The role of key biomarkers in lymphatic malformation: An updated review.

The lymphatic system, crucial for tissue fluid balance and immune surveillance, can be severely impacted by disorders that hinder its activities. Lymphatic malformations (LMs) are caused by fluid accumulation in tissues owing to defects in lymphatic channel formation, the obstruction of lymphatic vessels or injury to lymphatic tissues. Somatic mutations, varying in symptoms based on lesions' location and size, provide insights into their molecular pathogenesis by identifying LMs' genetic causes. In this review, we collected the most recent findings about the role of genetic and inflammatory biomarkers in LMs that control the formation of these malformations. A thorough evaluation of the literature from 2000 to the present was conducted using the PubMed and Google Scholar databases. Although it is obvious that the vascular endothelial growth factor receptor 3 mutation accounts for a significant proportion of LM patients, several mutations in other genes thought to be linked to LM have also been discovered. Also, inflammatory mediators like interleukin-6, interleukin-8, tumor necrosis factor-alpha and mammalian target of rapamycin are the most commonly associated biomarkers with LM. Understanding the mutations and genes expression responsible for the abnormalities in lymphatic endothelial cells could lead to novel therapeutic strategies based on molecular pathways.

Pediatric mediastinal lymphatic malformation: misdiagnosis analysis and literature review.

OBJECTIVES: Mediastinal cystic lymphatic malformation (MCLM) in children is prone to misdiagnosis as cystic teratoma. We compared the clinical and radiologic features between the two diseases and performed a cross-comparison with previous research on adult cases. This study aims to identify characteristic pediatric manifestations to improve diagnostic accuracy. METHODS: A retrospective study of clinical and radiologic data was conducted on 12 MCLM and 20 cases of cystic teratomas confirmed by pathology or intervention biopsy. Clinical characters and radiology features (mass location and morphology, density, component, secondary complication) were recorded and compared. We reviewed clinical studies on MCLM published in the past decades, analyzing radiological differences and comparing pediatric MCLM cases at our hospital with those in the literature. RESULTS: Group comparison in pediatrics between MCLM and cystic teratomas: There were significant age differences (p = 0.036), shape (p = 0.003), CT difference value (p < 0.001), CT difference ratio (p < 0.001), calcification (p < 0.001), fat (p < 0.001), and typing (p < 0.001) between the two diseases. An analysis of literature data on MCLM cases involved 16 studies. CONCLUSION: The absence of internal fat or irregular morphology, along with a minimal CT difference value, may suggest the diagnosis of MCLM. In pediatric cases, anterior mediastinal diseases tend to extend toward the neck, and the presence of the thymus can complicate the component analysis, thereby increasing the risk of misdiagnosis. Clinical diagnosis and differential diagnosis of pediatric MCLM rely heavily on imaging evaluation.

Superficial Temple Lymphatic Malformation Appeared 13 Years after Initial Presentation With Orbital Lymphatic Malformation.

A 26-year-old male with a history of orbital lymphangioma and compressive optic neuropathy presented with recurrent proptosis in the OS. After examination and imaging, a left orbital lymphatic malformation and a new subcutaneous temporal-parietal vasculo-lymphatic malformation were diagnosed. The patient underwent a bleomycin injection for the orbital malformation and an excisional biopsy for the temporal lesion, leading to symptom resolution. Recurrence of lymphatic malformations and hemorrhage typically occurs at the same site, here we report a patient with the appearance of a new site lesion with orbital recurrence.

Endoscopic Resection for Vascular Anomalies in Children: A New Standard.

