Generalized Lymphatic Anomaly Research Articles

Lymphatic endothelial cell-specific NRAS p.Q61R mutant embryos show abnormal lymphatic vessel morphogenesis.

Generalized lymphatic anomaly (GLA) and kaposiform lymphangiomatosis (KLA) are rare congenital disorders that arise through anomalous embryogenesis of the lymphatic system. A somatic activating NRAS p.Q61R variant has been recently detected in GLA and KLA tissues, suggesting that the NRAS p.Q61R variant plays an important role in the development of these diseases. To address this role, we studied the effect of the NRAS p.Q61R variant in lymphatic endothelial cells (LECs) on the structure of the lymphatics during embryonic and postnatal lymphangiogenesis applying inducible, LEC-specific NRAS p.Q61R variant in mice. Lox-stop-Lox NrasQ61R mice were crossed with Prox1-CreERT2 mice expressing tamoxifen-inducible Cre recombinase specifically in LECs. Whole-mount immunostaining of embryonic back skin using an antibody against the LEC surface marker VEGFR3 showed considerably greater lymphatic vessel width in LEC-specific NRAS p.Q61R mutant embryos than in littermate controls. These mutant embryos also showed a significant reduction in the number of lymphatic vessel branches. Furthermore, immunofluorescence staining of whole-mount embryonic back skin using an antibody against the LEC-specific nuclear marker Prox1 showed a large increase in the number of LECs in LEC-specific NRAS p.Q61R mutants. In contrast, postnatal induction of the NRAS p.Q61R variant in LECs did not cause abnormal lymphatic vessel morphogenesis. These results suggest that the NRAS p.Q61R variant in LECs plays a role in development of lymphatic anomalies. While this model does not directly reflect the human pathology of GLA and KLA, there are overlapping features, suggesting that further study of this model may help in studying GLA and KLA mechanisms.

Cerebrospinal fluid–lymphatic fistula in a child with generalized lymphatic anomaly treated with targeted blood patch — a rare case report and review of the literature

Spontaneous intracranial hypotension may result in debilitating postural headaches and severe neurological symptoms due to secondary cerebellar sagging. The most common cause is the cerebrospinal fluid (CSF) leak within the spinal canal. Although previously reported in only a few cases, also paraspinal lymphatic malformations causing vertebral bone destruction may occasionally result in CSF leak to these pathological formations. Here, we present a case of a 9-year-old girl with generalized lymphatic anomaly (GLA) presenting with severe postural headache. Radiological imaging revealed a typical feature of cerebellar sagging. Myelography localized the CSF leakage into vertebral bodies of C7 and Th1, which both were partly involved in pathological paravertebral masses of known lymphatic anomaly, and from there along the right C8 nerve root sleeve into the anomaly. As the C8-nerve root could not be ligated due to the risk of significant neurological injury, we attempted image-guided targeted percutaneous epidural placement of a blood patch directly into the foramen at the affected level. The procedure resulted in obliteration of the fistula and regression of cerebellar sagging, with significant relief of symptoms. Although it is an extremely rare coincidence, patients with paraspinal lymphatic malformations may develop intraspinal CSF leak into these pathological formations. The present case report suggests that besides a direct surgical obliteration of the fistula and sacrificing the nerve root, a targeted percutaneous epidural blood patch may be a possible alternative in the case of a functionally important nerve root.

Generalized lymphatic anomaly in adult patients: An eminently radiological diagnosis

Generalized lymphatic anomaly (GLA) is an uncommon congenital disease secondary to the proliferation of lymphatic vessels in any organ except the central nervous system. GLA has a wide spectrum of clinical and radiological presentations, among which osteolytic lesions are the most widespread, being the ribs the most commonly affected bone. GLA is diagnosed mainly in children and young adults; nevertheless, on rare occasions it can remain asymptomatic and be detected incidentally in older patients. We present an unusual case of GLA in an asymptomatic 54-year-old man who had atypically distributed, purely cystic bone lesions on CT; measuring the Hounsfield (HU) of these lesions enabled us to suspect GLA. This suspicion was confirmed with MRI, PET/CT, CT-guided fine-needle aspiration biopsy, and fluoroscopy-guided percutaneous vertebral biopsy. After surgical resection of one of the lesions, histologic study provided the definitive diagnosis.

