Lymphatic Research and Biology

Our aim is to propose a framework for the development of a research case definition of lipedema, based on current available literature and those observations that can be applied to future lipedema research with the intent to standardize and strengthen the scientific evidence base.

We conducted a narrative review of the literature, and identified consensus characteristics and disputed characteristics that could be included in a research case definition of lipedema. After considering the strength of the evidence and how each characteristic might be measured in a research study, we recommended an approach for the development of a research case definition of lipedema that would be based on consideration of five agreed-upon characteristics, and five disputed, or less substantiated, characteristics as additional evidence to enhance specificity.

We present a case definition framework for lipedema drawn from the scientific literature that can be applied to future studies on lipedema. Utilizing this framework should help to increase the sensitivity and specificity of case definition and provide an opportunity for meta-analysis of clinical studies and facilitate future research intercomparisons.

Lipedema is a progressive condition involving excessive deposition of subcutaneous adipose tissue, predominantly in the lower limbs, which severely compromises quality of life. Despite the impact of lipedema, its molecular and genetic bases are poorly understood, making diagnosis and treatment difficult. Historical evaluation of individuals with lipedema indicates a positive family history in 60%–80% of cases; however, genetic investigation of larger family cohorts is required. Here, we report the largest family-based sequencing study to date, aimed at identifying genetic changes that contribute to lipedema.

DNA samples from 31 individuals from 9 lipedema families were analyzed to reveal genetic variants predicted to alter protein function, yielding candidate variants in 469 genes. We did not identify any individual genes that contained likely disease-causing variants across all participating families. However, gene ontology analysis highlighted vasopressin receptor activity, microfibril binding, and patched binding as statistically significantly overrepresented categories for the set of candidate variants.

Our study suggests that lipedema is not caused by a single exomic genetic factor, providing support for the hypothesis of genetic heterogeneity in the etiology of lipedema. As the largest study of its kind in the lipedema field, the results advance our understanding of the disease and provide a roadmap for future research aimed at improving the lives of those affected by lipedema.

Lymphedema and lipedema are debilitating conditions with no proven drug or surgical therapy. Effective treatment requires self-management through movement and compression to reduce limb volume and the incidence of cellulitis. The addition of personalized everyday physical activity (PA) could be transformative, increasing the therapy window to include all waking hours per week and enabling an increased dose of PA.

This service evaluation aimed to determine the feasibility of LymphActiv as a treatment option for lymphedema and lipedema patients.

This service evaluation followed an open observational cohort design, including 55 patients who participated in LymphActiv over 24 weeks. Patients wore an objective PA monitor and interacted with their data in an online dashboard, alongside remote mentor support. Primary outcomes were changes to PA, body weight, limb volume and quality of life. Clinical assessments occurred at baseline and after the 24-week program. Noncompleters were used as a quasi-control group for comparison.

Thirty-seven patients completed, of which 81% improved PA. On average, completers reduced their right and left lower limb volumes by −1.8% and −2.1%, respectively. Completers also experienced small average weight losses of −1.2 kg. Noncompleters experienced small average increases in each of these outcome measures.

These results establish the value of LymphActiv, providing benefit to patients who might otherwise have deteriorated. For services, this could lead to substantial cost-savings through reduced admissions, greater patient independence, and less need for community health care input. The next step is to undertake a randomized, controlled trial comparing the intervention with standard care.

Indocyanine green (ICG) lymphography, a key diagnostic tool for lymphedema, is influenced by the dilution process of ICG dye, impacting patient experience.

In our study, we assessed three different ICG diluents—water for injection (WFI), normal saline (NS), and Dextrose^® plus human albumin—in five healthy volunteer individuals undergoing superficial lymphography of the upper limb over 3 weeks. Results indicated that NS, as a diluent for ICG, caused the least discomfort during injection, in contrast to WFI, which led to the highest levels of discomfort. Transport time of ICG from the injection site to the axillary lymph nodes was notably shorter in intradermal injections than in subdermal injections.

Our findings advocate for using NS as the optimal and cost-effective diluent for ICG, enhancing patient experience.

Breast cancer-related lymphedema (BCRL) remains a significant postcancer treatment challenge with no definitive cure. Recent supermicrosurgical treatments, such as lymphovenous anastomosis (LVA), have shown promise but lack established objective indicators for outcome evaluation. We investigated the utility of Technetium-99m (Tc-99m) lymphoscintigraphy, an imaging technique providing objective information on lymphatic fluid flow, for assessing LVA surgical outcomes.

A retrospective cohort analysis of patients undergoing LVA for BCRL was conducted. Lymphoscintigraphy images pre- and 1-year postsurgery were compared to determine changes in lymphatic fluid flow of 18 patients based on newly defined parameters “uptake ratio” and “washout rates.” Statistically significant reduction in the uptake ratio was observed in the forearm at 30 and 60 minutes postinjection phases. In addition, the forearm showed higher washout rate, indicating an improved lymphatic function in the forearm.

Tc-99m lymphoscintigraphy can provide valuable objective data for evaluating LVA surgical outcomes in BCRL patients. However, site-specific differences in outcomes highlight the need for individualized surgical planning. Further large-scale studies are necessary to validate these preliminary findings and develop a standardized approach for LVA assessment.

We aimed to determine the course of arm swelling caused by the use of taxanes and to identify valid predictors of persistent swelling.

