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The presence of Stemmer's sign is considered pathognomic for the presence of lymphedema. In a patient with unilateral lower extremity lymphedema, when compared with the normal limb (A), there is an inability to 'tent' the skin of the lymphedematous interdigital skin fold (B).
Source publication
Despite the central, complex role for the lymphatic system in the maintenance of human health, the biology of this important and complex vasculature has been relatively under-investigated. However, the last decade has witnessed a substantial growth in the elucidation of lymphatic structural biology and the function of this system in health and in d...
Context in source publication
Context 1
... clinical diagnosis of lymphedema relies most heav- ily upon observations made at the bedside. Distinction from other, non-lymphatic forms of edema requires recognition of the unique cutaneous sequelae of lymphedema, 2,5 includ- ing peau d'orange and the presence of inelasticity of the skin at the base of the digits, known as the Stemmer sign (Figure 2). 47 The differential diagnosis of lymphedema includes both chronic venous insufficiency and lipedema. ...
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Citations
... Secondary lymphedema is frequently seen in patients undergoing axillary lymph node dissection and postoperative radiotherapy, with significant impacts on the quality of life, including reduced limb function, chronic pain, recurrent infections and a deterioration in psychological well-being [1][2][3]. The lymphatic system plays a critical role in maintaining fluid homeostasis, immune function and the removal of metabolic waste products [4]. Dysfunction in this system, as seen in lymphedema, results in the disruption of these processes, leading to chronic inflammation, tissue remodeling and immune dysregulation. ...
Background/Objectives: Lymphedema, a common source of disability among oncology patients, necessitates continuous targeted rehabilitation. Recent studies have revealed the role of connective tissue in this pathology; however, despite existing research on ultrasound (US) use in lymphedema, no studies have specifically addressed the use of ultrasound to assess fasciae in patients with lymphedema. This study aims to provide a more objective characterization of typical US alterations in these patients by quantifying the thickness of superficial and deep fasciae and comparing them with those of healthy volunteers. Methods: A cross-sectional study was performed using US imaging to measure the thickness of superficial and deep fascia in different regions and levels of the arm and forearm in a sample of 50 subjects: 25 chronic lymphedema patients and 25 healthy participants. Results: No significant difference in fascial thickness was observed between affected and unaffected upper limbs, but patients had notably thinner superficial fascia and deep fascia compared with healthy volunteers. The findings for superficial and deep fascia revealed statistically significant differences (p < 0.0001) in all regions and levels. Conclusions: This study demonstrates the effectiveness of US imaging as a non-invasive tool for detecting subtle fascial changes in chronic lymphedema patients, revealing thinner fasciae compared with those in healthy volunteers. These findings suggest a potential anatomical predisposition to lymphedema, highlighting the importance of incorporating detailed US assessments in diagnosis and management to improve early intervention and patient outcomes. Future studies could, therefore, investigate whether preventive fascia assessment might improve the early identification of individuals at risk.
... Lymphedema is a common side effect of cancer treatment with an overall incidence of 15.5%, and increased risk among patients who undergo pelvic dissections (22%) or radiation therapy (31%) (1)(2)(3). The average incidence of secondary lymphedema in women following breast cancer treatment is 20% (3) and a number of studies report an increased incidence of up to 60% (4)(5)(6). ...
Secondary lymphedema is a common condition among cancer survivors, and treatment strategies to prevent or treat lymphedema are in high demand. The development of novel strategies to diagnose or treat lymphedema would benefit from a robust experimental animal model of secondary lymphedema. The purpose of this methods paper is to describe and summarize our experience in developing and characterizing a rat hindlimb model of lymphedema. Here we describe a protocol to induce secondary lymphedema that takes advantage of micro computed tomography imaging for limb volume measurements and visualization of lymph drainage with near infrared imaging. To demonstrate the utility of this preclinical model for studying the therapeutic benefit of novel devices, we apply this animal model to test the efficacy of a biomaterials-based implantable medical device.
... An estimated 250 million individuals worldwide suffer from lymphedema, and yet the only recommended therapies from the International Society of Lymphology are compression garments and manual massage [7]. There are currently few, if any, feasible pharmacological targets for the specific and effective therapeutic modulation of lymphatic vessels [8,9]. Thus, the discovery of pharmacologically tractable factors that preferentially and specifically control and modulate the functions of lymphatics remains a high priority. ...
