Post on 31-Mar-2015
Lymphatic Anomalies: Classification,
Lung Involvement, andNew Treatment Options
Denise M. Adams, MDMedical Director Hemangioma and Vascular
Malformations Center, Cincinnati Children’s HospitalDebra Boyer, MDPulmonary Liaison
Vascular Anomaly ClinicBoston Children’s Hospital
Case Presentation
• 13 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
CXR
Case Presentation
Vascular Anomalies
TumorsTumors MalformationsMalformations
Mulliken & Glowacki. Plast Recon Surg 1982
Low Flow High Flow
Vascular Anomalies: Lymphatic
• Tumors– Kaposiform Hemangioendotheliomas– Lymphangiosarcoma
• Combined Malformations– Venous/Lymphatic– Capillary/Venous/Lymphatic
• Lymphatic Malformations– Macrocystic– Microcystic– Diffuse
Vascular Anomalies with Lymphatic Components
Confusing Terminology
• Vascular Anomaly• Lymphatic Malformation• Lymphangioma• Lymphangiomatosis:
– Angio: from the blood vessel– Lymphangio: from lymphatic vessel– Matosis: condition or process that is abnormal
• Gorham Syndrome• Lymphangiectasia
Review of the Literature
• All Articles until present to date• Retrospective case studies and case series –
Largest 53 patients• 287 Articles• Search: Lymphangiomatosis: bone, chest,
diffuse; Lymphatic malformation: bone, chest, diffuse; Gorham Syndrome, Gorham Stout Syndrome, lymphangioma
Review of the Literature
• Equal male to female ratio• Majority of cases involve multiple sites: bones,
chest, effusions (pleural/pericardial), spleen, GI, liver, skin
• Rarely isolated to only one area• Cases reported are complicated patients
Risk Stratification
• Presentation at a young age • Female gender• Cervical spine involvement• Thoracic soft-tissue involvement• Fluid complication: pleural effusion,
pericardial effusion, ascites
Re-classification of Lymphatic Anomalies
Tumors• Kaposiform
Hemangioendothelioma• Lymphangiosarcoma
Malformations• Common malformations• Generalized Lymphatic
Anomaly (GLA)• Gorham Stout Disease
(GSD)• Kaposiform
Lymphangiomatosis (KLA)• Conduction Channel
Anomalies (CCA)• Lymphedema
Classification • Common malformations: localized micro and/or macrocystic lesions• GLA: lymphatic anomaly in multiple areas without cortical destruction of
the bone• GSD: cortical destruction and osteolysis• KLA: aggressive presentation of lymphatic anomaly with coagulopathy
and focal areas of spindle cells• Conducting 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.
Common Malformations
• Usually localized• Can cause issues depending
on where the lesions are located
• Can be macro or microcystic• More common in the head
and neck
Generalized Lymphatic Anomaly(GLA)
• Can present at any age• Multiple areas of
involvement: lungs, bone, GI tract, skin
• Bony lesions do NOT destroy the cortex
• Effusions can occur with infection, trauma or puberty
Gorham Stout Disease(GSD)
• Hallmark is progressive bony disease with destruction through the cortex
• Can have other areas of lymphatic disease: soft tissue, spleen, lung, GI tract
Kaposiform Lymphangiomatosis (KLA)
• New entity• Proliferative component• Areas of spindle cells• Hemorrhagic effusion• Multifocal• Lungs commonly involved
but also can present in the soft tissue and GI tract
Pulmonary Manifestations
Effusions
• Pleural• Pleural and pericardial• Chylous/Lymphatic• Hemorrhagic Fluid: pleural, pericardial, ascites
Parenchymal Lung Disease
• Kaposiform Lymphangiomatosis• Lymphangiectasia• Soft tissue Lymphatic malformation (usually
microcystic)
Evaluation
• CT• MRI• Lymphangiograms• Pulmonary Function Tests
Treatment
Treat the anomaly: medicine, intervention, surgeryPulmonary medicationsRespiratory therapyPhysical therapyLung transplant
Questions 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 testing
• What is the best treatment? Surgical, interventional, medical, combination
• What can we learn from the phenotypes of lung disease?• Will any medication or therapy make these anomalies go
away completely?