EML4::ALK fusions in complex lymphatic malformations.

Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications, including pain and pathologic fractures. As with other vascular anomalies, somatic mosaic mutations in oncogenes are often present, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggests additional targeted therapies could be effective.

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.

Anomalía linfática generalizada en un paciente adulto, un diagnóstico eminentemente radiológico

Generalized lymphatic anomaly (GLA) is an uncommon congenital disease secondary to the proliferation of lymphatic vessels in any organ except the central nervous system. GLA has a wide spectrum of clinical and radiological presentations, among which osteolytic lesions are the most widespread, being the ribs the most commonly affected bone. GLA is diagnosed mainly in children and young adults; nevertheless, on rare occasions it can remain asymptomatic and be detected incidentally in older patients. We present an unusual case of GLA in an asymptomatic 54-year-old man who had atypically distributed, purely cystic bone lesions on CT; measuring the Hounsfield (HU) of these lesions enabled us to suspect GLA. This suspicion was confirmed with MRI, PET/CT, CT-guided fine-needle aspiration biopsy, and fluoroscopy-guided percutaneous vertebral biopsy. After surgical resection of one of the lesions, histologic study provided the definitive diagnosis.

Impact of High Fat Diet and Bolus Feeding on Chyle Accumulation in a Mouse Model of Generalized Lymphatic Anomaly.

Background: Generalized lymphatic anomalies (GLA) are complex vessel malformations that can impair lymphatic function. Potential GLA complications include lipid-rich lymph in the thoracic space or peritoneal cavity, respectively chylothorax and chylous ascites. To reduce the potential for chyle accumulation, GLA patients limit dietary fats. We hypothesized that dietary fatty acid composition impacts the potential for lymphatic dysfunction and chyle accumulation in GLA. Methods and Results: Adipose-specific overexpression of lymphatic growth factors has demonstrated lethal chylothorax in mice. Here, we utilized mice with inducible adipocyte overexpression of vascular endothelial growth factor-D (VD mice) to mimic lymphatic proliferation in GLA and assessed the incidence of chyle accumulation on a mixed high fat diet (HFD), high saturated fat diet (HSFD), or high unsaturated fat diet (HUSFD). Lipid transport was assessed by uptake rates of bolus oral triglyceride load and mesenteric fat analysis. Lymphatic expansion and inflammation were determined by whole mount immunofluorescence and gene expression. Body composition was assessed by MRI. HSFD 2-month wildtype groups resulted in an increase in TNF-α, IL-6, and IL-10 expression compared with chow-fed controls. The chyle accumulation incidence was highest in HFD-fed mice compared with either HSFD or HUSFD. Strikingly, increased mortality was observed irrespective of which high fat diet was consumed after administration of a bolus lipid load. Conclusion: Chronic HFD increases risk of chyle accumulation, however increased mortality was driven particularly by a bolus lipid load in VD mice. These findings suggest that although chronic HFD increases chyle accumulation risk, a single large meal feeding may increase risk of lethal chylothorax instances for GLA patients.

Use of Serum Antiopoietin-2 Assay for Therapeutic Decision-Making in Patients with Vascular Anomalies