Numerous studies have focused on the molecular signaling pathways that govern the development and growth of lymphatics in the hopes of elucidating promising druggable targets. G protein-coupled receptors (GPCRs) are currently the largest family of membrane receptors targeted by FDA-approved drugs, but there remain many unexplored receptors, including orphan GPCRs with no known biological ligand or physiological function. Thus, we sought to illuminate the cadre of GPCRs expressed at high levels in lymphatic endothelial cells and identified four orphan receptors: GPRC5B, AGDRF5/GPR116, FZD8 and GPR61. Compared to blood endothelial cells, GPRC5B is the most abundant GPCR expressed in cultured human lymphatic endothelial cells (LECs), and in situ RNAscope shows high mRNA levels in lymphatics of mice. Using genetic engineering approaches in both zebrafish and mice, we characterized the function of GPRC5B in lymphatic development. Morphant gprc5b zebrafish exhibited failure of thoracic duct formation, and Gprc5b−/− mice suffered from embryonic hydrops fetalis and hemorrhage associated with subcutaneous edema and blood-filled lymphatic vessels. Compared to Gprc5+/+ littermate controls, Gprc5b−/− embryos exhibited attenuated developmental lymphangiogenesis. During the postnatal period, ~30% of Gprc5b−/− mice were growth-restricted or died prior to weaning, with associated attenuation of postnatal cardiac lymphatic growth. In cultured human primary LECs, expression of GPRC5B is required to maintain cell proliferation and viability. Collectively, we identify a novel role for the lymphatic-enriched orphan GPRC5B receptor in lymphangiogenesis of fish, mice and human cells. Elucidating the roles of orphan GPCRs in lymphatics provides new avenues for discovery of druggable targets to treat lymphatic-related conditions such as lymphedema and cancer.
... All patients undergoing triple therapy are first medically optimized with complete decongestive therapy including compression garments, lymphatic massage, and elevation [6,[12][13][14]. Following stable medical management of lymphedema, patients were treated surgically based on our triple therapy algorithm ( Figure 1). ...
Surgical treatment of advanced lymphedema is challenging and outcomes are suboptimal. Physiologic procedures including lymphaticovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) improve lymphatic flow but cannot reverse fibrofatty tissue deposition, whereas liposuction removes fibrofatty tissue but cannot prevent disease progression. The adjunctive use of nanofibrillar collagen scaffolds (BioBridgeTM) can promote lymphangiogenesis. We report a treatment algorithm utilizing a multimodality approach to achieve sustained normal limb volumes in patients with stage II-III lymphedema. A retrospective review of late stage II-III lymphedema patients treated with liposuction, physiologic procedures, and BioBridgeTM from 2016 through 2019 was conducted. Treatment outcome in the form of excess volume reduction is reported. Total of 14 patients underwent surgical treatment of late stage II and III lymphedema according to our triple therapy algorithm. Patients had a baseline median volume excess of 29% (19.8, 43.3%). The median volume excess was improved to 0.5% (−4.3, 3.8%) at 14.4 months from the first stage surgery (p < 0.05) and further improved to −1.0% (−3.3, 1.3%) after triple therapy with BB placement at 24.6 months. A triple therapy surgical treatment algorithm can optimize outcomes and achieve sustained normalization of limb volume in late stage II-III lymphedema. The incorporation of nanofibrillar collagen scaffold technology allows for improved and sustained volume reduction.
... Biomarker development is informed by knowledge of BCRL etiology: when lymphatic load exceeds transport capacity, lymph fluid accumulates in the interstitium and macroscopic swelling or lymphedema results. Advanced stages of lymphedema are clinically characterized by external measures of asymmetric limb volume attributed to thickening of the subcutaneous adipose tissue (SAT) with or without fibrosis [12]. Indeed, molecular MRI and vascular MR lymphangiography techniques developed by us and others demonstrate sensitivity to features of unilateral lymphedema, including lymph stasis and lymphatic vessel dilation [13][14][15][16], as well as edematous [17,18] and proteinaceous [19,20] tissue composition. ...
Purpose
Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL.
Methods
MRI at 3.0 T of upper extremity and torso anatomy, fat and muscle tissue composition, and T2 relaxometry were applied in left and right axillae of healthy control (n = 24) and symptomatic BCRL (n = 22) participants to test the primary hypothesis that fat-to-muscle volume fraction is elevated in symptomatic BCRL relative to healthy participants, and the secondary hypothesis that fat-to-muscle volume fraction is correlated with MR relaxometry of affected tissues and BCRL stage (significance criterion: two-sided p < 0.05).