OBJECTIVE: To report an innovative endoscopic surgery for subcutaneous vascular malformations and intramuscular fibro-adipose vascular anomaly (FAVA) at our center. BACKGROUND: Historically, open surgical resection has been the treatment of choice. Recent advances in minimally invasive surgery have led to the successful application of endoscopic resection techniques for the surgical management of diseases of soft tissue. METHODS: Patients who underwent endoscopic resection of vascular anomalies were included in this retrospective review. Data were extracted from our Vascular Anomalies Center database between September 2019 and October 2022, including sex, age, symptoms, diagnosis, sites of surgery, previous treatment, surgery, and follow-up. RESULTS: There were 13 females and 15 males in the current study, with ages ranging from 1 to 17 years. The diagnoses included microcystic lymphatic malformation (LM) (n = 8), Klippel-Trénaunay syndrome (n = 7), venous malformation (n = 6), FAVA (n = 6), and mixed cystic LM (n = 1). Surgical sites included the lower extremity (n = 24), abdominal wall (n = 2), upper extremity (n = 1), and thoracic wall (n = 1). Five patients had an intramuscular lesion (FAVA). The endoscopic technique used 2 or 3 small ports in a gas inflation manner. Surgery included thrombectomy, radical resection, and debulking of vascular anomalies. Postoperative sclerotherapy with bleomycin was performed through a drainage tube in 6 patients with microcystic LM. Technical success was obtained in 27 patients. The conversion to open surgery was performed in one patient owing to the deep location of the lesion. No wound-related complication was observed. CONCLUSIONS: Endoscopic surgery is a minimally invasive, effective, and safe treatment for subcutaneous vascular malformations and intramuscular FAVA. This approach can set a new standard that minimizes wound complications and reduces recovery time in patients undergoing resection for benign soft-tissue lesions.

Spectrum of lymphatic anomalies in patients with RASA1-related CM-AVM.

BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) is characterized by multifocal fast-flow capillary malformations, sometimes with arteriovenous malformations/fistulas, skeletal/soft tissue overgrowth, telangiectasias, or Bier spots. Lymphatic abnormalities are infrequently reported. We describe seven patients with CM-AVM and lymphatic anomalies. METHODS: Following IRB approval, we identified patients with CM-AVM and lymphatic anomalies seen at the Vascular Anomalies Center at Boston Children's Hospital from 2003 to 2023. We retrospectively reviewed records for clinical, genetic, laboratory, and imaging findings. RESULTS: We found seven patients with CM-AVM and lymphatic abnormalities. Five patients were diagnosed prenatally: four with pleural effusions (including one suspected chylothorax) and one with ascites. Pleural effusions resolved after neonatal drainage in three patients and fetal thoracentesis in the fourth; however, fluid rapidly reaccumulated in this fetus causing hydrops. Ascites resolved after neonatal paracentesis, recurred at 2 months, and spontaneously resolved at 5 years; magnetic resonance lymphangiography for recurrence at age 19 years suggested a central conducting lymphatic anomaly (CCLA), and at age 20 years a right spermatic cord/scrotal lymphatic malformation (LM) was detected. Chylous pericardial effusion presented in a sixth patient at 2 months and disappeared after pericardiocentesis. A seventh patient was diagnosed with a left lower extremity LM at 16 months. Six patients underwent genetic testing, and all had RASA1 mutation. RASA1 variant was novel in three patients (c.1495delinsCTACC, c.434_451delinsA, c.2648del), previously reported in two (c.2603+1G>A, c.475_476del), and unavailable in another. Median follow-up age was 5.8 years (4 months-20 years). CONCLUSION: CM-AVM may be associated with lymphatic anomalies, including pericardial/pleural effusions, ascites, CCLA, and LM.

[Lymphangioma of the scrotum].

