Presentation on theme: "Lymphatic Anomalies: Classification, Lung Involvement, and New Treatment Options Denise M. Adams, MD Medical Director Hemangioma and Vascular Malformations."— Presentation transcript:
1Lymphatic Anomalies: Classification, Lung Involvement, and New Treatment Options Denise M. Adams, MDMedical Director Hemangioma and Vascular Malformations Center, Cincinnati Children’s HospitalDebra Boyer, MDPulmonary LiaisonVascular Anomaly ClinicBoston Children’s Hospital
2Case Presentation13 yo AA female transferred from PMD to ED w/ SOB and increased WOB. Reports progressive SOB with exertion over 3 months, leading to limitations in ADL.Albuterol trial at PMD: no response, tachycardia to 200s transferred to ED.
4Case PresentationPost-chest tube placement. The intercostal vessels, presumably lymphatics, are prominent posteriorly. Bright T2 signal extends through the posterior mediastinum into the retroperitoneum. Some of this is somewhat lobular, suggesting lymph nodes. In other areas as it is slightly more confluent, and may represent lymphatic channels. Multiple: lesions bright on T2, dark T1, showing initially no enhancement, but subsequently fillingin following intravenous contrast administration on delayed sequences. are seen throughout the bones including the vertebral bodies, left scapula, and bilateral ribs.
6Vascular Anomalies: Lymphatic TumorsKaposiform HemangioendotheliomasLymphangiosarcomaCombined MalformationsVenous/LymphaticCapillary/Venous/LymphaticLymphatic MalformationsMacrocysticMicrocysticDiffuseNumerous subsets of lymphatic AnomaliesCombinedCVLM Cap Ven Lymph MalformationsTumors – KHE - spindle cell tumor w/ lymphatic component with proliferation of the lymphatics, the more lymphatic component the higher the mortalityLymphatic AnomaliesMacrocysticMicrocysticGorham Syndrome –Is this all one disease process? Extremely variable presentations,Multiple boney lesions – progressive, but w/ eventual stabilization, can result in total bone loss “disappearing bone”Diffuse - often with other soft tissue involvement, chylothoraxp, rogressive with life threatening complications.Others: Ie lymphangiectasias of the GI tract or pulmonary system
7Vascular Anomalies with Lymphatic Components Extremely wide variety of expression, all of these vascular lesions contain significant lymphatic component.Starting in upper left clockwise:Kaposiform Hemangioendothelioma (KHE)Diffuse microcystic lymphatic malformation with pleural disease or Gorham SyndromeCapillary venous lymphatic malformation (CVLM) – mostly lymphaticMacrocystic lymphatic malformationReally a field in early in it’s development and understanding.--Extremely variable presentations, diseases states, involvement, prognosis--Often unable to get adequate specimens or pathology--No known biomarkers to follow--No known way to risk stratify other than expert opinion and clinical gestalt.
8Confusing Terminology Vascular AnomalyLymphatic MalformationLymphangiomaLymphangiomatosis:Angio: from the blood vesselLymphangio: from lymphatic vesselMatosis: condition or process that is abnormalGorham SyndromeLymphangiectasia
9Review of the Literature All Articles until present to dateRetrospective case studies and case series – Largest 53 patients287 ArticlesSearch: Lymphangiomatosis: bone, chest, diffuse; Lymphatic malformation: bone, chest, diffuse; Gorham Syndrome, Gorham Stout Syndrome, lymphangioma
10Review of the Literature Equal male to female ratioMajority of cases involve multiple sites: bones, chest, effusions (pleural/pericardial), spleen, GI, liver, skinRarely isolated to only one areaCases reported are complicated patients
11Risk Stratification Presentation at a young age Female gender Cervical spine involvementThoracic soft-tissue involvementFluid complication: pleural effusion, pericardial effusion, ascites
13ClassificationCommon malformations: localized micro and/or macrocystic lesionsGLA: lymphatic anomaly in multiple areas without cortical destruction of the boneGSD: cortical destruction and osteolysisKLA: aggressive presentation of lymphatic anomaly with coagulopathy and focal areas of spindle cellsConducting Channel Anomalies: congenital anomalies of the central conducting lymphatics include abnormal morphology and function such as anomalous channel size (dilatation, stenosis, atresia), abnormal distribution, incompetence with poor contractile function (reflux, leak) and aplasia of the lymphatics.Lymphedema: results from either dysplastic or obstructed collecting lymphatic vessels or non-functional peripheral lymphatic vessels.
