Pathophysiology Of Lymphedema Research Articles

The Arteria Lymphatica and Lymphatic Microperforators: A Dedicated Blood Supply to Collecting Lymphatics and Their Potential Implications in Lymphedema: Anatomical Description.

Lymphedema is common after lymphatic damage in cancer treatment, with negative impacts on function and quality of life. Evidence suggests that blood vessel microvasculature is sensitive to irradiation and trauma; however, despite knowledge regarding dedicated mural blood supply to arteries and veins (vasa vasorum), equivalent blood vessels supplying lymphatics have not been characterized. We studied collecting lymphatics for dedicated mural blood vessels in our series of 500 lymphaticovenous anastomosis procedures for lymphedema, and equivalent controls. Microscopic images of lymphatics from lymphedema and control patients were analyzed for lymphatic wall vascular density. Collecting lymphatics from 20 patients with lymphedema and 10 control patients were sampled for more detailed analysis (podoplanin immunostaining, light/confocal microscopy, microcomputed tomography, and transmission electron microscopy) to assess lymphatic wall ultrastructure and blood supply. Analysis revealed elaborate, dense blood microvessel networks associating with lymphatic walls in lymphedema patients and smaller equivalent vessels in controls. These vasa vasora or "arteria lymphatica" were supplied by regular axial blood vessels, parallel to lymphatic microperforators linking dermal and collecting lymphatics. Lymphatic walls were thicker in lymphedema patients than controls, with immunohistochemistry, computed tomography, transmission electron microscopy, and confocal microscopy characterizing abnormal blood vessels (altered appearance, thickened walls, elastin loss, narrow lumina, and fewer red blood cells) on these lymphatic walls. Dedicated blood vessels on lymphatics are significantly altered in lymphedema. A better understanding of the role of these vessels may reveal mechanistic clues into lymphedema pathophysiology and technical aspects of lymphedema microsurgery, and suggest potential novel therapeutic targets.

It Is Time to Curb the Dogma in Lymphedema Management

Lymphedema is an under-recognized and underappreciated disease. Advances in imaging and a deeper understanding of the pathophysiology of lymphedema are shedding new light on this disease that affects millions of people worldwide. As new evidence continues to emerge about the microcirculation and revised Starling Principle, etiological factors, related conditions, specific genes, and surgical innovations, the traditional approach to management must also evolve. This evolution is vital to maximize outcomes and improve quality of life. This commentary is a call to action to embrace innovation to better manage lymphedema and expand educational opportunities by leveraging technology to properly train healthcare providers to manage this disease.

The Future of Lymphedema: Potential Therapeutic Targets for Treatment.

This review aims to summarize the current knowledge regarding the pharmacological interventions studied in both experimental and clinical trials for secondary lymphedema. Lymphedema is a progressive disease that results in tissue swelling, pain, and functional disability. The most common cause of secondary lymphedema in developed countries is an iatrogenic injury to the lymphatic system during cancer treatment. Despite its high incidence and severe sequelae, lymphedema is usually treated with palliative options such as compression and physical therapy. However, recent studies on the pathophysiology of lymphedema have explored pharmacological treatments in preclinical and early phase clinical trials. Many potential treatment options for lymphedema have been explored throughout the past two decades including systemic agents and topical approaches to decrease the potential toxicity of systemic treatment. Treatment strategies including lymphangiogenic factors, anti-inflammatory agents, and anti-fibrotic therapies may be used independently or in conjunction with surgical approaches.

Skin microbiome alterations in upper extremity secondary lymphedema.