INTRODUCTION: Lymphangioma (lymphatic malformation) is a congenital malformation of lymphatic vessels. According to the classification of the International Society for the Study of the Vascular Anomalies, there are macrocystic, microcystic and mixed types of lymphatic malformations. The typical location of the lymphangiomas is the area of large lymphatic collectors (head, neck, axillary areas), while the scrotum is not frequently affected. AIM: To present a rare clinical case of lymphatic malformation of the scrotum with successful minimally invasive treatment (sclerotherapy). MATERIALS AND METHODS: A clinical observation of a 12-year-old child with a diagnosis of "Lymphatic malformation of the scrotum" is presented. From the age of 4, there was a large lesion in the left half of the scrotum. In other clinic, a surgical removal with a diagnosis of "left-sided inguinal hernia", "spermatic cord hydrocele", "isolated left-sided hydrocele" was performed. However, there was a recurrence after the procedure. When contacting the Clinic of pediatrics and pediatric surgery, scrotal lymphangioma was suspected. The diagnosis was confirmed by magnetic resonance imaging. The patient underwent minimally invasive sclerotherapy using the drug "Haemoblock". After 6 months of follow-up, no relapse was seen. CONCLUSION: Lymphangioma (lymphatic malformation) of the scrotum is a rare urological pathology that requires specific diagnosis, in-depth differential diagnosis and treatment by a multidisciplinary team of doctors, including a specialist in the treatment of vascular pathology.

Microcystic lymphatic malformation presenting as firm, skin-colored papules of the lips.

Microcystic lymphatic malformation (MiLM), also known as lymphangioma circumscriptum, is a superficial collection of lymphatic vessels measuring <1 cm in the largest diameter, often with a more extensive deeper malformation. It commonly presents as discrete or grouped plaques of clear or hemorrhagic vesicles classically described as "frogspawn"; however, here we describe a case of its unique presentation as firm papules on the lips of a healthy six-year-old child. These skin-colored papules in the absence of vesicles with lymphatic and/or hemorrhagic fluid may not be clinically indicative of MiLM. This case represents a diagnostic challenge due to the unique morphology of pink, fleshy papules as opposed to the clear or hemorrhagic vesicles typically observed in MiLM.

Lymphatic malformations in children: retrospective review of surgical and interventional management.

PURPOSE: Lymphatic malformations (LMs) are classified as macrocystic, microcystic or mixed. Treatment depends on their characteristics: surgery, sclerotherapy, both combined, systemic treatment or observation. This study aims to analyze the surgical and interventional management of LMs in children over the last two decades in our university hospital. METHODS: Management of children born with LMs between 2000 and 2019 was reviewed. Parameters collected were: malformation characteristics, type of treatment, symptoms, imaging, timing of diagnosis and first treatment, number of interventions, recovery rate, complications and length of stay. RESULTS: Files of 48 children were reviewed: 27 with macrocystic and 21 with microcystic LMs. There was no statistically significant difference in type of treatment except for combined treatment, more performed in microcystic LMs (p = 0.04). Symptoms, imaging, timing of diagnosis and first treatment, number of interventions and complications were not statistically significant. Overall, the number of surgeries was lower than sclerotherapies (p = 0.04). Recovery rate after surgery was higher in macrocystic LMs (p = 0.01). Complications and length of stay were not statistically significant. CONCLUSION: A good rate of recovery was observed when surgery was performed, with no significant increase in complications and length of stay. A prospective study will be determinant to create a decisional algorithm for children with LMs.

Intralesional Bleomycin for Orbital Lymphatic Malformations: Comparison of Clinical Versus Radiologic Regression by Volumetric Analysis.