14Common Malformations Usually localized Can cause issues depending on where the lesions are locatedCan be macro or microcysticMore common in the head and neck
15Generalized Lymphatic Anomaly (GLA) Can present at any ageMultiple areas of involvement: lungs, bone, GI tract, skinBony lesions do NOT destroy the cortexEffusions can occur with infection, trauma or puberty
16Gorham Stout Disease (GSD) Hallmark is progressive bony disease with destruction through the cortexCan have other areas of lymphatic disease: soft tissue, spleen, lung, GI tract
17Kaposiform Lymphangiomatosis (KLA) New entityProliferative componentAreas of spindle cellsHemorrhagic effusionMultifocalLungs commonly involved but also can present in the soft tissue and GI tract
21EvaluationCTMRILymphangiogramsPulmonary Function Tests
22Treatment Treat the anomaly: medicine, intervention, surgery Pulmonary medicationsRespiratory therapyPhysical therapyLung transplant
23Questions to be answered What is the pathophysiology of disease? proliferation? If proliferation what is proliferating? Flow? Shear stress? Anatomical issues?Is treatment better at a younger age or when asymptomatic?What is the best evaluation? CT, MRI, lymphangiograms or similar testingWhat is the best treatment? Surgical, interventional, medical, combinationWhat can we learn from the phenotypes of lung disease?Will any medication or therapy make these anomalies go away completely?
24Medical Treatment in the Literature Interferon/BisphosphonatesChemotherapy agents (vincristine, cytoxan)Anti-angiogenic agents
25At the time of publication several patients were still on or very recently off of sirolimus. We have continued to follow these patients and others.Submitted December 2010
26The mTOR pathwayTie-2there were already several lines of evidence to suggest the importance of the mTOR pathway in vascular anomalies when we began using sirolimus.
27Summary of first 6 patients treated with sirolimus AgeGenderDiagnosisAffected LocationsPrevious Treatment(s)Results110 monthsFemaleKHE + KMPAbdomenBackChestLeft legPelvisRetroperitoneumSteroidsVincristineCyclophosphamideInterferonBevacizumabEmbolizationResolution of KMPResolution of high-output cardiac failureImprovement in size and color of lesion26 yearsMaleLMPleural effusionMediastinumParaspinalBone lesions Cutaneous (chest/back/shoulder)CelecoxibThoracoscopic decortication PleurodesisChest tubesResolution of pleural effusionsDecrease in size/discoloration of lesionStabilization of bony lesionsImprovement in pain scale score3CLVMLungLiverLeft lower extremityPelvis/buttocksLMWHIbuprofenSurgical debulkingSclerotherapyDecreased blebbing, leakingDrain removal Decreased leg circumference414 yearsChylous pleural effusionSpleenBone lesionsChest TubePleurodesisLigation of the thoracic ductResolution of pleural effusion Stabilization of bony lesions5Bilateral pleural effusionsPericardial effusionResolution of effusions67 monthsBilateral chylous pleural effusionsBone lesions T11-L4IntraabdominalVATS x2Ligation of thoracic ductPericardial windowResolution of pleural effusions andrespiratory failureNear-complete resolution of abdominallesionsNormalization of PT, PTT, fibrinogenImprovement in bony lesionsImprovement in gross motor skillsAs you may recall, these 6 patients, 3 males and 3 females, ranged in age from 7 months to 14 years. They had a variety of diagnoses, including one KHE with KMP, 1 capillary lymphaticovenous malformation, and 4 with diffuse microcystic lymphatic malformations involving bone and . They had extensive disease involvement in all cases, and were heavily pretreated with a variety of surgical, interventional, and medical therapies, but were still experiencing significant morbidity and even threat of mortality related to their lesions. Upon starting sirolimus, ALL of them had improvement in their symptoms with minimal/tolerable side effects.