Vascular anomalies (VA), comprised of tumors and malformations, are a spectrum of disorders including benign and malignant lesions characterized by abnormal growth or development of vascular and/or lymphatic vessels that can affect any organ. If left untreated VA can be associated with substantial morbidity and mortality through disfiguration, organ dysfunction, hemorrhage, infection, and/or thrombosis. Correct diagnosis is critical to provide optimal management recommendations but is often challenging due to the phenotypic heterogeneity of these lesions. The biomarker angiopoietin-2 (ang-2), a member of a family of growth factors that regulate blood vessel growth and development, has previously been reported to be elevated in certain VA associated with coagulopathy, including Kaposiform hemangioendotheliomas (KHE) and Kaposiform lymphangiomatosis (KLA) (Le Cras TD, Angiogenesis 2017). Ang-2 levels have been reported to decrease in some patients in response to treatment with sirolimus (Le Cras TD, Angiogenesis 2017; Crane J, Pediatr Blood Cancer 2020). Based upon the published methodology, a clinical serum ang-2 assay was developed that employs a quantitative sandwich enzyme immunoassay technique using a monoclonal antibody specific for human ang-2. Age specific normal ranges for serum ang-2 were determined and were congruent with those first reported for the research assay (range: 1,434-4,141 pg/mL). Here we describe two VA cases in which the clinical ang-2 assay was utilized to aid diagnosis and to detect treatment response, replacing or limiting more invasive, expensive, and high-risk evaluations such as sedated imaging or surgical biopsy.Patient 1 presented at birth with a large purpuric tumor of the right leg associated with thrombocytopenia and hypofibrinogenemia concerning for Kasabach-Merritt phenomenon (KMP). MRI imaging was suggestive of KHE, and the diagnosis was confirmed by biopsy. He was started on methylprednisolone 0.8mg/kg q12h for 1 week and then tapered over 2 months. He was also started on sirolimus 0.4mg/m 2 q12h. His ang-2 serum level was elevated at diagnosis (23,674 pg/mL) and showed reductions over time (graph 1). His ang-2 level continued to decrease as steroids were weaned despite initially having increased swelling and discoloration of the tumor. His steroid wean was slowed; however, therapy was not escalated due to continued decreases in ang-2 levels. Clinically the patient is doing well 1-year post-diagnosis, with improvement in appearance of the tumor and without recurrence of KMP.Patient 2 is a 13-year-old male initially diagnosed at 5 years of age with generalized lymphatic anomaly (GLA) after presenting with acute respiratory failure secondary to significant pleural effusions, bony lesions, and splenic involvement. Prior attempts to classify his diagnosis by histology were inconclusive. He was treated with sirolimus, intermittent pulse steroids, celecoxib, and zoledronic acid, with suboptimal response to therapy. During puberty he presented with significantly increased coagulopathy (D-dimer 32,815 ng/mL and fibrinogen 62 mg/dL: ranges <500ng/mL and 150-400mg/dL respectively) and worsening pericardial and pleural effusions. The lesion was not clinically behaving as expected for GLA, with features suggestive of KLA. Serum ang-2 was measured as an additional diagnostic aid and was elevated at 8,903 pg/mL. GLA has not been reported to be associated with elevations in ang-2. Based on this new information his diagnosis was re-classified as KLA. He was started on weekly vincristine and trametinib, a mitogen activated protein kinase (MEK) inhibitor, with reported efficacy in treatment of KLA, replacing his sirolimus. After 2 months, there were improvement in coagulopathy (D-Dimer 23,306ng/mL and fibrinogen 154mg/dL) and decreasing ang-2 levels (graph 2).These cases demonstrate the potential utility of serum ang-2 as a diagnostic tool and biomarker to monitor response to treatment in selected patients with VA. Next steps are to evaluate ang-2 levels in an expanded group of VA to understand which diagnoses can be distinguished by elevated levels at baseline and how treatment impacts ang-2 over time. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

CT and MRI Findings of Focal Splenic Lesions and Ascites in Generalized Lymphatic Anomaly, Kaposiform Lymphangiomatosis, and Gorham-Stout Disease.

Objectives:This study aimed to evaluate the CT and MRI findings of focal splenic lesions and ascites in generalized lymphatic anomaly (GLA), kaposiform lymphangiomatosis (KLA), and Gorham-Stout disease (GSD).Material and Methods:Twenty-three patients (10 with GLA, 5 with KLA, and 8 with GSD) who underwent abdominal CT and/or MRI before treatment were included in this study, and their imaging findings were retrospectively evaluated.Results:Focal splenic lesions were observed in nine patients; these lesions were observed frequently in GLA (n = 5; 50%) or KLA (n = 3; 60%) compared with GSD (n = 1; 13%); however, no significant differences were found between the three groups (P = 0.190). On CT images among eight patients (4 with GLA, 3 with KLA, and 1 with GSD) with focal splenic lesions who underwent CT, the number of focal splenic lesions per patient ranged from 2 to 189 (mean, 42) and the maximum diameter of focal splenic lesions ranged from 2 to 39 mm (mean, 8 mm), while more than 30 focal splenic lesions per patient were observed in 2 (50%) GLA and focal splenic lesions with maximum diameters of ≥10 mm were observed in 4 (100%) GLA but not in KLA or GSD. Ascites was observed in five patients; significant differences were observed among KLA (n = 4; 80%), GLA (n = 1; 10%), and GSD (n = 0; 0%) (P < 0.01). Ascites was significantly more frequent in KLA than in GSD (P < 0.05).Conclusion:More than 30 focal splenic lesions per patient and/or focal splenic lesions with maximum diameters of ≥10 mm were observed only in GLA. Focal splenic lesions tended to be less frequent in GSD, whereas ascites tended to be frequent in KLA.

