Annual prevalence estimation of lymphatic malformation with a cutaneous component: observational study of a national representative sample of physicians.

BACKGROUND: Lymphatic malformations (LMs) represent a potentially life-threatening, rare disease of the lymphatic system characterized by development of abnormal vessels, outpouchings, or cysts filled with lymphatic fluid. There are three morphologic types of LMs based on the size of the individual cysts: macrocystic (typically > 2 cm), microcystic (generally < 2 cm), and mixed (includes aspects of both). Macrocystic LMs typically exist beneath the skin and often can involve vascular components and/or organs. Microcystic LMs often have a cutaneous component and clinically present with lymphorrhea, bleeding, pain, itching, malodor, and functional deficits. There are no treatments approved by the US Food and Drug Administration (FDA) for either macrocystic or microcystic lymphatic malformations. The totality of the epidemiologic literature for LM is limited to the incidence of the disease among various birth cohorts. This is the first nationally representative study to estimate the national managed prevalence for patients with microcystic LM or combined LM with a cutaneous component annually across physician specialties likely to manage this condition. We conducted a retrospective observational survey of a nationally representative sample of patient-care physicians in the United States most likely to manage lymphatic malformations with a cutaneous component (LMC). Once recruited, target physicians participated via an electronic questionnaire. We weighted study physician self-estimates of the number of LMC patients treated in the past 12 months to reflect the specialists' corresponding proportion in the national universe. All patient information was anonymous; no personally identifiable information was collected. RESULTS: Of the 420 physicians who visited the study website, 316 agreed to be screened and to participate (75.2% participation rate). Our survey results indicated the estimated number of unique annually managed LMC patients by target specialists is 79,920 (CI 66,600-93,250). This number corresponds to managed prevalence of 24.1 LMC patients per 100,000 population (CI 19.6/100,000-28.4/100,000). CONCLUSIONS: The study indicates that while rare, LMC affects a substantial number of people in the US (79,920) who are being managed by one or more specialists. By better understanding the prevalence of people living with LMC who require treatment, efforts to both increase disease awareness and to identify underserved populations in need of potential new treatments can be better focused.

[New nosological and therapeutic perspectives in syndromic vascular malformations with a vein-lymphatic component]. / Nouvelles perspectives nosologiques et thérapeutiques pour les malformations vasculaires syndromiques à composante veino-lymphatique.

Vascular malformations are poorly recognized constitutional anomalies which arises during early childhood. Several classifications tried to draw a distinction across the different entities. Recent advances in molecular biology have contributed to the update of their nosology. Syndromic vascular malformations are an example: while Klippel-Trenaunay syndrome, Proteus or CLOVES syndrome share many common features, understanding of pathological mechanism and specially the role of the PIK3/AKT/mTOR pathway enables us to rethink their classification. Then, some syndromes associated with overgrowth and vascular malformation have been grouped under a single term: "PIK3CA-related overgrowth spectrum" (PROS), and this group continues to grow. This new approach suggests new treatment options. Rapamycin, a PIK3/AKT/mTOR pathway inhibitor, demonstrated its efficiency for some forms of PROS. Targeted therapies such as PIK3 or mTOR selective inhibitor are still in a developmental phase and results are encouraging. This is an example of personalized medicine with significant therapeutic benefit for some patients. However, genotype relation with therapeutic efficiency must be clarified and physicians should pay attention to possible negative effects of these drugs, especially for young patients.

National Characteristics of Lymphatic Malformations in Children: Inpatient Estimates and Trends in the United States, 2000 to 2009.

With ever increasing demands to manage finite resources for health care utilization, we performed an investigation to identify inpatient clinical characteristics and trends in children with lymphatic malformations using the Kids' Inpatient Database, years 2000 to 2009, to help identify populations best suited for resource deployment. Subjects included children 18 years and below with International Classification of Diseases (ICD), ninth revision code: 228.1-lymphangioma, any site. In the United States, between 2000 and 2009, inpatient pediatric patients with lymphatic malformations most commonly affected children aged 3 years and younger, urban hospital locations, and the South and West regions. There was no significant change in age of children with lymphatic malformations or the distribution of their age from year to year, P=0.948 and 0.4223, respectively. No significant evidence for seasonal variation or effect on inpatient admission was identified, P=0.7071. A great majority of admissions (>96%) were in urban locations across each year. There was also no significant change in breakdown of admissions by geographic location, P=0.7133. Further investigation may help to elucidate how to improve access to multidisciplinary vascular anomalies teams to optimize care for these children with unique and complex lymphatic malformations.

The Public Health Burden of Lymphatic Malformations in Children: National Estimates in the United States, 2000-2009.

