Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema.

Primary lymphedema is a long-term (chronic) condition characterized by tissue lymph retention and swelling that can affect any part of the body, although it usually develops in the arms or legs. Due to the relevant contribution of the lymphatic system to human physiology, while this review mainly focuses on the clinical and physiological aspects related to the regulation of fluid homeostasis and edema, clinicians need to know that the impact of lymphatic dysfunction with a genetic origin can be wide ranging. Lymphatic dysfunction can affect immune function so leading to infection; it can influence cancer development and spread, and it can determine fat transport so impacting on nutrition and obesity. Genetic studies and the development of imaging techniques for the assessment of lymphatic function have enabled the recognition of primary lymphedema as a heterogenic condition in terms of genetic causes and disease mechanisms. In this review, the known biological functions of several genes crucial to the development and function of the lymphatic system are used as a basis for understanding normal lymphatic biology. The disease conditions originating from mutations in these genes are discussed together with a detailed clinical description of the phenotype and the up-to-date knowledge in terms of disease mechanisms acquired from in vitro and in vivo research models.

A HGF Mutation in the Familial Case of Primary Lymphedema: A Report.

Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.

Visualization of Organ-Specific Lymphatic Growth: An Efficient Approach to Labeling Molecular Markers in Cleared Tissues.

Organ-specific lymphatics are essential for the maintenance of healthy organ function and lymphatic dysfunction can lead to the development of various diseases. However, the precise role of those lymphatic structures remains unknown, mainly due to inefficient visualization techniques. Here, we present an efficient approach to visualizing organ-specific lymphatic growth. We used a modified CUBIC protocol to clear mouse organs and combined it with whole-mount immunostaining to visualize lymphatic structures. We acquired images using upright, stereo and confocal microscopy and quantified them with AngioTool, a tool for the quantification of vascular networks. Using our approach, we then characterized the organ-specific lymphatic vasculature of the Flt4kd/+ mouse model, showing symptoms of lymphatic dysfunction. Our approach enabled us to visualize the lymphatic vasculature of organs and to analyze and quantify structural changes. We detected morphologically altered lymphatic vessels in all investigated organs of Flt4kd/+ mice, including the lungs, small intestine, heart and uterus, but no lymphatic structures in the skin. Quantifications showed that these mice have fewer and dilated lymphatic vessels in the small intestine and the lungs. Our results demonstrate that our approach can be used to investigate the importance of organ-specific lymphatics under both physiological and pathophysiological conditions.

Current Concepts in the Management of Primary Lymphedema.

Primary lymphedema is a heterogeneous group of conditions encompassing all lymphatic anomalies that result in lymphatic swelling. Primary lymphedema can be difficult to diagnose, and diagnosis is often delayed. As opposed to secondary lymphedema, primary lymphedema has an unpredictable disease course, often progressing more slowly. Primary lymphedema can be associated with various genetic syndromes or can be idiopathic. Diagnosis is often clinical, although imaging can be a helpful adjunct. The literature on treating primary lymphedema is limited, and treatment algorithms are largely based on practice patterns for secondary lymphedema. The mainstay of treatment focuses on complete decongestive therapy, including manual lymphatic drainage and compression therapy. For those who fail conservative treatment, surgical treatment can be an option. Microsurgical techniques have shown promise in primary lymphedema, with both lymphovenous bypass and vascularized lymph node transfers demonstrating improved clinical outcomes in a few studies.

Heterozygous deletion of the VEGFC gene in 4q34.3 is associated with Milroy-like lymphedema: First prenatal case report.

Deleterious variants in the vascular endothelial growth factor C (VEGFC) gene have been recently associated with Milroy-like primary lymphedema, an autosomal dominant disorder, characterized mainly by swelling of the lower limbs due to functional impairment of the lymphatic vessels. To date, only 26 patients with congenital lymphedema harboring VEGFC pathogenic variants were documented. Here, we describe the first prenatal case of a fetus with Milroy-like disease. Fetal ultrasound showed bilateral foot swelling. Chromosomal microarray analysis revealed a 137-kb copy number loss in 4q34.3 including only VEGFC gene in the propositus fetus. Segregation analysis showed that the deletion was inherited from the affected mother and grandmother. Taken together, our study highlights the important role of microarray analysis to detect subtle chromosomal imbalances in the prenatal setting and contributes to delineate the fetal phenotype of VEGFC-related primary congenital lymphedema.

