Lymphangioleiomyomatosis

(lim-fam'jē-ō-lī'ō-mī'ō-mă-tō'sis)

George Pappas, M.D., M.P.H.

Swedish Medical Center
Seattle, WA
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• Wiki
– Lymphangioleiomyomatosis (LAM) is a rare lung disease that results in a
proliferation of disorderly smooth muscle growth (leiomyoma) throughout the
lungs, in the bronchioles, alveolar septa, perivascular spaces, and lymphatics,
resulting in the obstruction of small airways (leading to pulmonary cyst
formation and pneumothorax) and lymphatics (leading to chylous pleural
effusion). LAM occurs in a sporadic form, which predominantly affects
females, usually of childbearing age; LAM also occurs in patients who have
tuberous sclerosis.
• Medscape
– Lymphangioleiomyomatosis (LAM) is a rare disorder resulting from
proliferation in the lung, kidney, and axial lymphatics of abnormal smooth
muscle–like cells (LAM cells) that exhibit features of neoplasia and neural crest
origin
 LAM 101
• LAM is a rare disease associated with:
– Damage to the lungs
• Cyst formation
• Blockage of airflow
– Abdominal tumors called angiomyolipomas (AMLs)
• Commonly in kidneys, also liver, spleen
– Abnormal growth and blockage of lymphatic vessels
• Lymphatic tumors called lymphangioleiomyomas
• Collections of a fluid called chyle in the chest and abdomen
 LAM: Symptoms
• Respiratory symptoms
– Shortness of breath
– Chest pain
– Cough
– Wheezing
• Abdominal symptoms
– Flank pain
– Hematuria
– Abdominal bloating/swelling
 Who Gets LAM?
• LAM occurs primarily in premenopausal
women
– LAM can be diagnosed in post menopausal
women (and very, very rarely in men)
• Because it is rare, LAM is often confused with
other more common conditions
– Often years between first symptoms and diagnosis
– Commonly misdiagnosed
 Who Gets LAM?
• “Sporadic LAM”
– Normal genes at birth
– Development of a new genetic abnormality
– Cannot be passed to children
• “TSC LAM” associated with tuberous sclerosis complex
– Abnormal gene present at birth and in all cells of the body
– Often associated with tumors of the skin, brain, kidneys,
lung and heart.
– Involves reproductive cells; has the potential to be passed
to children
Tuberous Sclerosis Complex
 LAM is Rare
• Sporadic LAM prevalence:
– 3.4 to 7.8/1,000,000 women
– Best estimates: 764-1212 patients in the US, of which
half have not been diagnosed
• TSC-LAM associated with tuberous sclerosis
– TSC more common; 1:6000 births
– 88-106/1,000,000
– Cystic lung changes increase with age
• 27% in women under 21
• 81% in women over 40
 Under the microscope
• LAM is characterized by the growth of
abnormal, immature smooth muscle-like cells
called “LAM cells”
• LAM cells are found in the lung, kidneys and
lymphatics.
• LAM cell growth results in lung destruction,
tumor formation and lymph system changes
• These cells are unique to patients with S-LAM
and TSC-LAM. Their origin is unknown
LAM Cells
 LAM Genetics, 101
• It was recognized years ago that there were great
similarities between the changes in lung tissues
of patients with TSC-LAM and S-LAM
• Advances in science allowed for identification of
the gene abnormalities in TSC-LAM
• In the late 1990s, it was shown that the same
genetic abnormalities are present in affected
tissues in S-LAM
• S-LAM and TSC-LAM are caused by mutations in
the tuberous sclerosis genes, TSC-1 and TSC-2
 TSC genes
• TSC genes code for proteins which regulate cell
growth, survival and motility through a pathway
called the mammalian target of rapamycin
(mTOR)
• When TSC genes do not work, the mTOR pathway
runs unchecked resulting in uncontrolled cell
growth and proliferation of abnormal cells—LAM
cells
• Without these regulatory proteins, cells grow
inappropriately, migrate inappropriately and
invade tissues
 Estrogen Effects
• Estrogens appear to:
– Reduce inhibition of cell growth involving the
mTOR pathway
– Enhance production of enzymes which cause lung
damage
– Enhance LAM cell survival in circulation
Reproduced from: Taveira-DaSilva A, Moss J Management of LAM F11000 Prime Reports 2014
 What is LAM?
• LAM is a rare condition which causes lung
damage, tumors and fluid collections
• It is seen both spontaneously and in association
with tuberous sclerosis
• LAM is characterized by the growth and
proliferation of abnormal, immature smooth
muscle-like cells called “LAM cells”
• Mutations in the tuberous sclerosis genes are the
cause of the alterations in cell growth and
behavior
Pulmonary Manifestations of
LAM
Lung Anatomy
 Lung Cysts
• Normal lung tissues are replaced by thin
walled air filled spaces called cysts
• Cysts form due to:
– blockage of airways
– destruction of lung tissues by inflammatory
substances released by LAM cells
• Progressive cystic changes and airway
blockage leads to loss of lung function and
shortness of breath
 Lung Cysts