Lymphedema is a chronic condition that commonly occur from lymphatic injury following surgical resection of solid malignancies. While many studies have centered on the molecular and immune pathways that perpetuate lymphatic dysfunction, the role of the skin microbiome in lymphedema development remains unclear. In this study, skin swabs collected from normal and lymphedema forearms of 30 patients with unilateral upper extremity lymphedema were analyzed by 16S ribosomal RNA sequencing. Statistical models for microbiome data were utilized to correlate clinical variables with microbial profiles. Overall, 872 bacterial taxa were identified. There were no significant differences in microbial alpha diversity of the colonizing bacteria between normal and lymphedema skin samples (p = 0.25). Notably, for patients without a history of infection, a one-fold change in relative limb volume was significantly associated with a 0.58-unit increase in Bray-Curtis microbial distance between paired limbs (95%CI = 0.11,1.05, p = 0.02). Additionally, several genera, including Propionibacterium and Streptococcus, demonstrated high variability between paired samples. In summary, we demonstrate high compositional heterogeneity in the skin microbiome in upper extremity secondary lymphedema, supporting future studies into the role of host-microbe interactions on lymphedema pathophysiology.

Association between the single-nucleotide polymorphism (rs1030868) variant in matrix metallopeptidase 2 gene and the development of lymphedema

BackgroundUnderstanding the genetic and molecular pathophysiology of lymphedema contributes to the identification of the complex interaction of genes associated with lymphedema and provides a key therapeutic opportunity to restore lymphatic function. This study aims to answer whether the single-nucleotide polymorphism (SNP) rs1030868 in the MMP-2 gene could be an associated variant in lymphedema development.MethodsThis study was carried out on 93 lymphedema cases (patients’ group) and 187 healthy individuals (control group). Genotyping of MMP-2 (rs1030868) was done following the protocol of Custom TaqMan® SNP Genotyping Assays. TaqMan™ Fast Advanced Master Mix (Cat# 4448892) was used.ResultsThe risk alleles for MMP-2 SNP rs1030868 were A and G of lymphedema development. The GG genotype was associated with triple the risk of lymphedema (OR 3.2, 95% CI 1.2–6.5, p = 0.019), while the AA genotype was associated with 5.9 times the likelihood of lymphedema (OR 5.9, 95% CI 2.3–11.9, p < 0.001).ConclusionsWe concluded that the single-nucleotide polymorphisms of rs1030868 in the matrix metallopeptidase 2 gene (allele A and allele G) could be associated variants with the development of lymphedema.

Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema.

Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.

Adipose Tissue in Lymphedema: A Central Feature of Pathology and Target for Pharmacologic Therapy.

Lymphedema is a chronic condition of impaired lymphatic flow that results in limb swelling and debilitation. The pathophysiology of lymphedema is characterized by lymphatic stasis that triggers inflammation, fibrosis, and adipose tissue deposition in the extremities. Most often, this condition occurs in cancer survivors in the years after treatment with combinations of surgery, radiation, or chemotherapy, with the major risk factor being lymph node dissection. Interestingly, obesity and body mass index are independent risk factors for development of lymphedema, suggesting interactions between adipose and lymphatic tissue biology. Currently, treatment of lymphedema involves palliative approaches, including compression garments and physical therapy, and surgical approaches, including liposuction, lymphovenous bypass, and vascularized lymph node transfer. Emerging lymphedema therapies that focus on weight loss or reducing inflammation have been tested in recent clinical trials, yielding mixed results with no effect on limb volumes or changes in bioimpedance measurements. These studies highlight the need for novel therapeutic strategies that target the driving forces of lymphedema. In this light, animal models of lymphedema demonstrate a role of adipose tissue in the progression of lymphedema and suggest these processes may be targeted in the treatment of lymphedema. Herein, we review both conventional and experimental therapies for lymphedema as well as the defining characteristics of its pathophysiology. We place emphasis on the aberrant fibroadipose tissue accumulation in lymphedema and propose a new approach to experimental treatment at the level of adipocyte metabolism.

Lymphatic Tissue Bioengineering for the Treatment of Postsurgical Lymphedema.

