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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 Children’s Hospital Debra Boyer, MD Pulmonary Liaison Vascular Anomaly Clinic Boston Children’s 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 Post-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. 

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

6 Vascular Anomalies: Lymphatic
Tumors Kaposiform Hemangioendotheliomas Lymphangiosarcoma Combined Malformations Venous/Lymphatic Capillary/Venous/Lymphatic Lymphatic Malformations Macrocystic Microcystic Diffuse Numerous subsets of lymphatic Anomalies Combined CVLM Cap Ven Lymph Malformations Tumors – KHE - spindle cell tumor w/ lymphatic component with proliferation of the lymphatics, the more lymphatic component the higher the mortality Lymphatic Anomalies Macrocystic Microcystic Gorham 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

7 Vascular 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 Syndrome Capillary venous lymphatic malformation (CVLM) – mostly lymphatic Macrocystic lymphatic malformation Really 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.

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 Malformations Kaposiform Hemangioendothelioma Lymphangiosarcoma 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 At 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

26 The mTOR pathway Tie-2 there were already several lines of evidence to suggest the importance of the mTOR pathway in vascular anomalies when we began using sirolimus.

27 Summary of first 6 patients treated with sirolimus
Age Gender Diagnosis Affected Locations Previous 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) 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 CLVM Lung Liver Left lower extremity Pelvis/buttocks LMWH Ibuprofen Surgical debulking Sclerotherapy Decreased blebbing, leaking Drain removal Decreased leg circumference 4 14 years Chylous pleural effusion Spleen Bone lesions Chest Tube Pleurodesis Ligation of the thoracic duct Resolution of pleural effusion Stabilization of bony lesions 5 Bilateral pleural effusions Pericardial effusion Resolution of effusions 6 7 months Bilateral chylous pleural effusions Bone lesions T11-L4 Intraabdominal VATS x2 Ligation of thoracic duct Pericardial window 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 As 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.

28 Summary of first 6 patients treated with sirolimus
Demographics Gender: 3 male, 3 female Age: 7 months to 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 Our 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.

29 Patient 6: Microcystic Lymphatic Malformation
Improvement in his abdominal/pelvic disease Before sirolimus therapy 16 months on sirolimus therapy

30 Patient 6: Bony Lesions Before sirolimus therapy
And gradual improvement in multiple vertebral 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 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 In summary Our patients were treated for an average of 21 months With average follow up of 43 months 4 of 6 patients have required re-treatment, with 3 still on sirolimus once daily dosing giving them drug levels of 3 to 4

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 We 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 life Sirolimus 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 cure Further 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

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 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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