Bridging the divide between pathogenesis and detection in lymphedema

Abstract

While our understanding of the lymphatic system has improved substantially in the past few decades, the translation of this knowledge into improved healthcare solutions for patients suffering from secondary lymphedema has been severely limited. The challenge facing clinicians is two-fold. First, there is no reliable, affordable, diagnostic capable of detecting the disease before symptoms of the lymphedema develop and the efficacy of treatment options becomes limited. Second, our understanding of the disease pathogenesis, its risk factors, and the underlying physiologic mechanisms is still in its infancy. These two challenges go hand in hand as limited diagnostic options have hindered our ability to understand lymphedema progression, and the lack of known underlying mechanisms involved in the disease prohibits the development of new diagnostic targets. This review serves to discuss the recent developments in clinical and lab research settings of both lymphedema diagnostic technologies and our understanding of the mechanisms driving disease risk and progression. We will show how these two lines of research are synergistically working with the ultimate goal of improving patient outcomes for those suffering from this horrible disease, identifying key areas of further research that are warranted to move the field forward and provide clinical relief for this neglected patient population.

The Lymphatic System in Disease Processes and Cancer Progression

“…Limb volume (LV) measurements—made simply by using a tape measure—are the most common way to identify lymphedema. If subsequent measurements are taken by an experienced user on the basis of anatomical landmarks, this method is reliable in detecting and monitoring lymphedema (185). Alternatively, the clinician may use perometry or multifrequency bioimpedance measurements, which are automated LV scanning methods that eliminate interobserver variability, but these are more expensive.…”

“…Lymphoscintigraphy is still considered the gold standard of imaging modalities (9, 174, 185) to investigate lymphatic function using two-dimensional imaging. The clearance of radioactive tracers injected intradermally or subcutaneously can quantify lymphatic clearance rates, map aberrant drainage patterns, and identify dermal backflow by imaging a location and assessing the increase in signal over time.…”

“…These characteristics are useful in both diagnosing and surgically managing lymphedema (191). Data suggest that T2-weighted MRI (magnetic resonance imaging) has a greater sensitivity, but contrast-enhanced MR lymphangiography produces better image quality (185). However, contrast-enhanced vascular structures may confound image interpretation.…”

“…However, there is limited understanding of the underlying biology that permits lymphedema formation. Known risk factors for lymphedema include obesity (196), elevated blood pressure, adjuvant radiation therapy following lumpectomy, the location of removed lymph nodes, and a greater number of lymph nodes removed during surgery (185). Additionally, combinations of genetic risk factors predispose patients to developing secondary lymphedema (197).…”

Winner of the society for biomaterials young investigator award for the annual meeting of the society for biomaterials, April 11–14, 2018, Atlanta, GA: S‐nitrosated poly(propylene sulfide) nanoparticles for enhanced nitric oxide delivery to lymphatic tissues

“…The lymphatics are involved in a wide variety of diseases either as the primary tissue of interest, such as with lymphedema or lymphatic filariasis, or as an accessory to the pathologies of other diseases, such as with myocardial infarction and cancer . Due to the integral role lymphatics play in tissue fluid regulation, lipid transport, and immune cell functions, an estimated forty million patients worldwide endure the combined effect of all diseases in which the lymphatics are affected.…”