Pulmonary lymphangioleiomyomatosis (PLAM) is a clinically rare disease that can be sporadic or accompanied by the genetic disease tuberous sclerosis complex (TSC). Sporadic PLAM occurs almost exclusively in women of reproductive age. Pathology is characterized by diffuse or nodular proliferation of smooth muscle-like cells (LAM cells, HMB-45) in the alveolar walls, bronchiolar walls, and vascular walls, leading to localized emphysema or thin-walled cyst formation, and ultimately extensive honeycomb lung.
Etiology
The etiology is not yet very clear, and its onset is related to the following factors.
TSC genes
The onset of LAM is closely related to TSC. TSC is an autosomal hereditary disease caused by mutations in the TSC1 and TSC2 genes. LAM can be divided into TSC-LAM, in which patients are with TSC; and sporadic LAM (S-LAM), in which patients are without TSC. The onset of TSC-LAM and S-LAM is related to mutations in the TSC1 or TSC2 genes. The TSC gene is a tumor suppressor gene, and the TSC1/TSC2 protein it encodes regulates downstream signals by combining into a functional complex. LAM patients have mutations in the TSC1 or TSC2 gene, which leads to functional defects in the encoded protein, causing continuous activation of the mammalian target of rapamycin kinase (mTOR) pathway, thereby promoting cellular hyperplasia, differentiation, and adhesion, and leading to inappropriate cellular hyperplasia, migration, and invasion.
Estrogen effect
Most LAM patients are women of reproductive age, and when pregnant or using estrogen drugs, symptom exacerbation suggests estrogen may play an important role in the onset of LAM. Estrogen receptors have been confirmed in LAM tissues.
Lymphatic system
LAM often involves the lymphatic system, and LAM tissues are rich in lymphatic vessels. Vascular endothelial growth factor (VEGF)-D is a lymphatic growth factor, and the serum VEGF-D level in LAM patients is significantly elevated.
Pathology
PLAM reveals pulmonary diffuse interstitial lesions; abnormal hyperplasia of immature smooth muscle around the interstitial lung, bronchi, blood vessels, and lymphatic vessels; airway obstruction causing alveolar dilation and diffuse cystic air cavities; pulmonary artery smooth muscle hyperplasia, luminal stenosis, pulmonary hypertension; and obstruction and dilation of pulmonary lymphatic vessels and thoracic ducts. It is often accompanied by extrapulmonary lymphadenopathy, medial LAM, and renal angiomyolipoma. Immunohistochemistry shows positive anti-smooth muscle antibody and positive anti-human melanoma black-45 antibody. Most LAM cells express estrogen or progesterone receptors.
Clinical manifestations
The main clinical manifestations are progressive exacerbation of dyspnea, recurrent pneumothorax and chylothorax, and occasionally hemoptysis. Pulmonary function test shows airflow limitation and gas exchange disorder, sometimes accompanied by restrictive ventilation dysfunction.
Chest HRCT characteristically shows variously sized, thin-walled cysts (2 - 20 mm in diameter) diffusely distributed in both lungs. The main difference between LAM and PLCH on CT is that PLCH generally does not affect the costophrenic angle, the cyst wall is thicker, and there are more nodules in the early stage.
Diagnosis
Patients with characteristic HRCT manifestations can be diagnosed with PLAM, and lung biopsy is not required.
Treatment
mTOR inhibitors (sirolimus, everolimus) are currently preferred for the treatment of LAM. Sirolimus can stabilize lung function, improve quality of life, reduce chylous ascites, reduce the volume of renal AML, and reduce serum VEGF-D. The treatment regimen is sirolimus orally 2mg/d. The dose needs to be adjusted by monitoring the whole blood drug trough concentration, treatment response, and adverse reactions.
In patients with dyspnea, inhaled bronchodilators can improve symptoms.
If pneumothorax occurs, appropriate needle aspiration or thoracotomy and closed drainage should be given; thoracoscopic pleurodesis is recommended for patients with recurrent pneumothorax.
In patients with chylous ascites, a low-fat or fat-free diet or medium-chain fatty acid is recommended.
Home oxygen therapy is recommended for patients with hypoxemia.
Drugs and foods containing estrogen should be avoided.
Pregnancy can exacerbate the disease and increase the risk of complications. Pregnancy requires individualized evaluation and consideration.
When accompanied by renal angiomyolipoma, observation, sirolimus treatment, interventional embolization, and renal preservation surgery should be selected.
When lung function is severely impaired in the late stage, lung transplantation should be evaluated. Lung transplantation is used in patients with advanced LAM, with a 5-year survival of about 65%.