Lymphedema is characterized by progressive and chronic tissue swelling and inflammation from local accumulation of interstitial fluid due to lymphatic injury or dysfunction. It is a debilitating condition that significantly impacts a patient’s quality of life, and has limited treatment options. With better understanding of the molecular mechanisms and pathophysiology of lymphedema and advances in tissue engineering technologies, lymphatic tissue bioengineering and regeneration have emerged as a potential therapeutic option for postsurgical lymphedema. Various strategies involving stem cells, lymphangiogenic factors, bioengineered matrices and mechanical stimuli allow more precisely controlled regeneration of lymphatic tissue at the site of lymphedema without subjecting patients to complications or iatrogenic injuries associated with surgeries. This review provides an overview of current innovative approaches of lymphatic tissue bioengineering that represent a promising treatment option for postsurgical lymphedema.

Immediate lymphatic reconstruction for breast cancer

: Upper extremity lymphedema remains a significant source of morbidity in breast cancer patients despite significant improvements in breast cancer care. The risk of lymphedema is particularly elevated in patients requiring an axillary lymph node dissection and/or adjuvant radiation to treat their disease. Current treatment options for lymphedema, including conservative management or surgery, are limited and are often aimed at improving symptoms and quality of life rather than curing the disease. In this review we describe immediate lymphatic reconstruction, a novel surgical procedure that is done concurrent with axillary lymph node dissection in an effort to prevent the development of breast cancer-related lymphedema. Based on our growing knowledge of the pathophysiology of lymphedema, microsurgical techniques are used at the time of axillary lymph node dissection to perform a lymphovenous bypass between transected, leaking lymphatic channels and an adjacent, small calibre vein in the axilla. Using several objective metrics for short- and long-term surveillance, patients are monitored for the development of postoperative lymphedema. Early outcomes from using this technique have been promising, both in the literature and within our own institutions, demonstrating significant improvements in rates of postoperative lymphedema. However, future study is still required to better understand the long-term efficacy of immediate lymphatic reconstruction.

Current Understanding of Pathological Mechanisms of Lymphedema.

Significance: Lymphedema is a common disease that affects hundreds of millions of people worldwide with significant financial and social burdens. Despite increasing prevalence and associated morbidities, the mainstay treatment of lymphedema is largely palliative without an effective cure due to incomplete understanding of the disease. Recent Advances: Recent studies have described key histological and pathological processes that contribute to the progression of lymphedema, including lymphatic stasis, inflammation, adipose tissue deposition, and fibrosis. This review aims to highlight cellular and molecular mechanisms involved in each of these pathological processes. Critical Issues: Despite recent advances in the understanding of the pathophysiology of lymphedema, cellular and molecular mechanisms underlying the disease remains elusive due to its complex nature. Future Directions: Additional research is needed to gain a better insight into the cellular and molecular mechanisms underlying the pathophysiology of lymphedema, which will guide the development of therapeutic strategies that target specific pathology of the disease.

Treatment of Lymphedema with Cell-Based Therapies: A Systematic Review

Introduction &#x0D; Lymphedema is a chronic condition that affects over 250 million people worldwide. It results from impaired lymphatic drainage, causing fluid and fat accumulation and eventually fibrosis of the affected limb. Lymphedema can be inherited (primary) or iatrogenic to surgery or parasitic infection (secondary). Breast cancer-related lymphedema is the most common etiology in the U.S. Current treatments have limited success and the disease mechanisms are not well understood. The purpose of this article is to review translational research into lymphedema therapies and its potential clinical impact. &#x0D; &#x0D; Methods &#x0D; A Pubmed search for novel treatment methods was performed with terms “lymphedema,” “cell therapy,” and “gene therapy.” Inclusion criteria were use of in vivo models, English language, and publication dates during the years 2000-2020. &#x0D; &#x0D; Results &#x0D; Secondary lymphedema is currently treated with compression garments and surgery; other approaches are being pursued. These include gene therapy (13 articles), stem cell transplant (16 articles), and immunosuppression (4 articles), which have all demonstrated considerable success in animal models of lymphedema. Growth factors such as VEGF-C are administered through adenoviral vectors and resolve limb swelling by inducing lymphangiogenesis. Stem cells derived from bone marrow or adipose tissue repair lymphatic damage directly by acquiring lymphatic characteristics or indirectly through paracrine signaling to surrounding cells. Immunosuppressive agents reduce inflammation and block antilymphangiogenic factors. Although these mechanisms have been studied in animals, only six human small studies were found, providing limited evidence. &#x0D; &#x0D; Conclusion &#x0D; Despite success in animal models, treatment in human subjects has been sparse. This limited translational feasibility is because of inadequate animal models, safety concerns, and lack of understanding about lymphedema pathophysiology. Although progress in lymphedema research has been made, further inquiry into its mechanism is needed in order to develop more effective and targeted therapies.