NORMAL LAM
 Measures of Lung Function
• Forced vital capacity or “FVC”
• The total volume of air you can blow out of your lungs
• Forced expiratory volume in 1 second or FEV1
• How much air you can blow out in 1 second
• Largely dependent on airway diameter
 Measures of Gas Exchange
• Diffusion Capacity to Carbon Monoxide
– “DLCO”
– Measures how long it takes for a small amount of
a tracer gas-carbon monoxide- to be absorbed
into your bloodstream
• Compared to reference populations of normal,
healthy, non smoking people
 Lung Function in LAM
• Changes in lung function are variable and
difficult to predict
• Average annual change in FEV1:
– Normal women lose about 10-25 ml of FEV1 per
year
– Patients who smoke lose about 70 ml per year
– On average, women with LAM lose about 90 ml
per year
– Changes are slower after menopause
 Lung Disease
• Unregulated growth of LAM cells in the lungs
leads to
– Airway changes resulting in airflow blockage
– Release of mediators which cause lung tissue
damage
– Formation of thin walled cysts
• Decline in lung function and shortness of
breath over time
 Pneumothorax
• Rupture of a cyst can result in air leaking into
the space between the lung and chest wall
 Symptoms of Pneumothorax
• Chest pain
– Often sharp, unilateral, worse with cough or
breathing
– Sometimes shoulder pain, back pain
• Shortness of breath
• Rapid heart beat
• Frequent and recurrent in LAM
 Pneumothorax
• Pneumothoraces occur in approximately 60%
of patients with LAM
• The highest among all chronic lung diseases
• Many patients require repeated interventions
and hospitalization at substantial cost
 Pneumothorax Management
• Observation
• Oxygen
• Simple aspiration of air with a needle
• Chest tube suction drainage
 Pneumothorax recurrence
• The recurrence rate following aspiration or
chest tube drainage is about 70%
• Given high rates of recurrence, pleurodesis is
often recommended after the initial event
– Chemical: tetracycline, bleomycin, talc
– Surgical
• Recurrence following chemical or surgical
pleurodesis are 27% and 32%, respectively.
Chylothorax
 Chylothorax
• LAM cells can obstruct lymph flow
• Chyle is a milky, fat rich lymphatic fluid which
flows through the thoracic duct in the chest
• Blockage of lymph flow can result in fluid
collection in the chest called a chylothorax
 Chylothorax Treatment
• Drainage with a needle or tube
• Reduce dietary fats to decrease chyle
formation
• Medications (such as Rapamycin)
• Pleurodesis
• Surgery to ligate the thoracic duct
LAM Outside the Lung
 Renal Angiomyolipomas
• Kidney tumors consisting of blood vessels,
immature muscle cells and fat
• TSC gene mutation is typically present
• S-LAM: 30%; small, often unilateral and
asymptomatic
• TSC-LAM: 90%, bilateral, often large, can be
prone to bleeding
Renal AML
AML: Complications and Treatment
• Many AML do not cause symptoms
• Some AML can cause pain and bleeding, at
times severe
• Bleeding risk increases with tumor size
• Intervention often recommended when they
exceed 4 cm in size
• Multiple AMLs can encroach on normal renal
tissue and compromise kidney function
 AML Treatment
• Embolization—blocking off of the blood
supply to the tumor
• Medications such as sirolimus and everolimus
• Surgery with the goal of removing the tumor
and sparing normal renal tissue
 Lymphangioleiomyomas