PURPOSE: The aim of the study was to investigate the clinical resolution versus radiologic regression of orbital lymphatic malformations (LMs) following treatment with intralesional bleomycin sulfate sclerotherapy. METHODS: A retrospective interventional study of 24 eyes with orbital LMs treated with nonimage-guided bleomycin sclerotherapy. The clinical and radiologic outcomes were classified as excellent, good, fair, and poor. Regression was assessed clinically and by radiologic volumetrics. RESULTS: Mean age at presentation was 17 ± 18 years (median 11, range 5 months to 70 years). Lesion morphology was microcystic in 11 (46%), macrocystic in 8 (34%), and mixed in 5 (21%) eyes. Mean units of bleomycin injected per session were 4 ± 2 IU (median 5 IU, range 1-6 IU). Mean number of treatment sessions required was 2 ± 1 (median 2, range 1-6). Cumulative units of bleomycin injected were 11 ± 9 (median 9, range 1-38 IU). The clinical response was excellent in 19 (79%), good in 4 (17%), and fair in 1 (4%). The mean preoperative and postoperative lesion volumes were 7 ± 4 cm3 and 0.8 ± 1.2 cm3, respectively (p < 0.0001, 95% CI, -7.89 to -4.51). Radiologic resolution of LM was excellent in 6 (25%), good in 8 (33%), fair in 7 (29%), and poor in 3 (13%) eyes. Spearman's rank correlation coefficient for correlation between clinical and radiologic grading was 0.51 (p = 0.01, 95% CI, 0.13-0.75%). There was a sustained tumor resolution without recurrence over a mean follow-up duration was 2 years (median 18 months; range 12-60 months). CONCLUSIONS: Bleomycin sclerotherapy for orbital LMs gives an excellent to good clinical response in 93%. However, a parallel radiologic regression is seen only in 58%. The endpoint to assess response should be clinical. Treatment till complete radiologic resolution may not be necessary.

Multidisciplinary guidelines for initial evaluation of complicated lymphatic anomalies-expert opinion consensus.

OBJECTIVE: Complicated lymphatic anomalies (CLAs) are chronic, progressive, and debilitating conditions that share clinical features, yet key elements for optimal evaluation and management have not been established. We aimed to formulate expert opinion consensus-based guidelines for comprehensive evaluation of CLAs. STUDY DESIGN: Patient support groups dedicated to CLAs organized an international conference for vascular anomaly experts from 16 specialties to address the objective. Participants received a set of questions before the meeting and reviewed the literature. Data extracted from international lymphatic anomaly registries were presented and the group separated for panel discussions during the conference. The recommendations achieving consensus within the panel were presented to the entire audience. Open debate occurred until majority approval was achieved. RESULTS: The expert group was composed of 52 physicians who defined the clinical elements required to evaluate and diagnose a CLA. The radiology panel established the preferred anatomical and functional imaging methods for diagnosis and the elements required to be described during interpretation. Two medical panels compiled the metabolic and hematologic tests at diagnosis and also recommended functional studies. The surgical group recommended precautions for biopsy and the pathology panel provided biopsy specimen processing guidelines. CONCLUSIONS: Patients with CLAs require a comprehensive and targeted diagnostic plan for appropriate management, prevention of complications, and conservation of resources. As this population is managed by diverse medical and surgical specialties, we offer an expert multidisciplinary consensus-based opinion on the current literature and on data extracted from international lymphatic anomaly registries.

Abnormal pulmonary lymphatic flow in patients with paediatric pulmonary lymphatic disorders: Diagnosis and treatment.

Pulmonary lymphatic disorders are characterized by the presence of the abnormal lymphatic tissues in the thoracic cavity, presenting clinically as chylothorax, chylopericardium, chyloptysis, interstitial lung disease and plastic bronchitis. These conditions include: neonatal chylothorax, cardiac and non-cardiac plastic bronchitis, non-traumatic chylothorax, post congenital cardiac surgery chylothorax and complex lymphatic malformations. Recently developed lymphatic imaging techniques, such as intranodal lymphangiography and dynamic contrast enhanced magnetic resonance lymphangiography demonstrated abnormal pulmonary lymphatic flow from thoracic duct into pulmonary parenchyma as a pathophysiological mechanism of these diseases. Novel minimally invasive lymphatic interventions, such as thoracic duct embolization, interstitial lymphatic embolization and surgical lympho-venous anastomosis, provide an effective treatment of these conditions.

Lymphatic malformations compromising the upper airway in children: ultrasound-guided intralesional focal sclerotherapy with bleomycin targeting culprit lesions.

