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Lymphatic Anomalies: Classification, Lung Involvement, and New Treatment Options Denise M. Adams, MD Medical Director Hemangioma and Vascular Malformations.

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Presentation on theme: "Lymphatic Anomalies: Classification, Lung Involvement, and New Treatment Options Denise M. Adams, MD Medical Director Hemangioma and Vascular Malformations."— Presentation transcript:

1 Lymphatic Anomalies: Classification, Lung Involvement, and New Treatment Options Denise M. Adams, MD Medical Director Hemangioma and Vascular Malformations Center, Cincinnati Childrens Hospital Debra Boyer, MD Pulmonary Liaison Vascular Anomaly Clinic Boston Childrens Hospital

2 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


4 Case Presentation

5 Vascular Anomalies Tumors Malformations Mulliken & Glowacki. Plast Recon Surg 1982 Low FlowHigh Flow

6 Vascular Anomalies: Lymphatic Tumors – Kaposiform Hemangioendotheliomas – Lymphangiosarcoma Combined Malformations – Venous/Lymphatic – Capillary/Venous/Lymphatic Lymphatic Malformations – Macrocystic – Microcystic – Diffuse

7 Vascular Anomalies with Lymphatic Components

8 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

9 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

10 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

11 Risk Stratification Presentation at a young age Female gender Cervical spine involvement Thoracic soft-tissue involvement Fluid complication: pleural effusion, pericardial effusion, ascites

12 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

13 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.

14 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

15 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

16 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

17 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

18 Pulmonary Manifestations

19 Effusions Pleural Pleural and pericardial Chylous/Lymphatic Hemorrhagic Fluid: pleural, pericardial, ascites

20 Parenchymal Lung Disease Kaposiform Lymphangiomatosis Lymphangiectasia Soft tissue Lymphatic malformation (usually microcystic)

21 Evaluation CT MRI Lymphangiograms Pulmonary Function Tests

22 Treatment Treat the anomaly: medicine, intervention, surgery Pulmonary medications Respiratory therapy Physical therapy Lung transplant

23 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?

24 Medical Treatment in the Literature Interferon/Bisphosphonates Chemotherapy agents (vincristine, cytoxan) Anti-angiogenic agents

25 Submitted December 2010

26 The mTOR pathway Tie-2

27 Summary of first 6 patients treated with sirolimus Patient Age Gender DiagnosisAffected LocationsPrevious Treatment(s)Results 1 10 months Female KHE + KMP Abdomen Back Chest Left leg Pelvis Retroperitoneum Steroids Vincristine Cyclophosphamide Interferon Bevacizumab Embolization Resolution of KMP Resolution of high-output cardiac failure Improvement in size and color of lesion 2 6 years Male LM Pleural effusion Mediastinum Paraspinal Bone lesions Cutaneous (chest/back/shoulder) Interferon Celecoxib Thoracoscopic decortication Pleurodesis Chest tubes Resolution of pleural effusions Decrease in size/discoloration of lesion Stabilization of bony lesions Improvement in pain scale score 3 6 years Male CLVM Lung Liver Left lower extremity Pelvis/buttocks Retroperitoneum LMWH Interferon Ibuprofen Surgical debulking Sclerotherapy Decreased blebbing, leaking Drain removal Decreased leg circumference 4 14 years Female LM Chylous pleural effusion Mediastinum Spleen Bone lesions Chest Tube Pleurodesis Ligation of the thoracic duct Celecoxib Resolution of pleural effusion Stabilization of bony lesions 5 14 years Female LM Bilateral pleural effusions Pericardial effusion Bone lesions Chest tubes Interferon Celecoxib Resolution of effusions Stabilization of bony lesions 6 7 months Male LM Bilateral chylous pleural effusions Bone lesions T11-L4 Liver Intraabdominal Spleen VATS x2 Pleurodesis Ligation of thoracic duct Pericardial window Chest tubes Resolution of pleural effusions and respiratory failure Near-complete resolution of abdominal lesions Normalization of PT, PTT, fibrinogen Improvement in bony lesions Improvement in gross motor skills

28 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

29 Patient 6: Microcystic Lymphatic Malformation Before sirolimus therapy 16 months on sirolimus therapy

30 Patient 6: Bony Lesions Before sirolimus therapy 16 months on sirolimus therapy

31 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

32 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

33 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/mL Eligible 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

34 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

35 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

36 Thank you Questions?

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