A MODIFIED MOUSE-TAIL LYMPHEDEMA MODEL

One of the main obstacles to studying the pathophysiology of lymphedema development is the lack of appropriate experimental models. Fol-lowing up on a mouse-tail method that has been described, we performed changes to the method which made it easier to perform in our hands and demonstrated similar results. Twenty C57Black mice were operated on using the previous tech-nique and euthanized after 3 or 6 weeks. Another twenty mice were submitted to the new technique developed in our laboratory and euthanized at the same time points. Tissue samples were collected from the proximal part of the tail (control) and from the distal part (lymphedema) for both mod-els. Animals in both operative groups developed marked edema in the distal part of the tail. This was characterized by lymph vessels dilation, edema, inflammatory cell infiltration, and adipose tissue deposition. Lymphedema was detected after 3 weeks in both models, reaching its maximum after 6 weeks. Adipocytes detected by histology (Oil red O staining) and molecular markers for adipogenesis, lymphangiogenesis and inflam-mation (lipin 1 and 2, SLP76, and F4-80) were demonstrated to be increased equally in both models. In conclusion, both models provide a reliable method to study lymphedema pathophys-iology. However, our modified technique is easier and faster to perform while still providing reliable and consistent results.

Anatomical Theories of the Pathophysiology of Cancer-Related Lymphoedema.

Lymphoedema is a well-known concern for cancer survivors. A crucial issue in lymphoedema is that we cannot predict who will be affected, and onset can occur many years after initial cancer treatment. The variability of time between cancer treatment and lymphoedema onset is an unexplained mystery. Retrospective cohort studies have investigated the risk factors for lymphoedema development, with extensive surgery and the combination of radiation and surgery identified as common high-risk factors. However, these studies could not predict lymphoedema risk in each individual patient in the early stages, nor could they explain the timing of onset. The study of anatomy is one promising tool to help shed light on the pathophysiology of lymphoedema. While the lymphatic system is the area least investigated in the field of anatomical science, some studies have described anatomical changes in the lymphatic system after lymph node dissection. Clinical imaging studies in lymphangiography, lymphoscintigraphy and indocyanine green (ICG) fluorescent lymphography have reported post-operative anatomical changes in the lymphatic system, including dermal backflow, lymphangiogenesis and creation of alternative pathways via the deep and torso lymphatics, demonstrating that such dynamic anatomical changes contribute to the maintenance of lymphatic drainage pathways. This article presents a descriptive review of the anatomical and imaging studies of the lymphatic system in the normal and post-operative conditions and attempts to answer the questions of why some people develop lymphoedema after cancer and some do not, and what causes the variability in lymphoedema onset timing.

The impact of radiation on lymphedema: a review of the literature.

Radiation therapy (RT) is a common adjunct therapy in oncology. However, it carries a significant risk of lymphedema when utilized in some anatomic locations. Recent studies have provided insight into lymphedema pathophysiology, diagnostic techniques, and RT. This review will examine the role of RT in upper and lower extremity lymphedema. Radiation's role in increasing the risk of lymphedema through decreased lymphatic proliferation potential, interstitial fibrosis compressing lymphatic vessels, and mechanical insufficiency of the lymphatic system will be reviewed.