Impact of Dietary Fatty Acids on Chylous Effusion in a Mouse Model of Generalized Lymphatic Anomaly

Introduction Generalized lymphatic anomalies (GLA) are complicated vessel malformations that can result in impaired lymphatic function. Potential GLA complications include lipid-rich lymph in the thoracic cavity or abdomen, respectively chylothorax and chylous ascites. To reduce the potential for chylous accumulation, GLA patients limit dietary fats. We hypothesized that dietary fatty acid composition impacts the potential for lymphatic dysfunction and chylous effusion in GLA. Methods Adipose-specific overexpression of lymphatic growth factors has demonstrated lethal chylothorax in mice. Here we utilized mice with inducible adipose overexpression of VEGF-D (Adipo-VD) to mimic GLA and tested the chylothorax incidence with a mixed high fat diet (HFD), high saturated (HSFD), or high unsaturated (HUSFD) fat diet. Lipid transport was assessed by oral triglyceride uptake and mesenteric fat analysis. Lymphatic expansion and inflammation were determined by whole mount immunofluorescence and gene expression. Body composition was assessed with by MRI. Results Oral gavage of a triglyceride bolus increased chylous effusion in all groups. HSFD resulted in a significant increase in TNF-α, IL-6, and IL-10 expression compared to HFD and HUSFD groups. HFD fed mice demonstrated a significant increase is body fat compared to HUSFD fed mice. Interestingly, the chylous effusion incidence was highest in HFD fed mice compared to either HSFD and HUSFD. Conclusion HFD results in increased chylous effusion driven particularly by a bolus lipid load in Adipo-VD mice. These findings suggest that dietary fatty acid composition, and in particularly large meal feeding, may result in increased chylothorax risk for GLA patients.

Lymphatics in bone arise from pre-existing lymphatics.

Bones do not normally have lymphatics. However, individuals with generalized lymphatic anomaly (GLA) or Gorham-Stout disease (GSD) develop ectopic lymphatics in bone. Despite growing interest in the development of tissue-specific lymphatics, the cellular origin of bone lymphatic endothelial cells (bLECs) is not known and the development of bone lymphatics has not been fully characterized. Here, we describe the development of bone lymphatics in mouse models of GLA and GSD. Through lineage-tracing experiments, we show that bLECs arise from pre-existing Prox1-positive LECs. We show that bone lymphatics develop in a stepwise manner where regional lymphatics grow, breach the periosteum and then invade bone. We also show that the development of bone lymphatics is impaired in mice that lack osteoclasts. Last, we show that rapamycin can suppress the growth of bone lymphatics in our models of GLA and GSD. In summary, we show that bLECs can arise from pre-existing LECs and that rapamycin can prevent the growth of bone lymphatics.

Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis

BackgroundKaposiform lymphangiomatosis (KLA) has recently been distinguished as a novel subtype of generalized lymphatic anomaly (GLA) with foci of spindle endothelial cells. All cases of KLA involve multiple organs and have an unfavorable prognosis. However, the molecular pathogenesis is unknown, and there are no useful biomarkers. In the present study, we performed genetic analysis to elucidate the cause of this disease and detect biomarkers for it.MethodsWe performed whole-exome sequencing of DNA samples from leukocytes and a biopsy specimen and analyzed cell-free DNA (cfDNA) from plasma and pleural effusion of patients to identify the NRAS c.182A > G (p.Q61R) mutation using the droplet digital polymerase chain reaction (ddPCR).ResultsAll KLA patients (patients 1–5) had invasive and aggressive features (hemorrhagic pleural effusions, coagulation disorder, and thrombocytopenia) and characteristic findings of KLA in their pathological examinations. In whole exome sequencing for patient 1, c.182A > G missense variant (p.Q61R) in NRAS was identified in fresh frozen samples of a mass on the left chest wall at a frequency of 5% of total alleles but not in his blood leukocytes. Furthermore, the same mutation was detected in cfDNA isolated from plasma and pleural effusion by using ddPCR. ddPCR analysis of plasma/pleural effusion samples from an additional four KLA patients showed that the same mutation was detected in isolated cfDNA in three of the four, as well as in a tissue sample from one of the three plasma/effusion-positive patients that had been obtained to confirm the mutation.ConclusionThese results provide the first evidence that NRAS oncogenic variant was identified in DNA samples from KLA patients from not only two affected lesions but also plasma and pleural effusion.

