothesized that dietary fatty acid composition impacts the potential for lymphatic dysfunction and chyle accumulation in GLA.

Adipose-specific overexpression of lymphatic growth factors has demonstrated lethal chylothorax in mice. Here, we utilized mice with inducible adipocyte overexpression of vascular endothelial growth factor-D (VD mice) to mimic lymphatic proliferation in GLA and assessed the incidence of chyle accumulation on a mixed high fat diet (HFD), high saturated fat diet (HSFD), or high unsaturated fat diet (HUSFD). Lipid transport was assessed by uptake rates of bolus oral triglyceride load and mesenteric fat analysis. Lymphatic expansion and inflammation were determined by whole mount immunofluorescence and gene expression. Body composition was assessed by MRI. HSFD 2-month wildtype groups resulted in an increase in TNF-α, IL-6, and IL-10 expression compared with chow-fed controls. The chyle accumulation incidence was highest in HFD-fed mice compared with either HSFD or HUSFD. Strikingly, increased mortality was observed irrespective of which high fat diet was consumed after administration of a bolus lipid load.

Chronic HFD increases risk of chyle accumulation, however increased mortality was driven particularly by a bolus lipid load in VD mice. These findings suggest that although chronic HFD increases chyle accumulation risk, a single large meal feeding may increase risk of lethal chylothorax instances for GLA patients.

We aimed to clarify whether pathological changes in skin and subcutaneous tissue with lymphedema affected the skin hardness sensed by palpation.

In 50 patients with unilateral legs with lymphedema (LE), the skin hardness of the lower inner thigh and lower inner calf was determined using a scale ranging from 1 (softest) to 7 (hardest) based on palpation. Then, the skin hardness was correlated with the measurements of skin/subcutaneous tissue ultrasonography images obtained from the palpated parts. Multivariate logistic regression analysis demonstrated that dermal thickness was a significant factor that affected the difference in skin hardness between the LE and the contralateral asymptomatic leg for both thigh (p < 0.05) and calf (p < 0.01). When the thigh and calf in the LE were individually studied, subcutaneous echogenicity (p < 0.05), indicating subcutaneous inflammation/fibrosis, and subcutaneous thickness (p < 0.01) also seemed to affect skin hardness, respectively.

The skin hardness sensed in the LE seemed to be affected predominantly by dermal thickening. In addition, the pathological changes in the subcutaneous tissue caused by LE seemed to have an impact on skin hardness. Clinical Trial Registration number 2020–150.

Recurrent cellulitis has high impact on physical, psychological, and social aspects for lymphedema patients. We speculated that identification of characteristics of skin and subcutaneous adipose tissue with cellulitis history can help considering new approach for prevention of recurrent cellulitis in lymphedema patients. Therefore, in this study, we aimed to noninvasively identify the ultrasonographic features of skin and subcutaneous tissue of lymphedema in patients with a cellulitis history.

This was a cross-sectional study, and all data were collected from patients' medical records. We assessed ultrasonographic images of the lower extremity of patients with lymphedema that were obtained in a lymphedema clinic. The ultrasonographic images were analyzed on the basis of the following five features: dermal hypoechogenicity, unclear dermal border, unclear superficial fascia, increased subcutaneous echogenicity, and subcutaneous cobblestone appearance. Fifty-two ultrasonographic images from 19 female patients with lower extremity lymphedema, including 8 with and 11 without a cellulitis history, were analyzed. The proportion of dermal hypoechogenicity on the upper leg was significantly higher in the patients with than in those without a cellulitis history (75.0% vs. 9.1%, p = 0.006).

Cellulitis history in lymphedema patients appears to be associated with dermal hypoechogenicity, particularly in the proximal lower extremity. This finding suggests that it may be the initial step to consider new approach for prevention of recurrent cellulitis in lymphedema patients.

Lipedema is a distinct adipose disorder from obesity necessitating awareness as well as different management approaches to address pain and optimize quality of life (QoL). The purpose of this proof-of-principle study is to evaluate the therapeutic potential of physical therapy interventions in women with lipedema.