Heparin-induced thrombocytopenia and thrombosis in primary lymphedema patients who underwent vascularized lymph node transplantations.

BACKGROUND: Heparin-induced thrombocytopenia and thrombosis (HITT) may result in microsurgical flap failure. This study investigated the outcomes of HITT in primary lymphedema patients who underwent vascularized lymph node transplantations (VLNT). METHODS: Between 2012 and 2019, primary lymphedema patients who underwent VLNTs were retrospectively included. The 4Ts score was used to categorize patients into HITT (scores of 5-7) and non-HITT (score < 5) groups. Outcome evaluations included the re-exploration rate, success rate, circumferential differences, cellulitis episodes, and Lymphedema Specific Quality of Life Questionnaire (LYMQoL) scores. RESULTS: Twenty-six and 15 patients with 31 and 16 VLNTs were included in the HITT and non-HITT groups, respectively. The HITT group had significantly greater first, second and third re-exploration rates of 38.7% (12/31), 25.7% (8/31), and 6.5% (2/31) than the non-HITT group (6.3%, 0%, and 0%, all p < 0.01), respectively. The platelet counts significantly decreased by 21.0% in the HITT group compared with the non-HITT group (14%) on postoperative Day one (p < 0.01) with a cutoff value of 17% and AUC = 0.88. CONCLUSIONS: HITT may cause a high re-exploration rate of VLNTs in primary lymphedema patients. The 17% reduction in platelets on postoperative day one was an early sign for detecting HITT.

Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic.

BACKGROUND: Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life. METHODS: Medical records of patients under 18 years of age referred between 1996 and 2021 to the specialized lymphedema clinic at the Sainte-Justine University Hospital Center were reviewed. Demographic data, sex, age at presentation, location of the lymphedema, clinical features, genetic testing, symptoms, complications, investigations, and treatment were collected. RESULTS: Of 180 referred patients, lymphedema was confirmed in 151, and 137 were primary lymphedema. Median age of apparition of primary lymphedema was 7.00 years and was significantly lower in boys than in girls. Primary congenital lymphedema was more frequent in boys (51.0%, 27.3% in girls, P = .007), and onset of primary lymphedema during adolescence was more frequent in girls (53.4%, 25.0% in boys, P = .001). Lower limbs were the most impacted (88.3%). Sixty patients had genetic testing, and 38 (63.3%) of them were discovered to have a pertinent genetic mutation. The most common mutated gene was the FLT4 gene (in 9 patients). Seven patients (5.1%) had associated extensive/central lymphatic malformation and 24 (17.6%) had a polymalformative syndrome/syndromic lymphedema. CONCLUSIONS: Pediatric lymphedema is more frequent in girls, usually involves lower limb, and is most often sporadic, but often associated with a genetic mutation, and genetic testing should be performed.

[The morphology of the connective tissue matrix and lymphatic bed of the external genitalia in primary massive localized lymphedema]. / Morfologiya soedinitel'notkannogo matriksa i limfaticheskogo rusla naruzhnykh polovykh organov pri pervichnoi massivnoi lokalizovannoi limfedeme.

OBJECTIVE: To identify the structural organization of connective tissue and vascular bed of the external genitalia in primary massive localized lymphedema. To analyze a clinical case of the development of massive localized lymphedema of the external genitalia concurrent with primary lymphedema of the lower limb in a patient with a normal body mass index. MATERIAL AND METHODS: The samples obtained by resection during volume reduction surgery were used to study the morphological features of the lymphatic bed and extracellular matrix of the scrotal skin and testicular dartos versus the samples without pathological changes. Biological samples were processed using standard techniques for histological, immunohistochemical and ultrastructural analyses. Lymphatic vessels were differentiated using the molecular lymphatic endothelial marker Podoplanin. RESULTS: In lymphedema, there was an increase in the thickness of all scrotal skin layers, a decrease in the volumetric lymphatic vessel density, an expansion of the interstitial spaces, and a change in the structure of collagen fibers that were homogenized, loosened, and swollen and did not form a three-dimensional network. The testicular dartos exhibited intermuscular fibrosis, expansion of the interstitial spaces, and perivascular leukocytic infiltration. CONCLUSION: Histological and immunohistochemical analyses revealed changes in the structural organization of the connective tissue matrix and lymphatic bed of the scrotal skin and testicular dartos in long-standing massive localized lymphedema. The feature of the described clinical case was the absence of signs of chronic inflammation and severe diffuse fibrosis in primary scrotal massive localized lymphedema in a patient with a normal body mass index.