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly.

Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K-AKT-mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

Kaposiform Lymphangiomatosis: Update on Outcomes and Use of Sirolimus As a Therapeutic Intervention

▪Background: Kaposiform lymphangiomatosis (KLA) is a rare, aggressive lymphatic malformation that can lead to significant morbidity and mortality (Croteau et al 2014). First described as a distinct entity from generalized lymphatic anomaly (GLA) in 2014, KLA is histologically defined by spindled “kaposiform” endothelial cells associated with abnormal proliferation of lymphatic vessels. High risk features include pleural/pericardial effusions and coagulopathy. Respiratory failure, infections, and hemorrhage are common causes of death. In the largest case series of patients with KLA (n=20), five-year survival was 51%. Mean interval between diagnosis and death was 2.75 years. In recent years, the oral agent sirolimus has been used to treat KLA as a single agent or in combination with steroids and vincristine. No update has been published about overall outcomes for patients since the more widespread use of sirolimus.Methods: We conducted a retrospective chart review of 44 patients with biopsy-proven KLA referred to the Vascular Anomalies Center at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center between 1995 and 2018. Twenty patients were previously analyzed in a retrospective review. Patient data were gathered through the electronic medical record and and the Lymphatic Anomalies Registry. Response to treatment was defined by clinical assessment via extraction from the medical record, improvement in patient or parent-reported quality-of-life, improved coagulopathy, and decreased size of lesions on imaging. Toxicities were graded according to the NIH CTCAE grading scale. Clinical outcomes were evaluated up until July 2018.Results: Among 44 patients with KLA, the median age at onset of symptoms was 7 years (range=0-40.6 years). The median time from development of first symptoms to diagnosis of KLA was 16.4 months (range=0-12 years). Seventy-eight percent of patients had pleural or pericardial effusions at presentation (Figure 1). Anatomic involvement varied, with 65% of patients having bony involvement and 68% of patients having visceral disease. Bleeding was also common, with 14% of patients requiring transfusions of blood products. Twenty-four (56%) of 44 patients were treated with sirolimus. Of those 24 patients, 20 (83%) patients reported ever having a sustained response to sirolimus (>6 months) based on our criteria. Despite improvement in disease symptoms, there was no significant difference in overall survival between patients who were treated with sirolimus and those who were not (log-rank p=0.62; Figure 1).Of the 44 patients evaluated in our study, fourteen died. Nine of the patients did not receive sirolimus (they died prior to its use in treating vascular anomalies). Of the 5 patients who received sirolimus and subsequently died, one reported marked improvement in his quality of life, but died from a pneumothorax during chest tube placement for a pleural effusion. The other patient who responded died from respiratory failure after a period of non-adherence with taking sirolimus. The remaining three patients did not respond to sirolimus and died of multi-organ failure. Among the 14 patients who died, the median time from diagnosis to death was 2.2 years (range 0.2- 7.1 years).Among 24 patients treated with sirolimus, 16 (67%) patients were treated concurrently with either vincristine (n=10) and/or steroids (n=15). Eight patients had sustained response with sirolimus alone. Minimal side effects were observed; there was only one grade 3 thrombocytopenia that did not require cessation of sirolimus. Sixteen patients remained on sirolimus at last follow-up.Conclusions: Most patients treated with sirolimus report stabilization of their disease symptoms and improvement in quality of life. Sirolimus is well-tolerated and most patients who respond remain on sirolimus as a form of chronic therapy. However, overall mortality for KLA remains high, even for those patients treated with sirolimus. More research is needed to investigate possible risk factors for poor outcomes. Investigation regarding phenotype-genotype correlation for KLA is ongoing, with the hope of identifying additional treatment options. In our study, there was a gap of > 1 year between time of symptom onset and diagnosis of KLA, highlighting a need for increased awareness of this unique disease entity and prompt referral of patients to a center with expertise in vascular anomalies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abdominal lymphatic malformations.

