Lymphatic malformations: mechanistic insights and evolving therapeutic frontiers.

The lymphatic vascular system is gaining recognition for its multifaceted role and broad pathological significance. Once perceived as a mere conduit for interstitial fluid and immune cell transport, recent research has unveiled its active involvement in critical physiological processes and common diseases, including inflammation, autoimmune diseases, and atherosclerosis. Consequently, abnormal development or functionality of lymphatic vessels can result in serious health complications. Here, we discuss lymphatic malformations (LMs), which are localized lesions that manifest as fluid-filled cysts or extensive infiltrative lymphatic vessel overgrowth, often associated with debilitating, even life-threatening, consequences. Genetic causes of LMs have been uncovered, and several promising drug-based therapies are currently under investigation and will be discussed.

A case series of fetal lymphatic malformations and a review of the literature.

Lymphatic malformations are rare benign developmental anomalies of the lymphatic system that can be diagnosed by prenatal ultrasound. Depending on their anatomical site and size, the lesions can cause a variety of aesthetic and functional deficits. Several treatment options are available, the most suitable is still under debate. The experience gained at our Centre and the review of the literature can be useful to improve prenatal counseling, that is challenging due to the heterogeneity of clinical presentation and treatment.

[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.

French national diagnosis and care protocol (PNDS, protocole national de diagnostic et de soins): cystic lymphatic malformations.

Cystic lymphatic malformations (LMs) are rare chronic conditions which management differs according to the type (macrocystic LMs, microcystic LMs or both). Studies are lacking due to rarity of the pathology. We aimed to establish a French National Diagnosis and Care Protocol (PNDS: Protocole National de Diagnostic et de Soins), to provide health professionals with free open access synthesis on optimal management and care of patients with LMs ( https://www.has-sante.fr/upload/docs/application/pdf/2021-03/malformations_lymphatiques_kystiques_-_pnds.pdf ). The process included a critical review of the literature and multidisciplinary expert consensus. LMs are congenital but are not always discovered at birth. Nearly 75% of them are located in the head and neck because of the highly dense lymphatic system in this region. Physical examination (showing painless masses with normal skin color and depressible consistency, or cutaneous/mucosal lymphangiectasia) and color Doppler ultrasonography, usually allow for diagnosis. MRI (involving T2 sequences with fat saturation in at least two spatial planes) is the tool of choice for evaluating anatomical extension, characterizing lesions (microcystic and macrocystic), and before considering therapeutic management. A biopsy, coupled to a blood sample, can also be used for molecular biology analyses, to search for activating mutations of the PIK3CA gene, particularly with LM integrating in a syndromic form (CLOVES or Klippel-Trenaunay syndrome) but also in certain isolated (or common) LMs. The spontaneous evolution of LMs, in particular microcystic forms, is often toward progressive aggravation, with an increase in the number of vesicles, thickening, increased oozing and bleeding, while pure macrocystic LMs may regress due to "natural sclerosis", i.e. fibrosis secondary to an inflammatory reorganization after common infantile infections. In case of voluminous LMs or syndromic forms, functional and psychological repercussions can be major, deteriorating the patient's quality of life. LMs must be treated by physicians integrated in multidisciplinary teams, and be personalized. Management is a life-long process that involves one or several of these therapies: conservative management, physical therapy (compression), sclerotherapy, surgery, drugs such as mTOR inhibitors (sirolimus), that has shown efficacy in decreasing the volume of LMs, and, more recently, PI3K-inhibitors in syndromic forms. Psychological and social support is necessary, taking into account the patient and his family.

Association between malformation type, location and functional deficits in lymphatic malformations of the head and neck in children.