Use of lymphoscintigraphy to differentiate primary versus secondary lower extremity lymphedema after surgical lymphadenectomy: a retrospective analysis.

BACKGROUND: When managing patients with cancer, lymphedema of the lower limbs (LLL) is commonly reported as secondary to the surgical excision and/or irradiation of lymph nodes (LNs). In the framework of lymphoscintigraphic imaging performed to evaluate secondary LLL, some lympho-nodal presentations have been observed that could not be explained by the applied treatments, suggesting that these LLL might be primary. Therefore, all our lymphoscintigraphic examinations that were performed in patients for LLL after surgery for gynecological or urological cancer were retrospectively analyzed in order to evaluate the frequency in which these LLL might not be secondary (either completely or partially) but primary in origin. METHODS: Lymphoscintigraphies performed in 33 patients who underwent LN dissection (limited to the intra-abdominal LN) with or without radiotherapy for histologically confirmed ovarian cancer (n = 6), uterine cancer (n = 14 with cervical cancer and n = 7 with endometrial cancer), or prostate cancer (n = 6) were compared to lymphoscintigraphies obtained in primary LLL. RESULTS: In 12 (33% of the) patients (3 men plus 9 women, 4 with cervical cancer and 5 with endometrial cancer), scintigraphy of the lower limbs revealed lympho-nodal presentation that did not match with the expected consequences of the surgical and/or radiological treatments and were either suggestive or typical of primary lymphedema. CONCLUSIONS: This retrospective analysis of a limited but well-defined series of patients suggests that the appearance of LLL might not be related to cancer treatment(s) but that these LLL may represent the development of a primary lymphatic disease latent prior to the therapeutic interventions.

A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.

[Angiosarcoma in primary lymphoedema: A rare complication]. / Angiosarcome sur lymphœdème primaire du membre inférieur : une complication rare.

BACKGROUND: Chronic lymphoedema is classically complicated by recurring episodes of cellulitis. Degeneration to the angiosarcoma form (Stewart-Treves syndrome) is much less common. It occurs mainly in the upper limbs following surgery or radiotherapy for mammary neoplasia. Herein we report a rare case of Stewart-Treves syndrome (STS) of the lower limb as a complication of congenital lymphoedema. PATIENTS AND METHODS: A 69-year-old woman treated for bilateral lower-limb oedema present for 30years developed painful necrotic lesions in her left lower limb. A diagnosis of angiosarcoma was made based on biopsy of a nodular lesion. Since surgical excision was precluded by the extent of the lesions, chemotherapy was initiated with paclitaxel 175mg/m2 every 21days. The outcome was rapidly unfavourable and the patient died at her home during the third course of treatment. DISCUSSION: Angiosarcoma is an extremely rare complication of primary lymphoedema; treatment is poorly codified and the prognosis is unfavourable.

A Novel Mutation in the FOXC2 Gene: A Heterozygous Insertion of Adenosine (c.867insA) in a Family with Lymphoedema of Lower Limbs without Distichiasis.

BACKGROUND: Primary lymphoedema is a rare genetic disorder characterized by swelling of different parts of the body and highly heterogenic clinical presentation. Mutations in several causative genes characterize specific forms of the disease. FOXC2 mutations are associated with lymphoedema of lower extremities, usually distichiasis and late onset. PATIENTS AND METHODS: Subjects from three generations of a family with lymphoedema of lower limbs without distichiasis were searched for mutations in the FOXC2 gene. RESULTS: All affected family members with lymphoedema of lower limbs without distichiasis, and still asymptomatic six years old girl from the same family, carried the same previously unreported insertion of adenosine (c.867insA) in FOXC2. CONCLUSIONS: Identification of a novel mutation in the FOXC2 gene in affected family members of three generations with lymphoedema of lower limbs without distichiasis, highlights the high phenotypic variability caused by FOXC2 mutations.

Effects of matrix rhythm therapy on primary lymphedema: a case report.