Medical Treatment in the Literature
• Interferon/Bisphosphonates• Chemotherapy agents (vincristine, cytoxan)• Anti-angiogenic agents
Submitted December 2010
The mTOR pathway
Tie-2
Summary of first 6 patients treated with sirolimus
Patient AgeGender Diagnosis Affected Locations Previous Treatment(s) Results
110 months Female
KHE + KMP
AbdomenBackChestLeft legPelvisRetroperitoneum
SteroidsVincristineCyclophosphamideInterferonBevacizumabEmbolization
Resolution of KMPResolution of high-output cardiac failureImprovement in size and color of lesion
26 years Male
LM
Pleural effusion MediastinumParaspinalBone lesionsCutaneous (chest/back/shoulder)
InterferonCelecoxibThoracoscopic decorticationPleurodesis Chest tubes
Resolution of pleural effusionsDecrease in size/discoloration of lesionStabilization of bony lesionsImprovement in pain scale score
36 years Male
CLVM
LungLiver Left lower extremityPelvis/buttocksRetroperitoneum
LMWHInterferonIbuprofenSurgical debulkingSclerotherapy
Decreased blebbing, leakingDrain removalDecreased leg circumference
414 years Female
LMChylous pleural effusionMediastinumSpleenBone lesions
Chest TubePleurodesisLigation of the thoracic ductCelecoxib
Resolution of pleural effusionStabilization of bony lesions
514 years Female
LMBilateral pleural effusionsPericardial effusionBone lesions
Chest tubesInterferonCelecoxib
Resolution of effusionsStabilization of bony lesions
67 months Male
LM
Bilateral chylous pleural effusionsBone lesions T11-L4LiverIntraabdominalSpleen
VATS x2PleurodesisLigation of thoracic ductPericardial windowChest tubes
Resolution of pleural effusions and respiratory failureNear-complete resolution of abdominal lesionsNormalization of PT, PTT, fibrinogenImprovement in bony lesionsImprovement in gross motor skills
Summary of first 6 patients treated with sirolimus
• Demographics– Gender: 3 male, 3 female– Age: 7 months to 14.75 years (mean 7.25years) – Diagnoses: 1 KHE with KMP, 1 CLVM, 4 lymphatic
malformations– Heavily pretreated (3 to 6 prior interventions)
• Results– All had improvement in symptoms– None had exacerbation of disease while on sirolimus– Side effects were tolerable
Patient 6: Microcystic Lymphatic Malformation
Before sirolimus therapy 16 months on sirolimus therapy
Patient 6: Bony Lesions
Before sirolimus therapy 16 months on sirolimus therapy
Update Summary
• Average length of initial treatment: 21 months (range 2-31 months)
• Average length of follow up: 43 months (range 28 -59 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 taper
Conclusions
• Sirolimus is an effective medication for these patients, with good responses and limited side effects
• Our patients have had no long term or developmental issues observed to date
• Patients with symptoms of recurrence elected to be restart sirolimus for improvement in quality of life
• Sirolimus shows particular promise in the treatment of KHE and can stabilize other diagnoses, but is not a cure
• Further studies are needed to identify mechanisms and to determine optimal length of therapy, as well as to continue to monitor for long-term side effects
Phase II Clinical Trial• FDA funded, drug supplied by Pfizer, two institution study• Children and young adults with complicated vascular anomalies (0-31 years)• Primary Aims:
Determine Efficacy Demonstrate Safety
• Secondary Aim: Biomarker Analysis Blood: VEGF-A, C, D, Il-8, Pleiotrophin, IGF-1, Endothelin-1,
Thrombospondin and Angiopoietin-1/2 Tissue: Phosphorylated Akt, phosphorylated ERK-1/2, mTOR, and
phosphorylated S6 kinase• Accrual: 60 patients (currently 39 enrolled)• Oral sirolimus therapy: initial dosing 0.8mg/m²/dose BID; target 10-15
ng/mLEligible Diagnoses:
KHE +/- KMP Tufted Angioma +/- KMP Capillary Lymphaticovenous
Malformation (CLVM) Lymphaticovenous Malformation
(LVM) Microcystic Lymphatic Malformation Capillary Lymphatic Arterial Venous
Malformations PTEN Overgrowth syndrome +
vascular anomaly Lymphangiectasia Syndromes
Qualifying Complications: Coagulopathy Chronic pain Recurrent cellulitis (>3/year) Ulceration Visceral and or bone involvement Cardiac dysfunction
Clinicaltrials.gov
Questions• 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
Conclusion
• No patient is exactly the same but patients have similar characteristics
• There are similarities to other vascular anomalies and we can learn from all
• Complicated patients need at least an initial evaluation at a multidisciplinary vascular anomaly center
• LGDA and other parent/patient support groups are wonderful resources
Thank you
Questions?