1. Lymphangioleiomyomatosis (lim-fam'jē-ō-lī'ō-mī'ō-m ă -tō'sis) George Pappas, M.D., M.P.H. Swedish Medical Center Seattle, WA

2. Google Search 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.lung diseasesmooth muscleleiomyomabronchiolesalveolar septalymphaticspneumothoraxlymphaticschylouspleural effusion 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

3. 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

4. LAM: Symptoms Respiratory symptoms – Shortness of breath – Chest pain – Cough – Wheezing Abdominal symptoms – Flank pain – Hematuria – Abdominal bloating/swelling

5. 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

6. 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

7. Tuberous Sclerosis Complex

8. 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

9. 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

10. LAM Cells

11. 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

12. 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

13. 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

14. Reproduced from: Taveira-DaSilva A, Moss J Management of LAM F11000 Prime Reports 2014

15. 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

16. Pulmonary Manifestations of LAM

17. Lung Anatomy

18. 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

19. Lung Cysts NORMAL LAM

20. 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

21. 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

22. 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

23. 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

24. Pneumothorax Rupture of a cyst can result in air leaking into the space between the lung and chest wall

25. 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

26. 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

27. Pneumothorax Management Observation Oxygen Simple aspiration of air with a needle Chest tube suction drainage

28. 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.

29. Chylothorax

30. 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

31. 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

32. LAM Outside the Lung

33. 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

34. Renal AML

35. 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

36. 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

37. Lymphangioleiomyomas Lymph containing cyst like structures usually in the abdomen Most do not cause symptoms Some can cause abdominal bloating or discomfort

38. Lymphangioleiomyomas

39. 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

40. 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)

41. LAM Treatment

42. 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

43. 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

44. 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

45. 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

46. Sirolimus Positive effects on lung function waned after stopping therapy Not everyone improved Possible side effects – Mouth sores, diarrhea, skin rash, high cholesterol, infection

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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

53. Thank You!