[Purpose] Primary lymphedema occurs because of genetic predisposition and developmental insufficiency of the lymphatic system. Matrix Rhythm Therapy was developed as an external and dynamic method that supplies rhythmic mobilization of the fluids in tissues. The aim of the study was to investigate the effects of Matrix Rhythm Therapy in primary lymphedema. [Subject and Methods] A 36-year-old female with left lower limb lymphedema was evaluated. Leg circumference was measured before and at the end of treatment, and 1 and 3 months later. The circumferences were converted to volumetric values. Twenty sessions of Matrix Rhythm Therapy (5 days/week) were applied to the affected leg, spine, and abdominal regions. Patient satisfaction was assessed with the Global Rating of Change scale. [Results] Volumetric values were 1,573.28 ml before treatment, 1,573.13 ml at the end of treatment, 1,516.70 ml 1 month later, and 1,441.61 ml 3 months later. At the end of treatment, the volumetric reduction was not significant; however, when compared with baseline, measurements at 1 and 3 months decreased by 3.59% and 8.36%, respectively. The Global Rating of Change score was 2. [Conclusion] Matrix Rhythm Therapy could not reduce lymphedema when used alone, but long-term treatment may show positive effects.

Generalized lymphedema associated with neurologic signs (GLANS) syndrome: a new entity?

BACKGROUND: Primary lymphedema in children, especially generalized disease with facial involvement, is rare. OBJECTIVE: We sought to report 3 childhood cases of lymphedema with associated neurologic findings and to provide a pathophysiologic explanation for this association. METHODS: Clinical observations, electroencephalography, and neuroimaging studies were evaluated. Microcomparative genomic hybridization was performed in 1 case. RESULTS: The 3 children had primary lymphedema of all 4 limbs and the face. This was confirmed by lymphoscintigraphy, which showed hypoplasia of vessels and hypofixation of lymph nodes. They had nonspecific neurologic disorders and electroencephalography abnormalities, without intellectual deficit. Neuroimaging revealed normal findings. Microcomparative genomic hybridization in 1 patient revealed no cytogenetic anomaly. The outcome was fatal in 1 case with development of visceral lymphedema and coma. LIMITATIONS: Genetic studies were performed in only 1 case. CONCLUSION: These observations suggest that neurologic assessment and electroencephalography are indicated for patients with lymphedema of the limbs and face to identify this syndrome.

Self-care status, symptom burden, and reported infections in individuals with lower-extremity primary lymphedema.

PURPOSE: The purposes of this study were (a) to evaluate self-care, symptom burden, and reported infections among individuals with lower-extremity primary lymphedema; (b) to examine the differences in self-care, symptom burden, and reported infections between individuals with unilateral and those with bilateral lower-extremity primary lymphedema; and (c) to examine the associations among self-care status, symptom burden, and reported infections in individuals with lower-extremity primary lymphedema. DESIGN: A secondary data analysis was used. Data were collected from a cross-sectional survey study supported by the National Lymphedema Network from March 2006 through January 2010. The surveys were available both online and in hard copy in order to increase accessibility. METHODS: Descriptive statistics were conducted and associations between variables were assessed using Mann-Whitney tests and chi-square tests of independence. Multiple logistic regression was used to test for associations while controlling for potentially confounding variables. FINDINGS: A total of 803 participants reported having lower-extremity primary lymphedema. The majority of the participants were female (82.9%), White (74.2%), and from the United States (90.7%). Approximately two thirds of the respondents conducted some home daily lymphedema self-care. Over half of the respondents reported experiencing symptom burden and 44.8% reported at least one episode of infection. Compared to individuals with unilateral lower-extremity primary lymphedema, individuals with bilateral lower-extremity lymphedema were more likely to conduct skin care (p = .004), use alternative medications (p = .005), more frequently reported symptoms (p < .05), and more likely to report at least one episode of infection (p = .002). Respondents who reported use of compression garments also were less likely to have self-reported pain (p = .002), poor range of motion (p = .026), and numbness (p = .001). Participants who reported exercising also were less likely to have self-reported pain (p = .003). Participants who reported at least one episode of infection also reported experiencing more symptoms (p < .001). CONCLUSIONS: Individuals with lower-extremity primary lymphedema experienced substantial symptom burden and infection episodes. Significant associations were identified among self-care, symptom burden, and reported infections. CLINICAL RELEVANCE: The findings support the need for clinicians to educate patients with lower-extremity primary lymphedema regarding the importance of self-care, symptom management, and infection control. It is critically important for clinicians to evaluate symptom burden and reduce infections in individuals with lower-extremity primary lymphedema.