PURPOSE: Lymphatic malformations (LM) are congenital malformations of the lymphatic system, mainly located in the head and neck area. They can be staged based on location according to de Serres and based on different morbidity items using the Cologne Disease Score (CDS), a clinical staging system. In many cases, functional impairment greatly affects the life of patients suffering from lymphatic malformations. The present study aims to analyze a cohort of pediatric patients with LM. METHODS: A retrospective analysis of 144 pediatric patients with head and neck LM was performed. Location, type of malformation (microcystic, macrocystic, mixed), scoring according to two different scoring systems and therapy were analyzed. Kruskal-Wallis test was used to analyze the difference in CDS between the patient groups and Dunn's test was used for post-hoc pairwise comparison. RESULTS: The average age at presentation was 6.1 years. The most common sites were neck (47%), cheek/parotid gland (26%), tongue (17%) and orbit (8%). Macrocystic malformations dominated the lateral neck, while microcystic malformations were predominantly localized in the tongue and floor of mouth. Macrocystic malformations (mean CDS 9.44) were associated with significantly better CDS than microcystic (mean CDS 7.11) and mixed (mean CDS 5.71) malformations (p < 0.001). LM in stage V according to de Serres had the lowest values (mean CDS: 4.26). The most common therapeutic procedures were conventional surgical (partial) resection, laser therapy and sclerotherapy with OK-432. CONCLUSIONS: There is an association between malformation type, location according to de Serres and CDS in children with LM of the head and neck. Patients with microcystic and mixed malformations in stage V had lowest CDS levels.

Complex Lymphatic Anomalies: Report on a Patient Registry Using the Latest Diagnostic Guidelines.

Background: Generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), kaposiform lymphangiomatosis (KLA), and central conducting lymphatic anomaly (CCLA) are rare, multisystem lymphatic disorders, referred to as complex lymphatic anomalies (CLAs). Their etiology remains poorly understood; however, somatic activating mutations have recently been discovered, and the results of targeted treatments are promising. This study aimed to elaborate on the phenotypic description of CLA. Methods: Thirty-six consecutive patients were recruited for the "GLA/GSD Registry" of the University Hospital of Freiburg, Germany (2015-2021). Clinical data were prospectively collected provided that a signed informed consent form was obtained. The latest proposed diagnostic guidelines were retrospectively applied. Results: Thirty-two patients (38% males) were included in the study; 15 GLA, 10 GSD, 3 KLA, and 4 CCLA patients were identified. Eighty-four percent already had symptoms by the age of 15 years. Osteolysis and periosseous soft-tissue infiltration were associated with GSD (p < 0.001 and p = 0.011, respectively), ascites and protein-losing enteropathy with CCLA (p = 0.007 and p = 0.004, respectively), and consumption coagulopathy with KLA (p = 0.006). No statistically significant differences were found in organ involvement, distribution of osteolytic lesions, number of affected bones and fractures. Twenty-five patients had complications; one patient with GLA died despite multimodal treatment. Spontaneous regression was seen in one patient with untreated KLA. Conclusions: CLA are rare, and their overlapping clinical presentations make differential diagnosis difficult. The characterization of our case series contributes to the phenotypic description and differentiation of these four clinical entities. A further understanding of their pathogenesis is crucial for evaluating targeted therapies and optimizing medical care.

Percutaneous sclerotherapy for head and neck lymphatic malformations in neonates and infants ≤12 months of age.

BACKGROUND: Percutaneous sclerotherapy is an effective treatment for lymphatic malformations (LM) of the head and neck in adults. The purpose of this study was to examine the indications and efficacy of sclerotherapy for head/neck LM in the neonate and infant population. METHODS: We retrospectively reviewed patients treated with percutaneous sclerotherapy for LM of the head/neck at age ≤12 months at a single vascular anomalies clinic. The clinical, anatomic, and technical aspects of each treatment, complications, and post-treatment clinical and imaging outcomes were analyzed. RESULTS: 22 patients underwent 36 treatments during the first year of life. Median age at first treatment was 6.2 months (range 2-320 days). Severe airway compromise was the most frequent indication for treatment (31.8%). Sclerosants included doxycycline (80.5%), sodium tetradecyl sulfate (55.5%), bleomycin (11.1%) and ethanol (2.8%). There were no immediate procedure-related complications; sclerosant-related laboratory complications included transient metabolic acidosis (8.3%) and hemolytic anemia (5.5%). Median follow-up was 3.7 years (IQR 0.6-4.8). 47.6% of patients showed >75% lesion size reduction and 19.0% showed minimal response (<25% improvement). At last follow-up, 71.4% of children were developmentally normal and asymptomatic, 23.8% had recurring symptoms, and 4.8% required permanent tracheostomy. Patients with ongoing symptoms or limited response to percutaneous sclerotherapy (33.3%) were treated with long-term sirolimus. CONCLUSIONS: Percutaneous sclerotherapy is a safe and effective treatment for symptomatic LM of the head and neck in neonates and infants. Treatment strategy and management of recurrent symptoms requires consensus from an experienced, multidisciplinary team.