OBJECTIVE: Describe inpatient resource utilization trends in children with lymphatic malformations using a national database. DATA SOURCE: Kids' inpatient database, years 2000-2009. METHODS: Subjects included children 18 years and under with International Classification of Diseases (ICD), 9th revision code: 228.1-lymphangioma, any site. Data elements were extracted and used to calculate related inpatient costs and trended over time. RESULTS: No significant increase in admission rates was noted over time, p = 0.5128. Average total charges per admission were $30,995. There is a clear and increasing trend of total charges per admission; even when adjusted for inflation, this has increased disproportionately. In 2009, the mortality rate increased to 2.58%, which was significantly higher than in previous years, p = 0.0346. In multivariate analysis for mortality, the only factor that was noted to be significant was between survey years 2000 and 2009. The odds ratio (OR) for mortality was 2.97, 95% CI: [1.423-6.202], which indicated that there was an almost three times higher likelihood of mortality in 2009 than in 2000. CONCLUSIONS: Admission rates appear to remain stable for pediatric inpatients with lymphatic malformations but resource utilization related to charges has been increasing from 2000 to 2009. Controlling for inflation does not explain our observed trend in total charge increases. Previously, surgical resection was the most commonly performed procedure, and now the trend has shifted away from operative intervention. Mortality rates, while low, experienced a rise in 2009. Further investigation may be warranted.

Prenatal diagnosis of obstructive head and neck masses and perinatal airway management: the ex utero intrapartum treatment procedure.

Advances in prenatal imaging in the last 20 years have enabled prenatal diagnosis of obstructive head and neck masses. These advances, coupled with improvements in maternal-fetal anesthesia, have made possible the development of the ex utero intrapartum treatment (EXIT) procedure for management of obstructive head and neck masses, during which the airway is managed in a controlled fashion while maintaining fetal circulation for oxygenation. This review addresses the preoperative and perioperative assessment and management of patients with prenatally diagnosed airway obstruction, indications and contraindications for the EXIT procedure, technical details of the procedure, and outcomes.

Prognostic value of a simplified anatomically based nomenclature for fetal nuchal lymphatic anomalies.

OBJECTIVE: To propose an anatomic classification for fetal nuchal lymphatic anomalies that will be clinically useful and to evaluate the classification's value in predicting chromosomal abnormalities, pregnancy outcomes, other associated fetal anomalies, and spontaneous resolution of these lesions. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic hospital and affiliated tertiary children's hospital. SUBJECTS AND METHODS: Mother-baby pairs diagnosed with fetal nuchal lymphatic anomalies in a prenatal ultrasound database. Anomalies were classified as nuchal thickening, dorsal lymphatic malformation, or ventral lymphatic malformation. Pregnancy outcomes, prevalence of chromosomal and anatomic abnormalities, and rates of spontaneous lesion resolution were determined for each group. RESULTS: The study included 189 patients: 58 with nuchal thickening, 120 with dorsal lymphatic malformation, and 11 with ventral lymphatic malformation. In fetuses for whom chromosomal analysis was available, chromosomal abnormalities were strongly associated with dorsal lymphatic malformations (83%), less associated with nuchal thickening (29%), and not associated with ventral lymphatic malformations. Dorsal lymphatic malformation predicted high rates of elective (43%) and spontaneous (20%) termination of pregnancy and showed the strongest association with cardiac, renal, and skeletal anomalies. Nuchal thickening was more likely to resolve in utero than dorsal lymphatic malformations, while no ventral lymphatic malformation resolved spontaneously. CONCLUSIONS: Fetal nuchal anomalies demonstrate significant and clinically important prognostic differences depending on their anatomic location. The simple classification system proposed here therefore provides useful information to clinicians involved in the pre- and postnatal management of children with these anomalies.

Linfedema primario / Primary lymphedema

El linfedema primario se origina por una alteración intrínseca del sistema linfático, que en función de la edad de aparición se clasifica en 3 grupos: congénito, precoz y tardío. El linfedema primario, sobre todo en las formas congénitas como la enfermedad de Milroy, se ha relacionado con alteraciones genéticas, encontrándose en muchos casos distintas mutaciones (VEGFR3, FOXC2, SOX 18 y HGF/MET). La valoración es fundamentalmente clínica, siendo necesaria la realización de pruebas complementarias que descarten otros procesos que cursen con edema. La linfogammagrafía es la prueba diagnóstica principal para su confirmación. Las formas hereditarias requieren una correcta historia familiar, debiendo ser valoradas en consultas específicas de consejo genético (AU)