Abdominal lymphatic malformations (LM) are relatively rare findings in the differential diagnosis of focal abdominal lesions; however, they represent achallenge especially in younger patients. The aim of this review article is to provide up-to-date information about the different kinds of LM manifestations. In addition, related syndromes and typical imaging features to facilitate the diagnosis are discussed. The clinical presentation of abdominal LM is unspecific, whereby most are asymptomatic and comprise incidental findings of thin-walled cystic masses anywhere in the abdomen. The fluid in the cystic masses may be proteinaceous, contain blood, or be infected. Radiological imaging features overlap with other cystic diseases; hallmark in LM is alack of asolid component and exclusive enhancement of the walls and septa. In cystic abdominal masses in early childhood or young adults, abdominal LM must be taken into account by the radiologist. Newly defined entities in this spectrum of diseases are central conducting lymphatic anomaly (CCLA) and generalized lymphatic anomaly (GLA).

Causes and manifestations of chylothorax in children in China: Experience from a children's medical center, 2007-2017.

ImportanceChylothorax is the most common cause of pleural effusion in neonates and relatively rare in children. It can cause significant respiratory morbidity. Many clinical entities may contribute to chylothorax.ObjectiveTo investigate the causes and manifestations of chylothorax in infants and children in China.MethodsCase records of 107 cases with chylothorax seen in Beijing Children's Hospital from 2007 to 2017 were retrieved and analyzed; follow‐up was carried out by telephone.ResultsOf 107 cases, 58.9% (63/107) were primary chylothorax (PC) and 41.1% (44/107) were secondary chylothorax (SC). Also, 36.4% (39/107) were neonatal chylothorax (NC) and 35.5% (38/107) were postoperative chylothorax. In PC with a verified lymphatic anomaly, there was one case of diffuse pulmonary lymphangiomatosis (DPL) and six cases of generalized lymphatic anomaly (GLA), which accounted for 6.5% (7/107) of cases. In most patients, chylothorax was alleviated by conservative treatment based on total parenteral nutrition (TPN); 13.1% (14/107) of cases needed further surgery. In NC, the median duration of TPN was 9 days, but 10 of 20 cases who improved had recurrence upon re‐introduction of a fat‐free diet, which was alleviated by further TPN. The duration of hospitalization was (23 ± 14) days for congenital chylothorax. Upon long‐ term follow‐up, except for GLA and DPL, most patients were doing well without recurrence.Interpretation NC and postoperative chylothorax are the common subtypes. TPN is effective for most patients. Despite a prolonged and fluctuating clinical course, most patients had a good long‐term prognosis.

Abdominal lymphatic malformations. German version

Abdominal lymphatic malformations (LM) are relatively rare findings in the differential diagnosis of focal abdominal lesions; however, they represent achallenge especially in younger patients. The aim of this review article is to provide up-to-date information about the different kinds of LM manifestations. In addition, related syndromes and typical imaging features to facilitate the diagnosis are discussed. The clinical presentation of abdominal LM is unspecific, whereby most are asymptomatic and comprise incidental findings of thin-walled cystic masses anywhere in the abdomen. The fluid in the cystic masses may be proteinaceous, contain blood, or be infected. Radiological imaging features overlap with other cystic diseases; hallmark in LM is alack of asolid component and exclusive enhancement of the walls and septae. In cystic abdominal masses in early childhood or young adults, abdominal LM must be taken into account by the radiologist. Newly defined entities in this spectrum of diseases are central conducting lymphatic anomaly (CCLA) and generalized lymphatic anomaly (GLA).

MR imaging findings of vertebral involvement in Gorham-Stout disease, generalized lymphatic anomaly, and kaposiform lymphangiomatosis.