Curettage and sclerotherapy technique: A hybrid approach to superficial lymphatic malformation.

OBJECTIVE: To describe the curettage and sclerotherapy technique, a hybrid approach to treatment for superficial lymphatic malformations. METHODS: A retrospective analysis of a lymphatic malformation data base was performed. Patients with superficial lymphatic malformation treated by curettage and sclerotherapy technique with bleomycin were included in this study. Safety and efficacy of the curettage and sclerotherapy technique with bleomycin were evaluated. RESULTS: Between September 2019 and October 2021, 10 consecutive patients (male/female ratio: 4:6; mean age, 10.9 years; range, 3-35 years) presented with superficial lymphatic malformations that were subsequently treated by curettage and sclerotherapy technique with bleomycin. All lesions were located on the trunk and extremities. Each patient received one treatment session and a mean follow-up of 12 months. We observed minor complications. No postoperative infections occurred in this series. No patient developed skin ulceration or necrosis. Scarring and recurrence occurred in one patient. Complete regression was confirmed for all 10 patients by photographic evaluation. CONCLUSION: A curettage and sclerotherapy technique is proposed to treat superficial lymphatic malformation in this study. This technique seems to be safe and highly effective.

Percutaneous sclerotherapy of microcystic lymphatic malformations: the use of an innovative gravity-dependent technique.

BACKGROUND: In the last few decades there has been development of innovative therapies for the treatment of craniofacial lymphatic malformations. Percutaneous sclerotherapy has demonstrated efficacy in the management of macrocystic lymphatic lesions, but it is less suitable for microcystic lesions given their size. The gravity-dependent technique is a novel augmentation of standard percutaneous sclerotherapy: the technique enables a sclerosing agent to permeate the small microchannels seen in microcystic lesions that would otherwise be difficult to treat. METHODS: Between 2005 and 2021, 124 patients with microcystic or mixed lymphatic malformations were treated using a novel gravity-dependent sclerotherapy technique. Bleomycin at a maximum dose of 15 IU per session was used as the main sclerosing agent. Fluoroscopy and ultrasound were used to ensure proper positioning of the catheter prior to injecting the sclerosing agent. The response to treatment was assessed clinically and with cross-sectional imaging. RESULTS: Nearly all cases showed significant improvement after the gravity-dependent technique. There have been no permanent complications from sclerotherapy treatment. There was a mild transient adverse effect from bleomycin in one case of erythema and tenderness that lasted several weeks then ameliorated. CONCLUSIONS: The gravity-dependent sclerotherapy technique is a suitable treatment option for microcystic lymphatic malformations.

Dual-agent percutaneous sclerotherapy technique for macrocystic lymphatic malformations.

Percutaneous sclerotherapy is an effective technique for treating lymphatic malformations of the head and neck, with clinical success rates exceeding 84%.1 Sodium tetradecyl, which damages lipid membranes and stimulates free radical-induced local damage, and doxycycline, which inhibits angiogenesis, have emerged as the safest and most effective of several available sclerosants.2-4 Although severe periprocedural morbidity is rare, temporary local complications are reported in 14% and skin necrosis or scarring in up to 0.8-5.8% of sclerotherapy procedures.5 As these lesions are frequently located in the face and/or neck, even minor complications can be disfiguring and must be avoided. This technical video describes a 'dual-agent' approach for percutaneous sclerotherapy of macrocystic lymphatic malformations using sodium tetradecyl as a 'primer' followed by doxycycline as a definitive sclerosant (video 1). This technique emphasizes meticulous backtable preparation and effective use of ultrasound and fluoroscopy to minimize complications. neurintsurg;15/9/931/V1F1V1Video 1 .

Doxycycline Sclerotherapy of Head and Neck Lymphatic Malformations: Intermediate Report of 27 Cases.