• Lymph containing cyst like structures usually

in the abdomen
• Most do not cause symptoms
• Some can cause abdominal bloating or
discomfort
Lymphangioleiomyomas
 Confirmation of Diagnosis
• High resolution CT consistent with LAM
– Lung biopsy consistent with LAM
– Renal angiomylipoma
– Chylous effusion
– Lymphangioleiomyoma
– TSC
– Biomarkers: Vascular endothelial growth factor D
(VEGF-D) can be helpful
 Prognosis
• Average age of diagnosis: 35-40 years old
• Estimated 10 year survival transplant free:
86%
• Estimated transplant free survival time for
LAM patients in the US:
– 29 years from symptom onset
– 23 years from diagnosis
(Lung 2013: 191: 35-42)
LAM Treatment
 General Principles
• Maintain a healthy weight
• Exercise regularly
• Seek evaluation for sudden shortness of
breath or chest pain
• Get Educated about LAM
• LAM Foundation
• See a doctor who knows about LAM
 Estrogen
• The striking predominance of LAM occurring in women
suggests a role for estrogen
• Estrogen exposures have been reported to clinically
accelerate LAM
– pregnancy, oral contraceptives, fertility treatments
• Lab models show estrogens promote LAM cell survival
and spread
• Avoid estrogens
– Estrogen containing contraceptives
– Limit foods which contain plant based estrogens (soy, flax)
– Discuss pregnancy with your physician
 Estrogen and LAM
• Ovarian ablation and progesterone therapy as initial
treatments
– No clear benefit to these modalities in retrospective
studies, but case reports suggest some are helped
– Medical oopherectomy in small studies did not provide
benefit
• Ongoing area of investigation
– Aromatase inhibitors which block estrogen synthesis
outside of the ovaries may play have a role-TRAIL study
– Faslodex, an estrogen receptor blocker, stopped LAM cell
spread and release of destructive mediators in an animal
model
 Medical Therapy: Sirolimus
• Sirolimus (rapamycin) blocks the mTOR pathway
• MILES trial: Treatment with sirolimus for 1 year
– Stabilization of FEV1
– Improvement in quality of life
– Improved functional performance
• Additional trials have shown decrease in size of
AMLs, chylous effusions and
lymphangioleiomyomas
 Sirolimus
• Positive effects on lung function waned after
stopping therapy
• Not everyone improved
• Possible side effects
– Mouth sores, diarrhea, skin rash, high cholesterol,
infection
 Clinical Trials
• Currently/soon enrolling:
– Sirolimus + Hydroxychloroquine: SAIL
– Sirolimus + Simvastatin: SOS
– Saracatanib: SLAM 1
– MIDAS: study of long term suppressive therapy with
sirolimus or everolimus
– MILD: study of low dose sirolimus in patients with
preserved lung function
– Exercise to Enhance Lung Function and Bone Density
in LAM
Siroliumus and Autophagy Inhibition in
LAM: SAIL
• Autophagy refers to the internal breakdown
cell components which leads to recycling of
internal constituents and cell survival during
times of stress
• The autophagy inhibitor hydroxychloroquine
which inhibits autophagy, combined with
sirolimus, will be more effective than either
agent alone in the treatment of LAM
 Sirolimus + Simvastatin: SOS
• In mouse models, simvastatin and sirolimus
displayed additive effects in blocking growth
of LAM lesions
• Simvastatin, a commonly prescribed
cholesterol lowering drug, also decreased
destruction of normal lung tissue
 Saracatinib: SLAM 1
• A protein called Src kinase is active in LAM
cells and is important for cell growth and cells’
ability to move around and invade tissues
• Saracatinib is an experimental drug which
blocks Src kinase activity
• Trial to determine whether the investigational
drug saracatinib is safe in LAM, and whether it
can reduce the growth and the spread of LAM
cells
 Lung transplant
• Lung transplant is a valuable therapeutic option
for patients with end stage LAM
• No one single determinant of transplant need
– Severe disease (FEV1 under 30%)
– Severe exercise limitation
– Hypoxia
– Impaired quality of life
• Transplantation offers survival rates equivalent to
or better than those receiving lung transplant for
other reasons
 Special Thanks
• LAM Foundation
• Dr. Lisa Young, M.D., Joel Moss, M.D., Ph.D.,
Jay Ryu, M.D., Frank McCormack, M.D. and
Simon Johnson, DM, FRCP who gave prior
LAM 101 talks and shared their slides
Thank You!