Lymphangioleiomyomatosis is a disease that occurs as a result of tumor–like proliferation of smooth muscle fibers along the course of small bronchi, lymphatic and blood vessels, leading to cystic transformation of the pulmonary parenchyma and damage to the lymphatic system. It develops mainly in women of childbearing age. It is manifested by progressive shortness of breath, recurrent pneumothorax and chylothorax. Diagnosis is based on CT data of the thoracic and abdominal cavities, the results of a lung biopsy. Conservative treatment with bronchodilators, progesterone is carried out, long-term oxygen therapy is prescribed. Surgical correction of complications is performed.
J84.8 Other specified interstitial lung diseases
Lymphangioleiomyomatosis (lung leiomyomatosis, diffuse pulmonary lymphangiectasia) occurs as an independent pathology or becomes one of the manifestations of a genetic disease – tuberous sclerosis. It is rare. The incidence is 1-2 cases per 500,000 women aged 16 to 55 years. Among patients suffering from tuberous sclerosis, lymphangioleiomyomatosis is detected in 20-40% of fertile women, in isolated cases – in men and children. It is often combined with uterine leiomyomas (fibromyomas), kidney angiomyolipomas and meningiomas. In 40% of patients, the development of spontaneous pneumothorax debuts. It worsens during pregnancy and when taking estrogen-containing drugs.
The etiology of the disease has not been established. It is assumed that there is an abnormal reaction of smooth muscle cells to the release of female sex hormones, primarily estrogen. This theory is confirmed by the activation of the pathological process in the premenstrual period, exacerbation during pregnancy and against the background of oral contraceptives, stabilization in menopause. The combination of lung leiomyomatosis with uterine fibromatosis also testifies in favor of the hormonal basis of this pathology. Lymphangioleiomyomatosis may have genetic causes or occur against the background of impaired immune functions.
Experts believe that there are a number of defective genes encoding the pathological response of smooth muscle cells to the level of estrogen in the blood. As a result, estrogens stimulate the proliferation of atypical smooth muscle (leiomyomatous) cells and ensure their migration to other organs. With leiomyomatosis, such cells acquire the ability to invasive growth and metastasis, the proliferation of smooth muscle fibers resembles a tumor process. Invasion of atypical cells into the lymphatic system causes lymphadenopathy.
In the lung, clusters of actively multiplying leiomyomatous cells are localized around bronchioles, arterioles and venules, in the pleura. The lumen of the bronchioles gradually narrows. Their patency is disrupted, which leads to the formation of small cysts. Rupture of subpleurally located cysts provokes pneumothorax. Due to the cystic transformation of the alveolar tissue, gas exchange is disrupted, respiratory failure develops. Compression of the walls of small blood vessels by leiomyomatous fibers leads to pulmonary hypertension, followed by the formation of a pulmonary heart disease. The germination of the pleura and lymphatic vessels potentiates the chylothorax. Leiomyomatous nodes located in the area of the lymphatic vessels of the abdominal cavity and pelvis become the cause of chyletic ascites.
There are lymphangioleiomyomatosis associated with tuberous sclerosis and an independent variant of the disease. Mainly the respiratory organs are affected, but the pathology is systemic. The process often involves the organs of the abdominal cavity, pelvis, meninges. Depending on the prevalence , the following forms of the disease are distinguished:
- Focal. It is characterized by the presence of single leiomyomatous foci (hamartomas). It proceeds asymptomatically, is detected during preventive examinations.
- Diffuse. Multiple lesions of pulmonary and extrapulmonary localization are detected. The disease is steadily progressing, leading to respiratory and cardiovascular insufficiency.
Symptoms of lymphangioleiomyomatosis
In the initial stage, lymphangioleiomyomatosis proceeds covertly. Changes in the lungs are detected accidentally when undergoing an X-ray examination for another reason. Later, the main clinical symptom of the disease becomes increasing shortness of breath. At first, it occurs with significant physical exertion – running, fast walking, climbing the stairs to the 3rd floor and above. Over time, breathing difficulties progress, the tolerance of physical exertion gradually decreases. In the terminal stage, shortness of breath bothers the patient even at rest.