OBJECTIVE: To evaluate the safety and efficacy of percutaneous doxycycline sclerotherapy of head and neck lymphatic malformations (LM) with a 40-month follow-up of 27 cases. MATERIALS AND METHODS: Twenty-seven consecutive patients with head and neck LM who underwent doxycycline sclerotherapy from 2010 to 2019 were retrospectively reviewed. Pre- and peri-interventional data collection included patients' demographics, clinical and radiological presentation, number of treatment procedures, amount of doxycycline used for each session of sclerotherapy. Postinterventional clinical outcome data were assessed based on the electronic, medical reports with special attention to clinical improvement, measurement of the lesion on ultrasound and magnetic resonance imaging after the last session of sclerotherapy and complications of sclerotherapy. RESULTS: Twenty-seven patients underwent a mean of four doxycycline sclerotherapy sessions (range 1-23). The mean total dose of injected doxycycline per session was 170 mg. Maximal diameter of the LM decreased from mean 59.7 mm (median 58 mm; 25-130 mm) before treatment to mean of 29.6 mm (median 30 mm; 0 mm 64 mm) after the last session (P < 0.0001). Over a mean follow-up period of 40 months, complete or incomplete disappearance of symptoms was found in 23 (85%) and 3 (11%) of patients, respectively. In one patient, sclerotherapy did not result in better clinical outcome. Two out of 27 patients presented with minor post-procedural complications, and one patient with a post-procedural intralesional bleeding considered as a major complication. CONCLUSION: Ultrasound-guided, percutaneous doxycycline sclerotherapy is a safe and effective method of managing symptomatic LM of the head and neck.

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations.

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.

Institutional Management of Abdominal Lymphatic Malformations: Evolution of Treatment Over a Decade.

INTRODUCTION: Abdominal lymphatic malformations (LM) have been historically managed with surgical resection; however, sclerotherapy and sirolimus have emerged as effective therapies. The purpose of our study is to evaluate our institutional change in management and outcomes for abdominal LM over the past decade. METHODS: A retrospective cohort study was performed for all children with an abdominal LM managed at our multidisciplinary Vascular Anomalies Center from 2011 to 2020. Patient demographics, symptoms, treatment, treatment response, and complications were analyzed with descriptive statistics. RESULTS: Twenty-nine patients with abdominal LM were identified with a median age at treatment of 6 y (interquartile range 3-14). A majority of lesions were identified as macrocystic (n = 18, 62%). The most common intervention was surgery alone (n = 14, 48%) followed by sirolimus alone (n = 4, 14%), and sclerotherapy + sirolimus (n = 4, 14%). Five patients were observed due to lack of symptoms at presentation. Prior to 2017, 91% (10/11) of LM were treated with surgery alone. Following 2017, only 31% (4/13) were treated with surgery alone. Sixty-seven percent (16/24) of treated patients had >95% reduction in LM maximum diameter. A majority of patients (23/24) who received treatment had improvement or resolution of symptoms at median 9-mo follow-up. Only three patients had post-treatment complications, including a drain site infection, small bowel obstruction, and an aspiration event. Complications only occurred after sclerotherapy sessions. CONCLUSIONS: Over the study period, our institution has transitioned to initial management of symptomatic abdominal LM with sclerotherapy and/or sirolimus with almost all treated patients having excellent or satisfactory treatment response. Post-treatment complications were rare.

Long-term outcomes of lymphatic malformations in children: An 11-year experience from a tertiary referral center.

BACKGROUND: Lymphatic malformations (LMs) are benign, congenital lesions that display considerable heterogeneity in terms of size, location and characteristics. This study aims to describe the long-term outcomes of current management strategies for patients with simple (cystic) LMs. METHODS: The case records of all patients (age ≤16 years) with simple (cystic) LMs at our tertiary institution between 2008 and 2019 were assessed for clinical features, imaging and details of management, including complications. RESULTS: Of a total of 164 patients (60% male), 66% were diagnosed aged <2 years. The median follow-up was 5 (0.3-16) years from diagnosis. LMs were located in the head and neck (40%), extremities (27%), trunk (23%), mediastinum (4%), or intra-abdominally (6%). Types were macrocystic in 47%, microcystic in 21% and mixed in 32%. Sclerotherapy was the most common intervention (38%). Primary surgery had been performed in 12%. Symptomatic improvement, reduction in size, or complete regression were observed in 82/102 (80%) of LMs after interventions; complications from treatment were uncommon (Clavien-Dindo grade I-II: 6%; grade III-IIId: 1%). Sixty-two patients (38%; median age 0.5 (range, 0-12) years) had not required interventions to date; spontaneous regression of the LM occurred in 16 (26%) of these expectantly followed-up cases. CONCLUSIONS: Most studies to date have focused on LMs in selected anatomical locations. Herein the outcomes of an entire population from a single tertiary unit of patients are presented, demonstrating the wide heterogeneity of simple (cystic) LMs and highlighting the importance of individualized, multidisciplinary approaches to care in achieving optimal outcomes.

