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?