Current Concepts in Management of Postmastectomy Lymphedema

Lymphedema is associated with irreversible changes in the lymphatic system. For this reason, it is difficult to develop a radical treatment due to the dermal sclerosis and the volume increase of fibrous and adipose tissues. Complex decongestive therapy (CDT) is the gold standard in every therapeutic protocol. However, in cases that conventional therapy is inadequate or unsuccessful, new surgical treatments are available nowadays combining microvascular reconstructive techniques: Lympho-Venous Anastomosis (LVA), Vascularized Lymph Node Transfer (VLNT), Lympho-Lymphatic Bypass (LL-Bypass). Finally, for simultaneous breast reconstruction and restoration of lymphedema, chimeric Diep Inferior Epigastric Perforator flap (DIEP flap) can be combined with vascularised lymph node transfer (VLNT) from the inguinal area. Retrospective review of the literature referred to the diagnosis and the treatment of primary or secondary lymphedema. Conventional, as well as microvascular techniques are shown with detailed description of each procedure. Worldwide interest in using microsurgical reconstructive techniques to treat lymphedema is gaining momentum. However, there is no consensus on the indications for which procedure to perform, when to intervene, and/or how to comparatively grade outcomes. Currently there is no cure for lymphedema. For this reason, further research and better understanding of lymphatic anatomy and lymphedema pathophysiology are needed in order to improve further the conventional as well as the surgical methods.

The Unresolved Pathophysiology of Lymphedema.

Lymphedema is the clinical manifestation of impaired lymphatic transport. It remains an under-recognized and under-documented clinical condition that still lacks a cure. Despite the substantial advances in the understanding of lymphatic vessel biology and function in the past two decades, there are still unsolved questions regarding the pathophysiology of lymphedema, especially in humans. As a consequence of impaired lymphatic drainage, proteins and lipids accumulate in the interstitial space, causing the regional tissue to undergo extensive and progressive architectural changes, including adipose tissue deposition and fibrosis. These changes are also associated with inflammation. However, the temporal sequence of these events, the relationship between these events, and their interplay during the progression are not clearly understood. Here, we review our current knowledge on the pathophysiology of lymphedema derived from human and animal studies. We also discuss the possible cellular and molecular mechanisms involved in adipose tissue and collagen accumulation during lymphedema. We suggest that more studies should be dedicated to enhancing our understanding of the human pathophysiology of lymphedema to pave the way for new diagnostic and therapeutic avenues for this condition.

Visualization of Lymphatic Vessels Using Photoacoustic Imaging.

Lymphedema occurs when interstitial fluid and fibroadipose tissues accumulate abnormally because of decreased drainage of lymphatic fluid as a result of injury, infection, or congenital abnormalities of the lymphatic system drainage pathway. An accurate anatomical map of the lymphatic vasculature is needed not only for understanding the pathophysiology of lymphedema but also for surgical planning. However, because of their limited spatial resolution, no imaging modalities are currently able to noninvasively provide a clear visualization of the lymphatic vessels. Photoacoustic imaging is an emerging medical imaging technique that provides unique scalability of optical resolution and acoustic depth of penetration. Moreover, light-absorbing biomolecules, including oxy- and deoxyhemoglobin, lipids, water, and melanin, can be imaged. Using exogenous contrast agents that are taken up by lymphatic vessels, e.g., indocyanine green, photoacoustic lymphangiography, which has a higher spatial resolution than previous imaging modalities, is possible. Using a new prototype of a photoacoustic imaging system with a wide field of view developed by a Japanese research group, high-resolution three-dimensional structural information of the vasculatures was successfully obtained over a large area in both healthy and lymphedematous extremities. Anatomical information on the lymphatic vessels and adjacent veins provided by photoacoustic lymphangiography is helpful for the management of lymphedema. In particular, such knowledge will facilitate the planning of microsurgical lymphaticovenular anastomoses to bypass the excess fluid component by joining with the circulatory system peripherally. Although challenges remain to establish its implementation in clinical practice, photoacoustic lymphangiography may contribute to improved treatments for lymphedema patients in the near future.

Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancer-related lymphedema: Clinical implications

Magnetic resonance lymphangiography (MRL) has increased our knowledge of lymphatic anatomy and lymphedema pathophysiology and improved the efficacy of microsurgical procedures to manage peripheral lymphedema. The aim of this study is to investigate the ability of MRL to detect communications between superficial and deep lymphatic systems in breast cancer-related lymphedema (BRCL) and to investigate whether these communications could preserve lymphatic drainage of the hand. Between 2008 and 2017 we used MRL imaging in 59 women with BCRL. Lymphedema of the arm and hand was detected in 30 patients while the hand was spared in 29. Using axial and coronal MRL reconstruction images we investigated the existence of any communication between the superficial and deep lymphatic systems. Among the 29 patients with spared hand, MRL revealed that 24 had at least one communicating lymphatic perforator at the wrist region (p <0.001). Lymphatic flow at the axilla was clearly visualized in 16 of the 29 patients (55.2%), no perforating lymphatic vessels were detected in the group with lymphedema in the hand (30 patients). Communications between the deep and superficial lymphatic systems at the wrist region in BCRL patients without hand lymphedema should be considered when planning microsurgical lymphatic procedures at the wrist and in postoperative compression therapy.

Electrical Stimulation in the Treatment of Lymphedema and Associated Skin Ulcers.

Background: Lymphedema is a disorder in which lymph accumulates in the interstitial spaces due to poor lymphatic flow resulting from hypoplasia or aplasia of the lymphatic vessels, or to morpho-functional alterations that impair lymphatic flow. Lymphedema is a debilitating condition associated initially with inflammation that then degenerates into hardening of affected tissues and the formation of ulcers on the skin of affected limbs. No definitive treatment is available. The only therapy for lymphedema consists of physiotherapy, surgery, and compression to reduce impairment, which only treats the symptoms, not the causes. A possible new therapy that could reinforce the treatment of lymphedema progression and complications is electrical stimulation (ES). Many studies underline the effects of electric currents on the different cell mechanisms associated with disease. Methods and Results: In this review, we summarize the effects of ES on the molecular and cellular processes involved in the pathophysiology of lymphedema, highlighting their therapeutic potential for edema reduction, ulcer repair, and restoration of lymphatic flow in vitro and in vivo. Conclusions: ES exerts its effect on the main stages that characterize lymphedema, from its onset to ulcer formation. There are few evidences on lymphatic models and more molecular studies are needed to understand the mechanism of action of this application in the treatment of lymphedema.

Abstract ES11-1: Lymphedema management in 2018: Are we making any progress?

Abstract Lymphedema is a common and morbid complication of cancer treatment. To date, lymphedema treatment has been palliative aiming to prevent disease progression and improve symptoms of swelling. Development of novel therapies for lymphedema has been limited by the fact that the pathophysiology of the disease remains unknown. While it is true that lymphatic injury during surgery is an important initiating event, the mechanisms that regulate the development of the disease in a subset of patients remain unknown. Recent studies in our lab have suggested that the pathophysiology of lymphedema is related to inflammatory changes that occur following surgery. We have shown that CD4+ T cells play a key role in the pathology of lymphedema by orchestrating a variety of changes including tissue fibrosis, lymphatic leakiness, impaired collecting vessel pumping, and changes in the lymphatic smooth muscle cells. More importantly, in preclinical models we have shown that inhibition of this response can prevent development of lymphedema following surgery or reverse it once it has been initiated. These findings have led to novel treatments for lymphedema that may be effective either as standalone therapies or used in conjunction with surgical treatments for lymphedema. Citation Format: Mehrara B. Lymphedema management in 2018: Are we making any progress? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES11-1.