Safety and Efficacy of Bleomycin Slow Infusion Sclerotherapy Using a Syringe Pump for Microcystic and Mixed Lymphatic Malformations.

PURPOSE: To evaluate the safety and efficacy of bleomycin infusion sclerotherapy using a syringe pump in microcystic and mixed (microcystic components with the presence of a cyst over 1 cm) lymphatic malformations (LMs). MATERIALS AND METHODS: Patients who received bleomycin sclerotherapy with a syringe pump for microcystic or mixed LMs were reviewed. Cystic components of LMs were accessed under sonographic guidance, followed by injection of an opacified bleomycin solution using a syringe pump (infusion rate, 10-20 mL/h) under fluoroscopic guidance. Imaging outcomes were graded as complete (> 90% size reduction), partial (25-90%), or no response (< 25%). Clinical outcomes and procedure-related complications were also reviewed. RESULTS: Forty-nine patients with 81 sclerotherapies were analyzed. The mean age was 17 years (range 0.1-65 y). Thirty-one (63%) patients had microcystic LMs, and 18 (37%) had mixed. A mean of 1.7 sessions (range 1-4) of sclerotherapy was performed using a mean cumulative dose of bleomycin of 10.8 U (range 1.5-39 U). The mean infusion time was 39 min (range 14-130 min). Regarding imaging outcomes, there was a complete response in 29% (n = 14), a partial response in 57% (n = 28), and no response in 14% (n = 7). Regarding clinical outcomes, there was a complete response in 39% (n = 19), a partial response in 51% (n = 25), and no response in 10% (n = 5). According to the CIRSE classification, no major complications were identified. CONCLUSIONS: Bleomycin slow infusion sclerotherapy provides gradual filling of sclerosant to target microcystic components. This technique is safe and feasible for the management of microcystic or mixed LMs. LEVEL OF EVIDENCE: Level 4, Case series.

Bowel perforation following percutaneous sclerotherapy of an intra-abdominal lymphatic malformation.

Mesenteric lymphatic malformations result from abnormal proliferation of disorganized mesenteric lymphatic channels. Sclerotherapy is often preferred over surgery as it is less invasive and has lower post-procedure morbidity. Sclerotherapy has been described as durable and effective with a low complication rate. We describe a serious complication from sclerotherapy of a lymphatic malformation extending from the mesentery through the bowel wall, highlighting the spectrum of this pathology and the need for multidisciplinary management of complex cases.

Lymphatic Anomalies in Children: Update on Imaging Diagnosis, Genetics, and Treatment.

Lymphatic anomalies comprise a spectrum of disorders ranging from common localized microcystic and macrocystic lymphatic malformations (LMs) to rare complex lymphatic anomalies, including generalized lymphatic anomaly, Kaposiform lymph-angiomatosis, central conducting lymphatic anomaly, and Gorham-Stout disease. Imaging diagnosis of cystic LMs is generally straightforward, but complex lymphatic anomalies, particularly those with multiorgan involvement or diffuse disease, may be more challenging to diagnose. Complex lymphatic anomalies are rare but associated with high morbidity. Imaging plays an important role in their diagnosis, and radiologists may be the first clinicians to suggest the diagnosis. Furthermore, radiologists are regularly involved in management given the frequent need for image-guided interventions. For these reasons, it is crucial for radiologists to be familiar with the spectrum of entities comprising complex lymphatic anomalies and their typical imaging findings. In this article, we review the imaging findings of lymphatic anomalies, including LMs and complex lymphatic anomalies. We discuss characteristic imaging findings, multimodality imaging techniques used for evaluation, pearls and pitfalls in diagnosis, and potential complications. We also review recently discovered genetic changes underlying lymphatic anomaly development and the advent of new molecularly targeted therapies.