28Summary of first 6 patients treated with sirolimus DemographicsGender: 3 male, 3 femaleAge: 7 months to years (mean 7.25years)Diagnoses: 1 KHE with KMP, 1 CLVM, 4 lymphatic malformationsHeavily pretreated (3 to 6 prior interventions)ResultsAll had improvement in symptomsNone had exacerbation of disease while on sirolimusSide effects were tolerableOur cohort included 6 patients, with diagnoses including 1 KHE with KMP, 1 capillary lymphaticovenous malformation, and 4 with diffuse microcystic lymphatic malformations involving bone and pleural effusions. They all had extensive disease involvement, and had been heavily pretreated with a variety of surgical, interventional, and medical therapies. Upon starting sirolimus, ALL of them showed improvement in their symptoms with minimal/tolerable side effects and no drug-related infections.
29Patient 6: Microcystic Lymphatic Malformation Improvement in his abdominal/pelvic diseaseBefore sirolimus therapy16 months on sirolimus therapy
30Patient 6: Bony Lesions Before sirolimus therapy And gradual improvement in multiple vertebral lesions.Before sirolimus therapy16 months on sirolimus therapy
31Update SummaryAverage length of initial treatment: 21 months (range 2-31 months)Average length of follow up: 43 months (range months)Five of six patients have required additional treatment: 4 are currently on low-dose sirolimus (once daily) and one of these is starting to taperIn summaryOur patients were treated for an average of 21 monthsWith average follow up of 43 months4 of 6 patients have required re-treatment, with 3 still on sirolimus once daily dosing giving them drug levels of 3 to 4
32ConclusionsSirolimus is an effective medication for these patients, with good responses and limited side effectsOur patients have had no long term or developmental issues observed to datePatients with symptoms of recurrence elected to be restart sirolimus for improvement in quality of lifeSirolimus shows particular promise in the treatment of KHE and can stabilize other diagnoses, but is not a cureFurther studies are needed to identify mechanisms and to determine optimal length of therapy, as well as to continue to monitor for long-term side effectsWe conclude that sirolimus is an effective medication for these patients, with no developmental or other long term issues to date.The 5 patients with recurrence chose to resume sirolimus with improvement in their quality of lifeSirolimus shows particular promise in the treatment of high risk KHE and can stabilize other diagnoses, but appears to be a useful tool rather than a cureFurther studies are still needed to identify the mechanisms responsible for these effects and to determine optimal length of therapy and any long-term side effects
33Phase II Clinical Trial FDA funded, drug supplied by Pfizer, two institution studyChildren and young adults with complicated vascular anomalies (0-31 years)Primary Aims:Determine EfficacyDemonstrate SafetySecondary Aim: Biomarker AnalysisBlood: VEGF-A, C, D, Il-8, Pleiotrophin, IGF-1, Endothelin-1, Thrombospondin and Angiopoietin-1/2Tissue: Phosphorylated Akt, phosphorylated ERK-1/2, mTOR, and phosphorylated S6 kinaseAccrual: 60 patients (currently 39 enrolled)Oral sirolimus therapy: initial dosing 0.8mg/m²/dose BID; target ng/mLEligible Diagnoses:KHE +/- KMPTufted Angioma +/- KMPCapillary Lymphaticovenous Malformation (CLVM)Lymphaticovenous Malformation (LVM)Microcystic Lymphatic MalformationCapillary Lymphatic Arterial Venous MalformationsPTEN Overgrowth syndrome + vascular anomalyLymphangiectasia SyndromesQualifying Complications:CoagulopathyChronic painRecurrent cellulitis (>3/year)UlcerationVisceral and or bone involvementCardiac dysfunctionClinicaltrials.gov
34Questions What is the phenotype that sirolimus is best for? Are there biological markers that can help us?What is the right dose?What is the right length of time on treatment?Are there other drugs available that may be effective
35ConclusionNo patient is exactly the same but patients have similar characteristicsThere are similarities to other vascular anomalies and we can learn from allComplicated patients need at least an initial evaluation at a multidisciplinary vascular anomaly centerLGDA and other parent/patient support groups are wonderful resources