Evaluation of Primary Lymphedema with Intranodal Lymphangiography.

PURPOSE: There are limited existing data on the lymphatic anatomy of patients with primary lymphedema (LED), which is caused by aberrant development of lymphatic channels. In addition, there is a paucity of contemporary studies that use groin intranodal lymphangiography (IL) to evaluate LED anatomy. The purpose of this retrospective observational study was to better delineate the disease process and anatomy of primary LED using groin IL. MATERIALS AND METHODS: We identified common groin IL findings in a cohort of 17 primary LED patients performed between 1/1/2017 and 1/31/2022 at a single institution. These patients were clinically determined to have primary lymphedema and demonstrated associated findings on lower extremity MR and lymphoscintigraphy. RESULTS: Ten patients (59%) demonstrated irregular lymph node morphology or a paucity of lymph nodes on the more symptomatic laterality. Eight patients (47%) demonstrated lymphovenous shunting from pre-existing anastomoses between the lymphatic and venous systems. Eight patients (47%) demonstrated passage of contrast past midline to the contralateral lymphatics. Finally, 12 patients (71%) failed to opacify the cisterna chyli and thoracic duct on their initial lymphangiograms. Delayed computed tomography of 3 patients showed eventual central lymphatic opacification up to the renal veins, but none of these patients showed central lymphatic opacification to the thorax. CONCLUSION: This descriptive, exploratory study demonstrates common central groin IL findings in primary LED to highlight patterns interventional radiologists should identify and report when addressing primary LED.

Chylous Reflux in Pediatric Primary Lymphedema of the Lower Limbs and Genitalia: A Retrospective Study of 167 Patients.

Background: Chylous reflux (CR) in primary lymphedema (PL) of the lower extremities is rare and requires particular diagnostic procedures. This study aimed to determine clinical and lymphoscintigraphic traits for efficient screening. Methods and Results: Pediatric patients with PL of lower extremities treated in our institution between January 2020 and December 2023 were reviewed. The medical history, lymphoscintigraphy, non-contrast MR lymphography, and direct lymphangiography were analyzed. Lymphoscintigraphic visual patterns were classified to detect CR. Patients with CR showed significantly higher proportions of childhood symptom onset (65.63% vs. 25.19%, p < 0.01), genital lymphedema (62.50% vs. 19.26%, p < 0.01), and proximal-to-distal swelling (31.25% vs. 8.89%, p < 0.01). Eight patients without skin lesions had milk discharge after acupuncture or skin breakdown. Pattern 4 shows diffused dermal backflow of the leg and an absence of superficial lymphatic drainage, or normal initial cephalad flow with subsequent reflux of tracer into the affected limb. CR showed significantly higher percentages of pattern 4 (87.50% vs. 12.59%, p < 0.01), normal/widened iliac lymphatics (78.13% vs. 11.11%, p < 0.01), and thigh/calf outlining (87.50% vs. 29.63%, p < 0.01). Genital swelling preceding limb swelling and genital radioactivity were more common in the CR group. Conclusions: CR tends to occur in childhood initially, begin centrally and progress distally, and involve genitals prior to lower extremities. Milk discharge after acupuncture or skin breakdown is important for screening CR without chylous vesicles. The patterns with typical "profiling of the leg" and normal or widened iliac lymphatic trunks strongly correlate with CR. Genital lymphedema with increased radioactivity indicates CR.

Polymorphism of angiogenesis regulation factor genes (VEGF/VEGFR), and extracellular matrix remodeling genes (MMP/TIMP), and the levels of their products in extracellular tissues of patients with primary and secondary lymphedema.