Results
Fat-to-muscle volume fraction in healthy participants was symmetric in the right and left sides (p = 0.51); in BCRL participants matched for age, sex, and BMI, fat-to-muscle volume fraction was elevated on the affected side (fraction = 0.732 ± 0.184) versus right and left side in controls (fraction = 0.545 ± 0.221, p < 0.001). Fat-to-muscle volume fraction directly correlated with muscle T2 (p = 0.046) and increased with increasing level of BCRL stage (p = 0.041).
Conclusion
Adiposity quantified by MRI is elevated in the affected upper extremity of women with BCRL and may provide a surrogate marker of condition onset or severity.
Clinical trial
NCT02611557.
... Treatment and prevention are cause-dependent; optimizing cardiac function and preventing further renal and hepatic deterioration may be relevant within patients with CHD. Persisting edema may be treated with exercise, decongestive physiotherapy, compression stockings, or pneumatic compression therapy [116,117]. ...
Purpose of review:
Lymphatic disorders have received an increasing amount of attention over the last decade. Sparked primarily by improved imaging modalities and the dawn of lymphatic interventions, understanding, diagnostics, and treatment of lymphatic complications have undergone considerable improvements. Thus, the current review aims to summarize understanding, diagnostics, and treatment of lymphatic complications in individuals with congenital heart disease.
Recent findings:
The altered hemodynamics of individuals with congenital heart disease has been found to profoundly affect morphology and function of the lymphatic system, rendering this population especially prone to the development of lymphatic complications such as chylous and serous effusions, protein-losing enteropathy and plastic bronchitis. Although improved, a full understanding of the pathophysiology and targeted treatment for lymphatic complications is still wanting. Future research into pharmacological improvement of lymphatic function and continued implementation of lymphatic imaging and interventions may improve knowledge, treatment options, and outcome for affected individuals.
... Lymphedema has a well-described inflammatory component that contributes to alteration of subcutaneous tissue, including alterations in fat content and the development of fibrosis. [36][37][38] Because of the significant contribution of inflammation in the pathology of lymphedema, 39 counteracting inflammation has been a major focus as a potential therapeutic target. Leukotriene B4 antagonism was shown to ameliorate experimental lymphedema. ...
Background:
Lymphatic endothelium plays significant roles in lymph transport and maintaining a barrier between the lymph and interstitial compartments. Lymphatic endothelial dysfunction is suspected to be a key factor in the pathogenesis of lymphatic diseases such as lymphedema. Sigma receptor-1 (σ1) was recently identified to promote endothelial-dependent production of nitric oxide and relaxation of collecting lymphatic vessels. In this study, we investigated the potential role of σ1 in lymphatic endothelial barrier function.
Methods and Results:
Cultured adult human dermal lymphatic endothelial cells (HDLEC) were grown into confluent monolayers. Transendothelial electrical resistance (TER) served as an index of barrier function. Glycolytic rate of HDLEC was determined with the Agilent Seahorse system. The σ1-selective agonist PRE-084 was used to test the impact of σ1 on HDLEC monolayer barrier function and endothelial bioenergetics, whereas the contribution of basal σ1 activity was assessed with small interfering RNA (siRNA)-mediated knockdown of σ1 expression. The ability of σ1 activation to counteract interleukin (IL)-1β-induced barrier dysfunction was also tested. The results show that PRE-084 increases HDLEC TER in a concentration-dependent manner, whereas reducing σ1 expression with siRNA decreases HDLEC TER. PRE-084 also enhances glycolytic rate parameters in HDLEC. Moreover, PRE-084 treatment partially counteracts IL-1β-induced HDLEC monolayer barrier dysfunction.
Conclusions:
Collectively, the results suggest that σ1 contributes to basal lymphatic endothelial barrier function, potentially through its ability to enhance glycolytic energy production. Our work also highlights the therapeutic potential of σ1 agonists for preventing lymphatic barrier dysfunction caused by inflammatory mediators.
... The lymphatic system is essential for tissue fluid homeostasis in higher vertebrates [1]. Furthermore, it is involved in the regulation of immunosurveillance and the absorption of dietary fats [2]. The lymphatic vasculature consists of capillaries, precollecting vessels and collecting lymphatic trunks, which form a complex network with interposed lymph nodes. ...