A total of 15 patients with unilateral arm swelling that developed during the course, or within 3 months after termination, of postoperative taxane-based chemotherapy were included in the present study. The patients attended follow-up appointments every 3–6 months for 24 months after their initial visit. Their arm circumference was measured at each follow-up appointment, while ultrasonography of the skin and subcutaneous tissues was performed at the 0-, 6-, 12-, and 24-month follow-ups. Of the 15 patients, 12 (80%) saw their taxane-induced arm swelling resolved within a median of 12 months (range, 3–29 months) after their final taxane administration. Of the 12 patients whose swelling resolved, 9 did not use compression sleeves; however, their course of resolution did not differ from the other 3 patients who regularly used compression sleeves. In the three patients with persistent swelling, the excess subcutaneous thickness in the medial upper arm (median, 283%) was significantly greater than that in the patients whose swelling resolved (120%; p < 0.05) during their initial visits.

Of the 15 patients included in the present study, 80% saw their taxane-induced arm swelling resolve within a median of 12 months after their final taxane administration, independent of the use of compression therapy. Persistent swelling may be predicted during the initial visit based on subcutaneous thickening of the medial upper arm.

Genital lymphedema is a chronic debilitating condition associated with highly impaired health-related quality of life (QoL). This prospective multicenter study evaluated the use of a new compressive garment in patients with secondary and primary genital lymphedema.

Thirty-two patients prospectively enrolled were advised to wear the compressive garment for 12 weeks (day and night). The primary endpoint was change in patient-reported QoL at 12 weeks via the patient global impression of change (PGI-C) instrument. Secondary outcomes included change in other QoL measures at 12 weeks (visual analog scale, Lymphedema Quality of Life Inventory [LyQLI], and EQ-5D questionnaires), lymphedema severity (genital lymphedema score [GLS]), and physician assessment (Clinical Global Impression–Improvement [CGI-I]). Safety and tolerability were also assessed.

After 12 weeks, improvement was reported in 78.6% of patients (PGI-C). Physician assessment (CGI-I) indicated clinical improvement in 82.8% of patients. Patient assessment of lymphedema symptoms showed a significant decrease in discomfort (p = 0.02) and swelling (p = 0.01). Significant declines in the mean global GLS (p < 0.0001), and in the proportion of patients reporting heaviness, tightness, swelling, or urinary dysfunction (p < 0.05 for all), were also observed. LyQLI scores decreased (indicating improved QoL) in each of the physical, psychosocial (p = 0.05), and practical domains. The compressive garment was well tolerated with high compliance, and adverse events (due to swelling or discomfort) led to permanent discontinuation in only three patients.

The use of a new genital compression garment over 12 weeks improves the QoL and clinical measures in patients with genital lymphedema (ClinicalTrials.gov ID: NCT04602559; Registration: October 20, 2020).

Recently, the usefulness of lymphatic ultrasound has been reported. It is beneficial not only to identify lymphatic vessels but also to evaluate lymphatic degeneration and diagnose lymphedema. We previously proposed D-CUPS (Doppler, Cross, Uncollapsible, Parallel, and Superficial fascia) to identify the lymphatic vessels on ultrasound. The purpose of this study was to clarify the sensitivity of each index of D-CUPS.

We performed a retrospective study of 27 patients (44 limbs, 98 sites) with lower extremity lymphedema, who underwent lymphaticovenous anastomosis (LVA). We performed a lymphatic ultrasound the day before surgery. We used a linear probe commonly used for venous ultrasound (Noblus EUP-L65; Hitachi Medical Corp., Tokyo, Japan). We applied the D-CUPS index to identify the lymphatic vessels on ultrasound. We checked whether lymphatic vessels consistent with preoperative lymphatic ultrasound findings were observed during the LVA. We also calculated the sensitivity of each D-CUPS index.

All the 27 patients were women, with a mean age of 59.7 years. Totally, 98 incisions were made (59 incisions on the thigh and 39 incisions on the lower leg). During LVA, lymphatic vessels consistent with the preoperative lymphatic ultrasound findings were observed at all the sites. The sensitivities of each indicator of D-CUPS were 100.0%, 100.0%, 68.4%, 19.4%, and 100.0%, respectively.

The sensitivity was 100.0% in D, C, and S. Although each index separately was not perfect, by combining them appropriately, we were able to identify lymphatic vessels with certainty.

In advanced lymphedema of lower limbs, stage III bandaging under the routinely applied pressure of 40–60 mmHg remains largely ineffective. This is caused by skin and subcutaneous tissue stiffness due to fibrosis. Edema fluid accumulates deep in the subcutaneous tissue. Evacuating this fluid requires a high external compression force to overcome the resistance of fibrous tissue. We aimed to investigate the effectiveness of the compression method, with high pressure lasting for 3 days.

Twenty-one patients with lower limb lymphedema, stage III, of the postinflammatory type were included. Patients with acute inflammatory symptoms, venous thrombosis, profuse varicose veins, diabetes, and cardiac insufficiency with edema were excluded. A 10-cm-wide rubber bandage was applied to the foot and calf. The interface pressure measured using PicoPress ranged from 58 to 120 mmHg. Skin and deep tissue tonometry, skin water concentration, leg circumference, and drop of interface pressure were measured. Ultrasound examination was done before and after each compression session. The calf circumference decreased by 15.9 ± 5.4%, deep tissue stiffness by 58.9 ± 18.9%, skin stiffness by 69.6 ± 13.5%, and skin water concentration by 43.8 ± 11.5%. Interface pressure dropped to 66.3 mmHg (28–110 mmHg); ultrasonography images showed less fluid in the tissue.

High-pressure 30-minute leg compression can remove excess edema fluid within 3 days and enable adjustment of nonstretch compression stockings. This method is more effective in advanced lymphedema at the beginning of therapy than the standard 30–50-mmHg bandaging as it provides an immediate effect.