Cells of various organs and systems perform their functions and intercellular interactions not in an inert environment, but in the microenvironment of tissue fluids. Violations of the normal drainage of tissue fluids accompany lymphedema. An important mechanism of angiogenesis and vasculogenesis regulation in tissue fluids is the production and reception of vascular endothelial growth factors in combination with the regulation of matrix metalloproteinases. The aim of the work was to perform: a comparative analysis of some polymorphisms of vascular endothelial growth factor and their receptors and the genes encoding matrix metalloproteinases in two forms of lymphedema; an analysis of the relationship of these genes' polymorphisms with the levels of vascular endothelial growth factor and matrix metalloproteinases and their inhibitors in serum and affected tissues. Polymorphism of VEGF (rs699947, rs3025039), KDR (rs10020464, rs11133360), NRP2 (rs849530, rs849563, rs16837641), matrix metalloproteinases MMP2 (rs2438650), MMP3 (rs3025058), MMP9 (rs3918242), Timp1 (rs6609533) and their combinations were analyzed by the Restriction Fragment Length Polymorphism method and TaqMan RT-PCR. The serum and tissue fluid levels were determined using the ELISA test system. Changes in the frequency distribution of MMP2 genotypes in primary and MMP3 in secondary lymphedema are shown. Significant frequency differences in NRP2 genotypes were revealed by comparing primary and secondary lymphedema. Features of the distribution of complex genotypes in primary and secondary lymphedema were revealed. The correlation analysis revealed the interdependence of the concentrations of the MMP, TIMP and VEGF products and differences in the structure of the correlation matrices of patients with both forms of lymphedema. It was shown that, in primary lymphedema, genotypes associated with low MMP2 and TIMP2 in serum and tissue fluid are detected, while in secondary lymphedema, other associations of the production levels with combined genetic traits are observed.

Effectiveness of lymphaticovenular anastomosis for adult-onset primary lower limb lymphedema: A retrospective study.

BACKGROUND: Surgical treatments such as lymphaticovenular anastomosis (LVA) are widely used in addition to conservative treatment of secondary lymphedema. However, their indications and effectiveness for primary lymphedema are unclear. This study aims to objectively demonstrate the effectiveness of LVA for adult-onset primary lymphedema from various perspectives. METHODS: We retrospectively examined patients with primary lower limb lymphedema who underwent LVA between January 2018 and December 2021 and were 21 or older. Treatment effects were evaluated using lymphoscintigraphy, questionnaires, body mass index, extracellular fluid ratio, and lymphedema index preoperatively and 6 months postoperatively. The LVA was performed under general anesthesia. RESULTS: We evaluated 11 patients (11 lower limbs). Out of seven patients with complete obstruction preoperatively, all presented partial obstruction according to the Taiwan Lymphoscintigraphy Staging classification with a significant decrease in the score. Significant improvements were observed in clinical symptoms ("hardness") and in quality of life ("appearance" and "ease of wearing compression garments") assessments. A significant change was observed in the extracellular water ratio but not in lower extremity lymphedema index (LELindex). CONCLUSION: LVA was suggested as one of the potential treatment options for patients with adult-onset primary lymphedema in whom lymphatic flow was confirmed by lymphoscintigraphy. In addition to clinical symptoms and physical examination, the evaluation of adult-onset primary lymphedema should include the patient's quality of life.

Surgical Treatment for Primary Lymphedema: A Systematic Review of the Literature.

This is a retrospective review of surgical management for primary lymphedema. Data were extracted from 55 articles from PubMed MEDLINE, Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials between the database inception and December 2022 to evaluate the outcomes of lymphaticovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT), and outcomes of soft tissue extirpative procedures such as suction-assisted lipectomy (SAL) and extensive soft tissue excision. Data from 485 patients were compiled; these were treated with LVA ( n = 177), VLNT ( n = 82), SAL ( n = 102), and excisional procedures ( n = 124). Improvement of the lower extremity lymphedema index, the quality of life (QoL), and lymphedema symptoms were reported in most studies. LVA and VLNT led to symptomatic relief and improved QoL, reaching up to 90 and 61% average circumference reduction, respectively. Cellulitis reduction was reported in 25 and 40% of LVA and VLNT papers, respectively. The extirpative procedures, used mainly in patients with advanced disease, also led to clinical improvement from the volume reduction, as well as reduced incidence of cellulitis, although with poor cosmetic results; 87.5% of these reports recommended postoperative compression garments. The overall complication rates were 1% for LVA, 13% for VLNT, 11% for SAL, and 46% for extirpative procedures. Altogether, only one paper lacked some kind of improvement. Primary lymphedema is amenable to surgical treatment; the currently performed procedures have effectively improved symptoms and QoL in this population. Complication rates are related to the invasiveness of the chosen procedure.