1. Lymphangioleiomyomatosis(LAM) Department of pulmonology R4 이민혜 MGR Review 1

2. Introduction Rare disease Young women of childbearing age Proliferation of atypical pulmonary interstitial smooth muscle cells and by cyst formation Significant airflow limitation  misdiagnosed as asthma or COPD Occur sporadically or in association with tuberous sclerosis LAM 2 J Clin Invest 2012;122;3807-16.

3. Epidemiology Incidence and prevalence : unknown Prevalence Sporadic LAM : ~1 in 400,000 adult females Tuberous sclerosis-associated LAM : much more common, 30-40% of adult females Caucasians >> other racial groups Menarche ~ menopause, Mean age of onset being 34yrs LAM 3

4. Pathology Proliferation of atypical smooth muscle and epithelioid cells around bronchovascular structures and into the interstitium Immunohistochemistry stains Melanocytic markers : HMB-45, Melan-A, tyrosinase, microphthalmia transcription factor, NKI/C3 Muscle markers : smooth muscle actin, pan-muscle actin, muscle myosin, calponin Distorted by multiple small cysts, ranging from 0.1 cm to several centimeters in diameter Diffuse, cystic dilatation of the terminal airspaces LAM 4

5. Pathogenesis The pathogenesis of LAM is unknown LAM Loss of tumor suppression functions Abnormalities in the synthesis of catecholamines LAM phenotype : not entirely clear 5

6. Pathogenesis LAM Chest 2008;133:507-16. 6

7. Pathogenesis LAM 7 J Clin Invest 2012;122;3807-16.

8. Symptoms and signs LAM Progressive dyspnea (70%) Spontaneous pneumothorax Wheezing Cough Hemoptysis Phlegm Physical examination End-expiratory crackles (22%) Hyperinflation Decreased or absent breath sounds Ascites Intraabdominal or adnexal masses Clubbing (5%↓) 8

9. Pulmonary function PFT : "obstructive" or "mixed" pattern Hyperinflation Total lung capacity (TLC)↑ Residual volume(RV)↑, RV/TLC ratio↑  gas trapping Airflow limitation DLCO↓↓ Alveolar-arterial oxygen difference↑ Bronchodilator responsiveness to albuterol varied from visit to visit A slightly greater number of patients showed reversibility with ipratropium than albuterol LAM 9

10. Imaging Chest X-ray Normal(early in the course of the disease) Interstitial opacities(reticular or nodular) that result from the compression of smooth muscle-rich interstitial tissue by more dilated, cystic airspaces Hyperinflation(33-62%) with severe emphysematous-like changes in advanced disease HRCT Very useful Much more sensitive than routine chest radiography in demonstrating the cystic nature of the disease Diffuse, homogeneous, small, thin-walled cysts (ie, 2-40mm in diameter and walls from 0.1-2mm in thickness) scattered throughout both lung fields Close correlation between the extent of the cystic parenchymal changes and disease severity Both a diagnostic and a prognostic role Abdominal-pelvic CT Identify renal angiomyolipomas, enlarged pelvic lymph nodes, and lymphangioleiomyomas LAM 10

11. Diagnosis LAM Eur Respir J 2006;27;1056-65. 11

12. Diagnosis LAM Characteristic histologic findings Immunohistochemical stains (actin, desmin, or HMB-45) Improve diagnostic sensitivity and specificity 12

13. Complications Spontaneous pneumothorax(50%) Chylothorax Chyloperitoneum(10%), Chylyria(2%), Chylopericardium(rarely reported) Lymphangioleiomyoma Renal angiomyolipomas Hemoptysis LAM 13

14. Prognosis Variable Progression is common Median survival of 8 to 10 years from diagnosis Sudden onset of rapid deterioration rarely complicates Pregnancy and the use of supplemental estrogen  accelerate the disease process Monitoring the response to treatment : difficult and has not been well studied  the need for further study Lung function studies (spirometry, lung volumes to assess the degree of airflow obstruction and hyperinflation) Measure gas exchange (diffusing capacity and arterial blood gases) Serial HRCT scan : useful since the abnormalities can be quantified LAM 14

15. Management LAM Chest 2008;133:507-16. 15

16. Management Hormonal manipulation Oophorectomy : not recommended, morbidity and a lack of proven benefit Progestin therapy  High dose medroxyprogesterone acetate, IM depot or PO  Tamoxifen  Luteinizing hormone-releasing hormone (LHRH) analogs Sirolimus(rapamycin): inhibitor of the mTOR Lung transplantation Considered in patients with progressive disease and severe disability (FEV1,30% predicted) and those dependent on oxygen Lung function and quality of life after transplant are improved compared with patients with advanced LAM LAM NEJM 2011;364:1595-606. 16

17. Management LAM Pregnancy To avoid pregnancy because the disease progresses during pregnancy Air travel The risk of spontaneous pneumothorax during air travel is low Recommendation : air travel should be avoided by women who have  New or worsening respiratory symptoms (breathlessness or chest pain)  A history of a pneumothorax or hemoptysis  Evidence of extensive subpleural bullous or cystic changes 17

18. Future directions in therapy LAM 18 J Clin Invest 2012;122;3807-16.