Complex lymphatic anomalies: Molecular landscape and medical management.

The lymphatic system is one of the most essential and complex systems in the human body. Disorders that affect the development or function of the lymphatic system can lead to multi-system complications and life-long morbidity. The past two decades have seen remarkable progress in our knowledge of the basic biology and function of the lymphatic system, the molecular regulators of lymphatic development, and description of disorders associated with disrupted lymphangiogensis. In this chapter we will touch on the clinical features of complex lymphatic anomalies, new molecular knowledge of the drivers of these disorders, and novel developmental therapeutics for lymphatic disease.

Lymphatic interventions in congenital heart disease.

Congenital heart disease affects 1/100 live births and is one of the most common congenital abnormalities. The relationship between congenital heart disease and lymphatic abnormalities and/or dysfunction is well documented and can be grossly divided into syndromic and non-syndromic etiologies. In patients with genetic syndromes (as examples listed above), there are known primary abnormal lymphatic development leading to a large pleiotropic manifestation of lymphatic dysfunction. Non-syndromic patients, or those without clear genetic etiologies for their lymphatic dysfunction, are often thought to be secondary to physiologic abnormalities as sequelae of congenital heart disease and palliative surgeries. Patients with congenital heart disease and lymphatic dysfunction have a wide variety of clinical manifestations for which there were not many therapeutic interventions available. The development of new imaging techniques allows us to understand better the pathophysiology of these problems and to develop different percutaneous interventions aiming to restore normal lymphatic function.

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.

[The Duplicity of Incidents: Cervical Lymphatic Malformation in two Newborns]. / Die Duplizität der Ereignisse: Zervikale lymphatische Malformation bei zwei Neugeborenen.

We report on two neonates born the same day, both with an isolated cervical lymphatic malformation. Cervical masses were detected by ultrasound late in the third trimester. Following interdisciplinary case conferences, a caesarean section in the presence of a neonatal team was the chosen delivery mode in both cases. Delivery and transition of the newborns were uneventful. The suspected diagnosis was confirmed by postnatal MRIs, which demonstrated neither associated malformations nor compression of vital structures. Therefore, an expectant approach was chosen for the newborn with the smaller lesion. The other newborn featured a sizeable lymphatic malformation, and due to consecutive head tilt, sclerotherapy was initiated in its second week of life. Our case report outlines the challenges of a rare connatal malformation. Guidelines are often missing. Individual decisions regarding delivery mode, diagnostics and therapy have to be made on an interdisciplinary basis and patients as well as parents need counseling and support over a long period. All the more significant is good, interdisciplinary collaboration between the involved disciplines.

Efficacy of Bleomycin-Lauromacrogol Foam in Pediatric Macrocystic Lymphatic Malformations With and Without Intracapsular Hemorrhage.

BACKGROUND: Sclerotherapy is purportedly less effective in patients with hemorrhagic than with non-hemorrhagic lymphatic malformations (LMs). We aimed to compare the efficacy of bleomycin-lauromacrogol foam (BLF) sclerotherapy in the treatment of macrocystic LMs with and without intralesional hemorrhage. METHODS: Fifty-five children with macrocystic LMs admitted to the Pediatric Surgery Department were retrospectively included. The patients were allocated into a hemorrhage group (23 cases) or a non-hemorrhage group (32 cases) based on the occurrence of an intracapsular hemorrhage. The diagnosis was confirmed by physical examination, color ultrasound, magnetic resonance imaging, and puncture findings. BLF was injected into the capsule after draining the cystic fluid under color ultrasound guidance. Patients whose lesions were unchanged or showed minor change after 1 month were treated again using the same method. Changes in lesion size and the number of treatments were recorded. Effectiveness was classified as excellent (volume reduction ≥90%), good (50%≤volume reduction<90%), or poor (volume reduction <50%). RESULTS: In the hemorrhage group, 17, 6, and 0 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 100%. In the non-hemorrhage group, 23, 7, and 2 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 93.8%. There was no significant difference in efficacy rate between groups (P = 0.767). CONCLUSIONS: BLF is an effective and safe treatment for macrocystic LMs with bleeding. The results were similar in patients with and without bleeding. LEVEL OF EVIDENCE: Treatment, Level III.

Percutaneous injection of sclerosant agents as an effective treatment for cystic malformations of the head and neck.

PURPOSE: To evaluate the clinical and aesthetic outcome of percutaneous injection of sclerosant agents to treat head and neck cystic malformations (HNCM) and to assess their recurrence rate based on histology and site. METHODS: Fifty-four subjects (mean age 46 years) with HNCM treated by percutaneous injection of sclerosant agents between January and December 2017 were included. Imaging and clinical data before and after the procedure were collected. Quality of Life Index, Pain Visual Analogue Scale, and Aesthetic Scale scores were measured to assess clinical and aesthetic outcomes. A size reduction of ≥ 70% assessed through the visual scale was considered significant. RESULTS: Of the 54 HNCM, there were 26 (48%) lymphatic malformations (LM), 13 (24%) salivary epithelial duct cysts of the parotid gland, 12 (22%) salivary mucoceles, and 3 (5%) branchial cysts. A significant size reduction and a satisfactory clinical-aesthetic outcome were observed in all types of LM. The number of reinterventions was significantly associated with the number of lesions (p < 0.001). The lowest number of interventions was observed in macrocystic lymphatic malformations (average of 1.2 interventions). All salivary epithelial duct cysts showed a significant reduction in size, a satisfactory clinical-aesthetic outcome, and an average of 1.16 interventions per patient. Mucoceles had a worse response, with only 3/14 patients showing a satisfactory and long-lasting clinical outcome (average of 1.16 interventions). Treatment of branchial cysts showed the worst outcome with a limited clinical response (3/3). CONCLUSION: Percutaneous injection of sclerosant agents may be considered as a first-line treatment for LM and salivary epithelial duct cysts.

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.

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.

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.

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.

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 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.

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.

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 .