Participants with Stage 1–2 lipedema and early Stage 0–1 lymphedema (n = 5, age = 38.4 ± 13.4 years, body mass index = 27.2 ± 4.3 kg/m²) underwent nine visits of physical therapy in 6 weeks for management of symptoms impacting functional mobility and QoL. Pre- and post-therapy, participants were scanned with 3 Tesla sodium and water magnetic resonance imaging (MRI), underwent biophysical measurements, and completed questionnaires measuring function and QoL (patient-specific functional scale, PSFS, and RAND-36). Pain was measured at each visit using the 0–10 visual analog scale (VAS). Treatment effect was calculated for all study variables. The primary symptomatology measures of pain and function revealed clinically significant post-treatment improvements and large treatment effects (Cohen's d for pain VAS = −2.5 and PSFS = 4.4). The primary sodium MRI measures, leg skin sodium, and subcutaneous adipose tissue (SAT) sodium, reduced following treatment and revealed large treatment effects (Cohen's d for skin sodium = −1.2 and SAT sodium = −0.9).

This proof-of-principle study provides support that persons with lipedema can benefit from physical therapy to manage characteristic symptoms of leg pain and improve QoL. Objective MRI measurement of reduced tissue sodium in the skin and SAT regions indicates reduced inflammation in the treated limbs. Further research is warranted to optimize the conservative therapy approach in lipedema, a condition for which curative and disease-modifying treatments are unavailable.

In patients with lymphedema (LE), in addition to hand dominance, between-group comparisons of interlimb soft tissue differences need to account for differences in whole-body adiposity, measured directly by dual energy X-ray absorptiometry (DXA) or indirectly by body mass index. No study has evaluated the effects of hand dominance and whole-body adiposity on limb composition in patients with LE. This study's purpose was to compare soft tissue composition of affected and unaffected limbs of women with breast cancer, who did and did not have LE, controlling for dominance and percent body fat.

Whole-body DXA scans were acquired and included measures of percent body fat, upper limb total mass, upper limb fat mass, and upper limb fat-free mass. Participants were classified into one of three groups: women without LE; women with only subjective LE; and women with objective signs of LE at the time of assessment. Differences among the LE groups were evaluated using analysis of variance (ANOVA) and Chi-square analyses. Analysis of covariance (ANCOVA) was used to control for percent body fat and for the affected limb dominance. Compared to women without LE, women with objective signs of LE have greater total limb mass, fat mass, and fat-free mass in their affected limbs, independent of affected side dominance and percent body fat. In addition, the interlimb differences in total mass, fat mass, and fat-free mass were greater for the women with objective signs of LE, compared to the other two groups.

DXA is useful in identifying soft tissue changes in patients with LE. Given that limb circumferences measure only changes in limb volume and that bioimpedance provides estimates of extracellular fluid, DXA has the advantage of being able to estimate the volumes of specific tissues in the limb.

A number of different classification schemes, with generally similar but not identical criteria, exist to describe the different stages of lymphedema. Criteria may include both subjective and objective assessments. The present study investigated whether bioelectrical impedance parameters had utility in staging breast cancer-related lymphedema.

Hierarchical agglomerative cluster analysis was used to assign women (n = 221) at risk of or with clinically ascribed lymphedema to clusters sharing similar impedance characteristics. Five clusters could be identified with each cluster containing proportions of participants that closely aligned with staging allocation, according to International Society of Lymphology criteria, at initial presentation. The use of cluster analysis for tracking of lymphedema progression or response to treatment is demonstrated.

No single assessment provides definitive assignment of a patient to lymphedema stage. Staging is usually achieved by identifying and allocating a patient to a lymphedema stage shared by a group of patients with similar clinical signs. Cluster analysis of impedance data provides similar groupings of patients and could provide a useful adjunct objective assessment for staging lymphedema.

Overweight and obesity are strongly implicated in breast cancer (BC) development and are also a risk factor for BC-related lymphedema (BCRL).

An online cross-sectional survey was conducted between November 2017 and January 2018. Analyses were restricted to women with localized BC, who provided information about BCRL (n = 238). Most women were not experiencing BCRL (55.46%). Mean self-reported weight at diagnosis was 68.55 kg for women without BCRL and 74.43 kg for women with BCRL (p = 0.0021). In this study, 50.9% with BCRL were overweight/obese at diagnosis (body mass index [BMI] ≥25) compared with 36.4% of women without BCRL (p = 0.003). For women without BCRL, 12.12% were classified as obese (BMI ≥30) versus 20.75% with BCRL. Women with BCRL were more likely to have gained >5% of body weight (p = 0.03), be currently overweight or obese (p = 0.004), and less active (48.11%) than they were at diagnosis than women without BCRL (33.33%) (p = 0.042). Having a structured exercise program, following a prescribed diet, and being accountable to someone else were identified as the main facilitators to successful weight loss and weight maintenance.