Vascularized lymph node (VLN) transfer is an emerging strategy to re-establish lymphatic drainage in chronic lymphedema. However, the biological processes underlying lymph node integration remain elusive. This study introduces an experimental approach facilitating the analysis of short-term molecular and cellular effects of ischemia/reperfusion on VLN flaps. Lymph node flaps were dissected pedicled on the lateral thoracic vessels in 44 Lewis rats. VLN flaps were exposed to 45 or 120 minutes ischemia by in situ clamping of the vascular pedicle with subsequent reperfusion for 24 hours. Flaps not exposed to ischemia/reperfusion served as controls. Lymph nodes and the perinodal adipose tissue were separately analyzed by Western blot for the expression of lymphangiogenic and angiogenic growth factors. Moreover, morphology, microvessel density, proliferation, apoptosis and immune cell infiltration of VLN flaps were further assessed by histology and immunohistochemistry. Ischemia for 120 minutes was associated with a markedly reduced cellularity of lymph nodes but not of the perinodal adipose tissue. In line with this, ischemic lymph nodes exhibited a significantly lower microvessel density and an increased expression of VEGF-D and VEGF-A. However, VEGF-C expression was not upregulated. In contrast, analyses of the perinodal adipose tissue revealed a more subtle decrease of microvessel density, while only the expression of VEGF-D was increased. Moreover, after 120 minutes ischemia, lymph nodes but not the perinodal adipose tissue exhibited significantly higher numbers of proliferating and apoptotic cells as well as infiltrated macrophages and neutrophilic granulocytes compared with non-ischemic flaps. Taken together, lymph nodes of VLN flaps are highly susceptible to ischemia/reperfusion injury. In contrast, the perinodal adipose tissue is less prone to ischemia/reperfusion injury.
... Pain, range of motion, and presence of neurologic abnormalities can help identify focal musculoskeletal, neurologic issues, and DVT. 7,8 The skin of the lower extremities needs to be thoroughly examined. Infection and thrombophlebitis can be accompanied by erythema and increased warmth. ...
... It generally utilizes Tc-99m radiolabeled sulphur colloid which is injected in the intradermally in the second and third web spaces of the feet with serial imaging using a scintigraphic camera for the assessment of lymph movement from the feet to the chest. 7,8 Indocyanine green (IGD) lymphography has been increasingly used to identify and stage lymphedema by plastic surgeons prior to and during certain types of treatment and is also used for objective staging and follow-up after surgery. 13 MR lymphography with and without contrast is a promising method providing good imaging and planning but rigorous assessment of the examination, availability, and interpretation expertise is lacking. ...
Patients with lower limb edema are frequently referred to vascular specialists for evaluation. Multiple etiologies must be considered and often more than one cause may be present. Notably, the role of lymphatic system regardless of the underlying pathology has been underestimated. A thorough history and physical examination and a carefully considered laboratory and imaging evaluation are critical in differentiating causes. In this opinion article, we propose a diagnostic algorithm that incorporates a systematic approach to the patient with leg swelling and provides an efficient pathway for the differential diagnosis for this problem.
... Secondly, this study had similar proportions of women with treated BCRL and women who had recently been diagnosed but had not started treatment in the BIS-DETECTED group. Early BCRL is characterised by soft pitting oedema [43]. The increased extracellular fluid that comprises this oedema may impact mechanoreceptors in the tissues and cause sensations of swelling [44], whereas other sensations such as heaviness and tightness may not be experienced until increases in limb volume occur as the lymphoedema progresses. ...
Introduction
In the absence of monitoring programs, those at risk of developing breast cancer–related lymphoedema (BCRL) must detect its development. However, the efficacy of self-assessment for BCRL has not been widely investigated. This study will determine if symptoms and signs of BCRL are associated with lymphoedema detected by bioimpedance spectroscopy (BIS) and whether those with and without BCRL can accurately assess the signs of its presence.
Methods and results
Participants with a history of breast cancer (n = 100) reported the presence/absence of symptoms associated with upper limb BCRL and underwent assessment for pitting oedema and differences in tissue texture between their arms (pinch). BIS detected BCRL in 48 women. Women were more likely to have BIS-detected BCRL if they reported swelling (odds ratio (OR), 58.8; 95% CI, 4.9 to 709.4; p = 0.001) or had inter-limb tissue texture differences in their forearm (OR, 73.5; 95% CI, 7.3 to 736.9; p = < 0.001) or upper arm (OR, 23.9; 95% CI, 2.8 to 201.7; p = 0.003). Agreement between therapist and self-assessment of signs of BCRL was almost perfect (kappa, 0.819 to 0.940). A combination of self-reported swelling and/or self-assessed forearm tissue texture difference identified all cases of BIS-detected BCRL.
Conclusion
Participants accurately identified the presence or absence of physical signs of BCRL in their arm. Perceived swelling and differences in tissue texture in the affected arm were associated with, and sensitive to, BIS-detected BCRL. These findings support the use of self-assessment to determine if BCRL is developing, indicating the need for professional assessment.