PURPOSE: Lymphatic malformations (LMs) compromising the upper airway is a life-threatening and intractable disease. Here, we establish a novel method to perform intralesional focal sclerotherapy targeting the culprit for airway stenosis. METHODS: Between July 2015 and February 2020, 11 patients with airway-compromising LMs were enrolled. To yield maximal effects on the compromised airway with minimal adverse effects, ultrasound-guided intralesional bleomycin sclerotherapy assisted by balloon was performed, aimed at the most responsible lesion around the airway. A retrospective analysis was performed. RESULTS: Ten patients presented with respiratory symptoms, eight of whom required airway support. The last asymptomatic patient showed airway compression on magnetic resonance imaging. The dose of bleomycin injected ranged from 1.3-9 mg per patient per course. A median of one course was required for withdrawal from airway support, and the median time was 15 days. A median of two courses was required to eliminate the lesion adjacent to the airway, which would have potential risk of airway stenosis. No complications were observed. CONCLUSIONS: Our intralesional focal sclerotherapy technique with bleomycin targeting the culprit lesion is dose-sparing, safe, and effective in achieving rapid shrinkage of LMs compromising the upper airway in children, thereby avoiding tracheostomy.

[Ex-Utero Intrapartum Treatment for airway management in congenital giant neck masses]. / Técnica EXIT como manejo de la vía aérea en masas gigantes congénitas de cuello.

INTRODUCTION: Congenital head and neck masses are associated with perinatal asphyxia and brain injury, increasing the risk of death. The EXIT (Ex Utero Intrapartum Treatment) technique con sists of ensuring the newborn's airway while is still receiving placental support. This technique has not been standardized in developing countries. OBJECTIVE: To describe the clinical outcomes of two infants who underwent the EXIT technique. CLINICAL CASE: We present two cases, one with lymphatic malformation diagnosed at 20 weeks of gestational age (WGE) and the second one, a preterm newborn with thyromegaly and polyhydramnios, diagnosed at 35 WGE. In both cases, during the C-section, the EXIT technique was performed with a team of a neonatologist, a gyne cologist, an anesthesiologist, a pediatric surgeon, an otolaryngologist, a nurse, and a respiratory therapist. In both patients, the neonatologist achieved to secure the airway through orotracheal intubation at the first attempt. In the first case, lymphatic malformation was confirmed and re ceived sclerotherapy, and the second one was diagnosed with congenital hypothyroidism which was managed with levothyroxine. The patients needed invasive mechanical ventilation for 7 and 9 days, respectively, and were discharged without respiratory complications. CONCLUSIONS: In these patients, the EXIT technique was a safe procedure, carried out without inconvenience. A multi disciplinary approach and the availability of a neonatal intensive care unit are needed to reduce potential complications and ensure postnatal management. Timely prenatal diagnosis is essential to perform this technique.

Use of topical rapamycin in the treatment of superficial lymphatic malformations.

BACKGROUND: The superficial lymphatic component of vascular malformations poses a significant treatment challenge. It is responsible for the majority of symptoms presented, and to date, there is no consensus regarding treatment. OBJECTIVE: To evaluate the effectiveness of topical rapamycin in treating superficial lymphatic malformations (LM). METHODS: A case series study was performed of patients with superficial LM, treated with topical rapamycin. The clinical characteristics of patients and the concentration and application mode of the drug were recorded. The changes in the signs and symptoms observed and associated adverse effects were noted and analyzed. RESULTS: The study population consisted of 11 patients of an average age of 10.5 years. All were treated with topical rapamycin: 6 patients with a 1% concentration, 1 with a 0.8% concentration, and 4 with a 0.4% concentration. Changes in the clinical appearance of the lesions were observed in all patients. The associated symptoms, present in 9 of 11 patients, improved in every case. The mean follow-up time was 16.1 months. LIMITATIONS: This study is retrospective, with a small sample size and considerable heterogeneity of lesions and treatment approaches. CONCLUSION: Treatment with topical rapamycin modifies the clinical appearance and alleviates symptoms of superficial LM.