To assess the MR imaging findings of vertebral involvement in Gorham-Stout disease (GSD), generalized lymphatic anomaly (GLA), and kaposiform lymphangiomatosis (KLA). Nine patients (three patients with GSD, three with GLA, and three with KLA) who underwent whole-spine MR examinations were included. MR findings of fatty marrow replacement and prolonged T1 and T2 lesions of the vertebrae were retrospectively assessed. Prolonged T1 and T2 lesions were defined as well-defined and round-, oval-, or geographic-shaped areas. Six patients [one (33%) patient with GSD, two (67%) with GLA, and three (100%) with KLA] showed both fatty marrow replacement and prolonged T1 and T2 lesions. Fatty marrow replacement was seen in the cervical spine of two (33%) patients, thoracic spine of six (100%), lumbar spine of six (100%), and sacral spine of two (33%). Prolonged T1 and T2 lesions were seen in the cervical spine of three (50%) patients, thoracic spine of three (50%), lumbar spine of six (100%), and sacral spine of three (50%). Both fatty marrow replacement and prolonged T1 and T2 lesions of the vertebrae could be observed in GSD, GLA, and KLA. The most commonly affected site was the lumbar spine, followed by the thoracic spine.

Angiopoietins as serum biomarkers for lymphatic anomalies.

Vascular anomalies can cause significant morbidity and mortality. Advances in diagnosis will be improved if noninvasive biomarkers can be identified, as obtaining a tissue biopsy can worsen the disease and precipitate complications. The goal of this study was to identify biomarkers for vascular anomaly patients to aid diagnosis and potentially give insights into pathogenesis. Blood was collected at baseline and then 6 and 12months after treatment with the mTOR inhibitor sirolimus. Patients groups included generalized lymphatic anomaly (GLA), kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE) with or without the Kasabach-Merritt phenomenon (KMP) coagulopathy. Serum was obtained from healthy controls selected to match the age and sex of the patients (21days-28.5years; 42% males; 58% females). Angiogenic and lymphangiogenic factors (VEGF-A, C, D, Ang-1 and Ang-2) were measured in serum using ELISA. In lymphatic anomaly patients, baseline levels of VEGF-A and VEGF-D were not different compared to controls. Angiopoietin-2 (Ang-2) levels were near controls levels in GLA patients but 10-fold greater in KLA patients and 14-fold greater in KHE patients when the KMP coagulopathy was present but not when it was absent. VEGF-C and angiopoietin-1 (Ang-1) levels were lower in KHE patients with KMP. Our analyses suggest that Ang-2 and Ang-1 can be used as biomarkers to help identify KLA and KHE patients with KMP coagulopathy with high sensitivity and specificity. After 12months of sirolimus treatment, Ang-2 levels were lower in KLA and KHE with KMP patients compared to baseline levels and with most patients showing a clinical response. Hence, serum Ang-2 and Ang-1 levels may help in the diagnosis of patients with lymphatic anomalies and are concordant to sirolimus response.

Complex lymphatic anomalies

Complex lymphatic anomalies include several diagnoses with overlapping patterns of clinical symptoms, anatomic location, imaging features, hematologic alterations, and complications. Lymphatic malformations likely arise through anomalous embryogenesis of the lymphatic system. Analysis of clinical, imaging, histologic, and hematologic features is often needed to reach a diagnosis. Aspiration of fluid collections can readily define fluid as chylous or not. The presence of chyle indicates dysfunction at the mesenteric or retroperitoneal level or above the cisterna chyli due to reflux. The imaging patterns of generalized lymphatic anomaly (GLA) and Gorham–Stout disease have been segregated with distinctive bone lesions and peri-osseous features. More aggressive histology (spindled lymphatic endothelial cells), clinical progression, hemorrhage, or moderate hematologic changes should raise suspicion for kaposiform lymphangiomatosis. Biopsy may be needed for diagnosis, though avoidance of rib biopsy is advised to prevent iatrogenic chronic pleural effusion. Lymphangiography can visualize the anatomy and function of the lymphatic system and may identify dysfunction of the thoracic duct in central conducting lymphatic anomalies. Local control and symptom relief are targeted by resection, laser therapy, and sclerotherapy. Emerging data suggest a role for medical therapies for complications of complex lymphatic anomalies. Outcomes include recurrent effusion, infection, pain, fracture, mortality, and rarely, malignancy. Complex lymphatic anomalies present significant diagnostic and therapeutic challenges. Results from a phase 2 study of sirolimus in these and other conditions are expected in 2014. Improved characterization of natural history, predictors of poor outcomes, responses to therapy, and further clinical trials are needed for complex lymphatic anomalies.