Clinicians should consider obesity when personalizing axillary treatment and encourage lifestyle interventions and lymphedema screening after BC treatment.

Axillary web syndrome (AWS) is a frequent complication after surgery for breast cancer, but its lymphatic involvement is not definitively established. Here we report the results of lymphoscintigraphic investigations in patients with AWS.

We conducted a retrospective, single-center review of lymphoscintigraphic investigations performed in 46 patients with AWS that was either clinically obvious or suspected. Of this group, 23 patients had two investigations with a mean interval of 19 weeks between them (range, 6–98 weeks). Results of the lymphoscintigraphic investigations, which were performed according to a well-standardized protocol, were classified into four patterns: normal; functional lymphatic insufficiency only (no lymphatic vascular morphologic abnormality); lymphovascular blockade without collateralization; and vascular collateralization and/or dermal backflow. Of the 46 patients, on the first lymphoscintigraphic investigation, four (8.6%) had a normal pattern, seven (15.2%) had functional lymphatic insufficiency only, four (8.6%) had lymphovascular blockade without collateralization, and 31 (67.3%) had vascular collateralization and/or dermal backflow. Among patients who underwent two investigations, four of the five who had only functional lymphatic insufficiency at the first investigation had developed vascular collateralization and/or dermal backflow by the second. The three patients who had lymphovascular blockade without collateralization at the first examination had also progressed to collateralization and/or dermal backflow at the second. None of the 15 patients who initially had vascular collateralization and/or dermal backflow showed any reversal at the second examination.

Our analysis confirms the lymphatic nature of AWS and shows the lymphoscintigraphic patterns and evolutions of the lymphatic lesions with potential therapeutic implications. The retrospective review of our database is approved by the institutional ethics committee under number 2048.

The updated Lymphedema Life Impact Scale (LLIS, version 2) has been widely used to evaluate the effect of lymphedema from the patient's perspective. We sought to assess its ability to accurately and efficiently measure lymphedema-related impact using modern psychometric techniques.

We collected a total of 1054 patient-reported outcome measure scores from 285 patients with upper extremity lymphedema and 65 patients with lower extremity lymphedema between 2016 and 2020. We first evaluated the relationship between the LLIS score, L-Dex score, and limb volume difference (LVD), and used classical test and item response theories to assess its psychometric performance. The LLIS score was only very weakly associated with LVD (r = 0.17, p < 0.001) and L-Dex score (r = 0.22, p < 0.001). The LLIS had acceptable dimensionality. Items 7 (affects body image) and 16 (affects proper fit of clothing/shoes) were locally dependent (Yen's Q3 = 0.45). Eight of the 17 items was interpreted differently between upper and lower limb lymphedema patients (pseudo R² ≥ 0.01). The scoring structure required correction for items 9 (affects intimate relations) and 12 (manages lymphedema). Removing items 18 (infection occurrence) and 7 resulted in substantially improved item response theory model fit (Tucker-Lewis index = 0.93, comparative fix index = 0.95, root mean square error of approximation = 0.07, and root means square of the residual = 0.06). The relationships between the LLIS and objective measures of lymphedema remained weak following modification (LVD; r = 0.13, p = 0.01, L-Dex; r = 0.26, p < 0.001).

We were able to slightly improve the psychometric properties of the LLIS. However, these improvements did not rectify apparent issues with construct validity and both versions of the LLIS displayed a weak relationship with objective measures of lymphedema severity.

Lymphedema is a progressive disorder characterized by impairment of lymph flow from tissues to the blood circulation due to damage of lymphatics. Treatment can be surgical or nonsurgical. A great number of operative procedures described in the literature demonstrate no single method exists that could be regarded as a standard. Nonsurgical therapy consists of a set of four physiotherapeutic measures, if properly performed; it treats the cause of lymphedema in a manner free of side effects, this set is called complex physical therapy (CPT). Criteria and facilities of CPT are not available in Iraq now.

Below is a short clinical experience of seven cases (nine diseased lower limbs) presented at our clinic for management of lymphedema who were all managed successfully during the decongestive period using adjustable Velcro wraps (AVW).

In the absence of ideal CPT facilities, AVW can be used as a single therapeutic modality for treatment of lymphedema.