Cervical lymphatic malformations: Prenatal characteristics and ex utero intrapartum treatment.

BACKGROUND: The ex utero intrapartum treatment (EXIT) is utilized to transition fetuses with prenatally diagnosed airway obstruction to postnatal life. We describe the unique clinical course, diagnosis, treatment, and outcomes of patients with cervical lymphatic malformation (CLM) managed with EXIT. METHODS: Review of fetuses with diagnosed CLM was delivered by EXIT (2001-2018) in a tertiary referral fetal center. Outcomes included survival, tracheostomy at discharge, neonatal course after delivery, and pulmonary hypoplasia. Data are reported as median [range] and rate (%). RESULTS: Out of 45 patients delivered by EXIT, 10 were delivered for CLM: seven had polyhydramnios, one had nonimmune hydrops, five delivered preterm, and three were emergency EXITs. The EXIT time and estimated blood loss were 125 minutes (95, 158) and 900 mL (500, 1500), respectively. Airway was secured in all. There was one neonatal death (day 8) with prematurity, sepsis, and pulmonary hypoplasia. Three out of nine were discharged with a tracheostomy. CONCLUSION: In CLM, close monitoring for structural neck involvement and development of polyhydramnios are important and may be an indication for EXIT as the optimal delivery mode. An experienced multidisciplinary team is a key factor for an effective approach to the obstructed airway in CLM.

Genetic tests in lymphatic vascular malformations and lymphedema.

Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention.

Normalization of Congenital Venous Stasis Retinopathy Following Sclerotherapy of a Macrocystic Lymphatic Malformation.

The authors describe, for the first time to their knowledge, a case of a congenital macrocystic lymphatic malformation of the orbit with associated venous stasis retinopathy that acutely normalized after drainage and sclerotherapy of the lesion. Prenatal ultrasound revealed prominence of the left orbital soft tissue, and at birth, the patient was noted to have unilateral proptosis, tortuous retinal vessels, and intraretinal hemorrhages in all 4 quadrants in the left eye. MRI demonstrated a primarily intraconal, multiloculated, T2-hyperintense mass consistent with a lymphatic malformation. Ultrasound-guided cyst aspiration and sclerotherapy was performed, with subsequent improvement of the proptosis and resolution of the vessel tortuosity and intraretinal hemorrhages. Although venous stasis retinopathy is usually related to central retinal vein occlusion or carotid artery occlusive disease, any entity that increases orbital venous resistance can generate retinal venous dilation and intraretinal hemorrhages, including an orbital lymphatic malformation.

Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations.

Lymphatic malformations (LMs) are developmental anomalies of the lymphatic system associated with the dysmorphogenesis of vascular channels lined by lymphatic endothelial cells (LECs). Seeking to identify intrinsic defects in affected LECs, cells were isolated from malformation tissue or fluid on the basis of CD31 and podoplanin (PDPN) expression. LECs from five unrelated LM lesions were characterized, including cells derived from one patient previously diagnosed with CLOVES. CLOVES-related LECs carried a known, activating mutation in PIK3CA (p.H1047L), confirmed by direct sequencing. Activating PIK3CA mutations (p.E542K and p.E545A) were identified in lesion-derived cells from the other four patients, also by direct sequencing. The five LM-LEC cultures shared a lymphangiogenic phenotype distinguished by PI3K/AKT activation, enhanced sprouting efficiency, elevated VEGF-C expression and COX2 expression, shorter doubling times and reduced expression of angiopoietin 2 and CXCR4. Nine additional LM-LEC populations and 12 of 15 archived LM tissue samples were shown to bear common PIK3CA variants by allele-specific PCR. The activation of a central growth/survival pathway (PI3K/AKT) represents a feasible target for the non-invasive treatment of LMs bearing in mind that background genetics may individualize lesions and influence treatments.