Lymphangioleiomyomatosis (LAM): Definition and Clinical Features
Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease characterized by the proliferation of abnormal smooth muscle-like cells in the lungs and lymphatic system, primarily affecting women of childbearing age and causing cystic lung destruction, recurrent pneumothorax, and chylous effusions. 1
Epidemiology and Pathophysiology
- LAM occurs in two forms: sporadically or in association with tuberous sclerosis complex (TSC), with sporadic LAM affecting approximately 1 in 400,000 adult females 1
- In patients with TSC, LAM occurs in 30-40% of adult females and rarely in males and children 1
- The disease is driven by mutations in TSC1/2 genes, resulting in constitutive activation of the mammalian target of rapamycin (mTOR) pathway 1
- LAM demonstrates a strong female predominance, suggesting hormonal influence in disease progression, with estrogen potentially driving LAM cell proliferation, migration, and metastasis 2
Clinical Presentation
- Progressive dyspnea on exertion is the most common symptom, often worsening during periods of high estrogen levels 1, 2
- Recurrent pneumothorax occurs frequently and can be the initial presentation 1
- Chylous collections in the chest and abdomen may develop due to lymphatic obstruction 1
- Occasional hemoptysis may occur 1
- Extra-pulmonary manifestations include:
- Symptoms may begin or worsen during pregnancy or estrogen replacement therapy 3
Diagnosis
- Diagnosis is made through a combination of:
- Clinical history and high-resolution computed tomography (HRCT) showing characteristic thin-walled cysts with diffuse distribution 1
- Tissue biopsy (lung, lymph nodes, or lymphangioleiomyomas) when necessary 1
- Pathological confirmation with LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies 1
- For patients with characteristic cystic changes on CT but without other confirmatory features, vascular endothelial growth factor D (VEGF-D) testing is recommended before proceeding to diagnostic lung biopsy 1
- Confirmatory features include TSC, angiomyolipomas, chylous effusions, or cystic lymphangioleiomyomas 1
Treatment
- Sirolimus (an mTOR inhibitor) is strongly recommended for patients with LAM who have abnormal or declining lung function 1
- Sirolimus is also suggested for selected patients with problematic chylous effusions before invasive management 1
- Supportive care includes:
- Hormonal therapies (including progestins, GnRH agonists, tamoxifen, and oophorectomy) are NOT recommended due to lack of evidence of effectiveness 1
- Doxycycline is NOT recommended for treatment of LAM 1
Prognosis
- Modern data suggests better survival than previously thought, with estimated median transplant-free survival of 29 years from symptom onset and 23 years from diagnosis 4
- The estimated 10-year transplant-free survival is approximately 86% 4
- Oxygen requirement is associated with worse outcomes (HR 4.53) 4
- Disease progression varies significantly between individuals, with some experiencing rapid decline and others having stable disease for many years 1
- Lung transplantation may be considered for patients with advanced disease 4
Monitoring
- Regular assessment of pulmonary function, particularly FEV1 and diffusing capacity (DLCO), is important for monitoring disease progression 5
- DLCO may be a more sensitive marker for early disease changes, while FEV1 tends to correlate with larger cystic changes 5
LAM remains a challenging disease with variable presentation and progression, requiring specialized care and regular monitoring. Early diagnosis and appropriate treatment with sirolimus can significantly improve outcomes and quality of life.