Primary lymphedema is caused by an intrinsic abnormality of the lymphatic system. Based on the onset age, it is classified into three groups: congenital, precox and tarda. Primary lymphedema, especially in congenital forms as Milroy disease, has been linked to genetic alterations, different mutations being described in many cases: VEGFR3, FOXC2, SOX 18 and HGF/MET. Clinical assessment is the key stone in diagnosis, additional tests being necessary to rule out other kinds of edema. Lymphoscintigraphy is the gold standard confirmatory test. In hereditary forms, a careful family history is necessary, so specific genetic counseling must be provided (AU)

Malformaciones linfáticas complejas: implicaciones diagnósticas y terapéuticas / Complex lymphatic malformations: diagnostic and therapeutical implications

Introducción. Las malformaciones linfáticas complejas (MLC) son alteraciones del desarrollo del sistema linfático, en la mayoría de los casos de origen genético, con afectación mixta del sistema vascular: linfático, venoso y capilar. Se caracterizan por afectar de forma extensa la superficie corporal del niño o por asociarse a otros síndromes o enfermedades sistémicas. Material y métodos. Revisamos los 21 pacientes con MLC tratados en nuestro centro en los últimos 15 años. Utilizamos el anticuerpo monoclonal D2-40 (inmunohistoquímica) para evaluar el grado de afectación linfática (como marcador de la afectación linfática). Así mismo analizamos las implicaciones quirúrgicas en este tipo de pacientes. Resultados. Doce niños tenían afectación linfática exclusivamente y nueve linfático-capilar o linfático-venosa. Dos fallecieron por insuficiencia respiratoria (período neonatal) e hipoproteinemia refractaria (a los 8 años de edad). La piel estaba afectada entre el 10 y 35% de la superficie corporal. En tres casos había afectación visceral (pulmonar y mediastínica) y en 18 musculoesquelética. La sintomatología más frecuente fue la deformidad severa (20), seguida de linforragia (15), linfangitis de repetición (7) y dolor crónico (5). La intensidad de la inmunorreacción con el anticuerpo monoclonal D2- 40 se correlacionó con la severidad de la afectación local y sistémica así como con la existencia de malformaciones asociadas. Quince de los pacientes fueron sometidos a tratamiento quirúrgico secuencial, siete recibieron esclerosis seriadas con OK-432 y cuatro vaporización con láser de CO2. La linforragia residual de los pacientes en los que se pudo extirpar completamente la malformación cedió tras punciones evacuadoras repetidas considerándose la curación de la enfermedad. Conclusiones: 1. El anticuerpo monoclonal D2-40 es un marcador de mal pronóstico en las MLC. 2. La extirpación radical de la malformación consigue la curación y la linforragia asociada no debe considerarse una recidiva, cediendo en todos los casos tras punciones evacuadoras. 3. Las MLC requieren protocolos de tratamiento por un equipo multidisciplinario para paliar las secuelas postoperatorias y a largo plazo (AU)

BACKGROUND: Complex lymphatic malformations (CLM) consist of disturbances of lymphatic system development, most often with a genetic origin and with mixed vascular system involvement: lymphatic, venous and capillary. They affect a large corporal area or are associated to other syndromes or systemic diseases. METHODS: We reviewed 21 patients with CLM treated in our hospital during the last 15 years. We used D2-40 monoclonal antibody (by immunohistochemistry) as lymphatic marker to evaluate the level of lymphatic involvement. Furthermore we analysed surgical implications in this group of patients. RESULTS: Twelve children had only lymphatic involvement and nine mixed lymphatic-capillary or lymphatic-venous one. Two died of: respiratory insufficiency (in the neonatal period) and refractory hypoproteinemia (at 8 years of age). The skin was affected between 10 and 35% of total body surface. Three patients suffered from visceral involvement (lungs and mediastinum) and eighteen musculoskeletal. Severe deformity (20), lymphorhagia (15), repeated lymphangitis and chronic pain (5) were the most common symptoms reported. The immunoreaction intensity with monoclonal antibody D2-40 was related to the severity of the local and systemic involvement as well as to the presence of associated malformations. Fifteen cases underwent sequential surgical treatment, seven were treated with sclerotherapy (OK-432) and four with CO2 laser vaporization. Residual lymphorhagia in patients with total extirpation of the lymphatic malformation stopped after repeated evacuator punctures and healing took place. CONCLUSIONS: (1) D2-40 monoclonal antibody is a marker of bad prognosis in CLM. (2) The complete excision of the lymphatic malformation lead to healing and the associated lymphorragia should not be considered as a recurrence, which will stop with evacuator punctures in all cases. (3) A multidisciplinary team approach is essential for the proper care of CLM in order to minimize postoperative sequelae and late complications (AU)