Lymphangioleiomyomatosis (LAM) is a rare, progressive disease that primarily affects the lungs, almost exclusively in women of childbearing age. It is characterized by the abnormal, uncontrolled proliferation of smooth muscle-like cells, known as LAM cells. These cells spread throughout the lungs, lymphatic system, and sometimes the kidneys. This proliferation leads to the formation of numerous thin-walled cysts that destroy normal lung tissue. As the disease advances, this cystic destruction progressively impairs lung function, leading to breathing difficulties and serious complications.
The Biological Basis of LAM
The underlying cause of LAM involves mutations in the TSC1 or TSC2 genes, which are associated with Tuberous Sclerosis Complex (TSC). These genes normally act as tumor suppressors, producing hamartin and tuberin proteins. This hamartin-tuberin complex regulates the mechanistic Target of Rapamycin (mTOR) signaling pathway, a central control point for cell growth and proliferation.
When a mutation occurs, the hamartin-tuberin complex becomes dysfunctional. This removes the inhibitory brake on the mTOR pathway, resulting in the hyperactivation of mTOR Complex 1 (mTORC1). This hyperactivation drives the uncontrolled growth and survival of LAM cells, which are thought to be metastatic and spread through the lymphatic and vascular systems.
A strong hormonal influence is evident, as LAM predominantly affects women during their reproductive years. The abnormal LAM cells express receptors for estrogen and progesterone. Estrogen is believed to stimulate the growth and survival of these cells, explaining why the condition can worsen during pregnancy or with the use of exogenous estrogen.
Clinical Manifestations
Progressive shortness of breath (dyspnea) is the most common symptom, initially occurring with physical exertion and gradually worsening. Other respiratory symptoms include a persistent cough and wheezing, sometimes leading to misdiagnosis as asthma or emphysema. These symptoms arise because growing lung cysts diminish the functional capacity of the lungs.
A significant complication is a pneumothorax (collapsed lung), which occurs when a cyst ruptures and air leaks into the space around the lung. This event causes sudden chest pain and rapid breathlessness; approximately two-thirds of women with LAM experience at least one pneumothorax. Extrapulmonary manifestations are also common, including benign fatty tumors called angiomyolipomas (AMLs) in the kidneys.
Most kidney AMLs are small and asymptomatic. However, larger tumors (typically exceeding 3 or 4 centimeters) risk hemorrhage, causing severe flank pain and hematuria (blood in the urine). Lymphatic system involvement can also lead to the accumulation of chyle, a milky, fat-rich fluid. This manifests as chylothorax (fluid around the lungs restricting breathing) or chylous ascites (fluid accumulating in the abdomen).
Diagnostic Procedures
Diagnosis is established through imaging, blood tests, and clinical findings. High-resolution computed tomography (HRCT) of the chest is the most accurate non-invasive imaging technique. It reveals the characteristic pattern of numerous, uniform, thin-walled cysts scattered throughout both lungs. HRCT findings are highly suggestive but are usually not sufficient for a definitive diagnosis alone.
A blood test measuring the serum level of Vascular Endothelial Growth Factor D (VEGF-D) is a non-invasive tool used for confirmation. A VEGF-D level greater than 800 pg/mL, combined with a characteristic HRCT scan, is considered diagnostic for LAM and often eliminates the need for a lung biopsy. This biomarker reflects lymphatic involvement and is elevated in approximately 60% of patients.
If imaging is ambiguous or the VEGF-D level is not elevated, a lung biopsy may be necessary to identify the abnormal LAM cells. Diagnosis can also be confirmed by typical lung cysts on HRCT combined with other clinical features, such as kidney angiomyolipomas or chylous effusions. Abdominal imaging is often performed to screen for these kidney tumors, supporting the overall diagnosis.
Management and Therapeutic Interventions
The standard of care focuses on stabilizing lung function and managing complications. The pharmacological cornerstone is the use of mTOR inhibitors, such as sirolimus (rapamycin). Sirolimus directly targets the overactive mTOR signaling pathway in LAM cells, suppressing their growth and proliferation.
Sirolimus treatment stabilizes the rate of decline in lung function and can shrink kidney angiomyolipomas and resolve chylous effusions. Since this treatment is suppressive, not curative, it must be taken long-term to maintain disease control. Everolimus, another mTOR inhibitor, is also used, particularly for managing kidney tumors, but sirolimus is the primary agent for pulmonary LAM.
Supportive care addresses respiratory symptoms and acute complications. Patients may receive inhaled bronchodilators to improve breathing. Oxygen therapy is introduced as the disease progresses and blood oxygen levels drop.
For recurrent pneumothorax, pleurodesis is recommended to prevent future lung collapses. This procedure involves instilling an irritant between the lung and chest wall to create scar tissue, permanently adhering the lung to the chest wall. Lung transplantation is considered for advanced disease when lung function is severely compromised despite medical management.