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 .

3. CXR

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
Clinicaltrials.gov

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?