Treatment
An FDA-approved drug for treatment of LAM, the mTOR inhibitor sirolimus, is available for stabilization of lung function decline. Lung transplant remains the last resort for patients with advanced disease. Pneumothorax
Pneumothoraces in LAM patients tend to recur, especially after conservative management such as observation, aspiration or simple tube thoracostomy. Over 65% of LAM patients develop pneumothorax during the course of their illness, averaging 3.5 pneumothoraces in those who have at least one pneumothorax. The LAM Foundation Pleural Consensus Group advocated the use of a pleural symphysis procedure with the first pneumothorax, given the greater than 70% chance of recurrence. Chemical sclerosis, mechanical abrasion, talc poudrage and pleurectomy have been effective in patients with LAM, but mechanical abrasion is preferred for those who may require pulmonary transplantation in the future. About half of LAM patients who have undergone transplant have had a prior pleurodesis procedure, and more than 75% of those had had prior bilateral pleurodesis. Although pleurodesis is not a contraindication to transplantation, it can result in increased perioperative bleeding. Chylothorax
Chyle does not generally cause pleural inflammation or fibrosis. Small stable chylous effusions rarely require intervention once the LAM diagnosis is made. Shortness of breath may mandate possibly repeated drainage. Sirolimus is effective for chylous effusions and most experts believe it should be used as the first line of therapy. Imaging the source of the leak with heavy T2-weighted MRI or contrast lymphangiography is an advised for refractory effusions. Some leaks are amenable to embolization through catheters threaded from groin lymph nodes into the thoracic duct.
mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. MTORC1 consists of five proteins including Raptor that positively regulate mTOR activity. MTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2 and modulates the assembly of the actin cytoskeleton through Rho GTPases, and Rac1 is required for mTOR activation. In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in LAM induces uncontrolled LAM cell growth and increases LAM cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of LAM cell viability and survival. LAM cells behave, in many ways, like metastatic tumor cells. LAM cells appear to arise from an extrapulmonary source and migrate to the lung. Increased LAM cell migration and invasiveness is rescued by TSC2 re-expression. The cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by LAM cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteinases (MMPs) and their endogenous inhibitors TIMPs. The invasive cell phenotype in LAM is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs.Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM. The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. VEGF-D serum levels are increased in LAM compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögrens syndrome, or Birt–Hogg–Dubé syndrome.