Lymphedema is a condition characterized by excess edema and protein in the tissues caused by fluid that is not drained by the lymphatic system. The lymphatic system is part of the body's circulatory system, and its main function is to drain fluid, absorb fats, maintain the body's fluid balance, and help defend the body against disease. The failure of this system can lead to lymphedema and other conditions.
There are two types of lymphedema: primary and secondary. Primary lymphedema is an inherited condition and is determined by genetic factors. Secondary lymphedema is usually caused by trauma, radiation therapy, surgery, or infection that causes a disruption in the lymphatic channels or loss of lymph nodes.
In time, lymphedema can lead to recurring infections, pain, and decreased or loss of function and mobility. Control of the condition usually involves exercise, compression bandaging, and massage. The practice of measuring limb girth with tape measures or the immersion of the limb in water to measure the displacement of the water is considered the gold standard for detection of lymphedema. One of the many problems associated with lymphedema involves early detection; however, detection in the early subclinical phase is difficult. While there is no cure for lymphedema, early detection and treatment are critical in achieving the optimal outcome for the individual.
There are five grades of lymphedema, using the Miller Classification:
- Grade 0 (subclinical): Individual has abnormal or nonefficient lymph rerouting but does not have clinical edema.
- Grade 1: Normal in appearance, positive for pitting edema, edema resolves or greatly decreases with elevation of the limb.
- Grade 2: Skin on affected limb develops yellowish discoloration, there is skin thickening, positive for pitting under moderate pressure, moderate decrease in edema with elevation, loss of limb mobility and function as edema increases, physical therapy is necessary.
- Grade 3: Development of vesicles and papules on the affected limb, keratosis of the effective limb, skin thickening with little pitting on pressure, minimal decrease of edema with elevation, decreased function and mobility of affected limb, physical therapy and medical intervention are necessary.
- Grade 4: Increased yellowish discoloration, increased pigmentation, weeping vesicles, increased keratotic papules, increased skin thickening, no pitting with pressure, no decrease in edema with elevation, marked loss of limb function and mobility, multimodality therapy is required.
The detection of lymphedema at a subclinical level is a current area of study. The detection of grade 0 lymphedema is problematic and may be present for months or years without physical manifestation. Optimally, the "at risk" limb is tested pre- and post-surgery (e.g., mastectomy or lumpectomy with lymph node dissection) using bioimpedance spectroscopy (BIS). BIS (i.e., impedance plethysmography) is a measure of the resistance met by a current passed through the skin via electrodes. The difference appreciated between the readings pre- and post-surgery is proposed to determine the presence or lack of lymphedema.
Currently, there is limited information regarding the technical and diagnostic performance of bioimpedance testing for the detection of lymphedema. Also, there are no comparative clinical trials that demonstrate the impact of bioimpedance on clinical outcomes. The approach to subclinical lymphedema (diagnosis and treatment) appears to be under active investigation. There is one multicenter randomized controlled trial (RCT), the PREVENT study, that examined the use of BIS in female individuals with breast cancer at risk of related lymphedema to determine if the use of BIS could reduce the rate of progression to clinical lymphedema compared to the use of standard tape measurements through early intervention. Two analyses were performed by Ridner et al.: a 2019 interim analysis and a final analysis in 2022. The interim analysis included 508 individuals and in the final was 963. Initial BIS threshold to undergo treatment was greater than or equal to 10 L-Dex units (3 standard deviations [SDs]) but was changed to greater than or equal to six L-Dex units (two SDs) in 2016 as result of early clinical findings. The change threshold to undergo treatment in the tape measurement group was greater than or equal to 5 and less than 10% above the presurgical baseline. Treatment was a compression sleeve and gauntlet worn for 4 weeks followed by another evaluation.
The results of interim analysis did not observe a statistically significant difference between the progression to clinical lymphedema between the two groups; however, BIS did trigger the intervention phase less often than the tape measure (15.8% vs. 28.5%; P=0.001). The final analysis did observe statistically significant triggering of the intervention in the group that received BIS (20.1% vs. 27.5%, P=0.011), which also had a lower rate of progression to clinical lymphedema compared to the tape measurement arm (7.9% vs. 19.2%; P=0.016; relative risk = 0.41; 95% CI, 0.13–0.81). In addition, some samples were excluded from the final analysis as 4.2% of the final study population progressed to clinical lymphedema before an intervention was triggered and 2.0% of the interim analysis were excluded with the same rationale. The limitations of the trial and related publications were the lack of blinding, intra- and interobserver variability with tape measurement, no comparison to other methods of measurement of breast cancer–related lymphedema, lack of report of patient symptoms such as quality-of-life or function. Additional RCTs investigating BIS for the detection of lymphedema are necessary to confirm the results of existing evidence, demonstrate effectiveness over other existing methods, and provide additional insights over the long-term along with patient-reported outcomes.