Chest pains are unstable and increase with deep breathing. In some patients, the disease is manifested by recurrent pneumothorax. This condition is characterized by sudden sharp intense pain on the side of the lesion, suffocation. Periodically, a chylothorax occurs, accompanied by an increase in shortness of breath, a feeling of heaviness in the lower parts of the chest. Pathognomonic for pulmonary leiomyomatosis is the connection of hemoptysis, accumulation of chyletic effusion or air in the pleural cavities with the menstrual cycle. Increased shortness of breath, the presence of blood in sputum, increased episodes of chilo- and pneumothorax are observed during pregnancy and while taking estrogenic drugs.
In addition to chylothorax, lymphangioleiomyomatosis in the late stages is often complicated by recurrent accumulation of chylus in the pericardium and chyletic ascites. Pregnancy and childbirth aggravate the course of the pathological process. In a number of patients, angiomyolipomas of the kidneys are detected, sometimes meningiomas. The growth of a tumor of the meninges causes an increase in intracranial pressure and compression of the brain. Against the background of cystic transformation of the lungs, a chronic pulmonary heart is gradually formed, respiratory and circulatory insufficiency progresses.
Anamnestic data, belonging to the female sex and features of clinical manifestations give the pulmonologist the opportunity to suspect lymphangioleiomyomatosis. There are a number of certain large and small criteria, the combination of which helps to confirm the diagnosis. The presence of such diagnostic criteria in the patient is established by:
- CT of the thoracic cavity. High-resolution CT scans reveal multiple small (from 3 to 30 mm) rounded air cysts. They have a thin wall, evenly located in the thickness of the alveolar tissue. There are no other pathological changes in the pulmonary interstitium.
- Laboratory tests. When analyzing pleural effusion and (or) ascitic fluid, the chyletic nature of the exudate is determined. Modern studies in the field of pulmonology have revealed an increase in vascular endothelial growth factor in the blood serum of patients. In the near future, it is planned to use this factor in the diagnosis of lymphangiomyomatosis as a marker.
- Methods of functional diagnostics. Spirometry is auxiliary in nature, allows you to determine the degree of respiratory failure and the rate of progression of the disease. Obstructive and mixed disorders of the function of external respiration are revealed. ECG data indicate signs of hypertrophy of the right parts of the heart.
- Additional research. CT scan of the abdominal cavity allows you to detect angiomyolipomas of the kidneys, lymphadenopathy. MRI of the brain often confirms the presence of meningiomas. Ultrasound examination of the pelvis in women determines single or multiple uterine fibromyomas.
Lymphangioleiomyomatosis should be differentiated with sarcoidosis, disseminated tuberculosis, histiocytosis X, some tumor processes, diseases of the hematopoietic organs. The patient may need to consult an oncologist, hematologist, phthisiologist, gynecologist. Lung biopsy with immunohistochemical examination of the obtained material is often performed to clarify the diagnosis.
Treatment for lymphangioleiomyomatosis
Etiotropic therapy of the disease has not been developed. Promising experimental studies of the action of inhibitors of enzymes regulating cell growth are being conducted. Rapid progression of pathology is an indication for the use of progesterone. In case of pulmonary heart failure, inhalation bronchodilators, oxygen therapy, cardiotropic agents are prescribed. Treatment of pneumothorax against the background of pulmonary leiomyomatosis is carried out by a thoracic surgeon. Chemical pleurodesis is carried out. With recurrent accumulation of air in the pleural cavity, a pleurectomy is performed. In the last stage of the pathological process, transplantation of one or both lungs is possible.
Prognosis and prevention
The focal form of the disease does not pose a danger to the patient and does not affect the quality of his life. Diffuse pathology gradually leads to respiratory heart failure and disability of the patient. Lymphangiomyomatosis on the background of tuberous sclerosis proceeds more favorably than sporadic. The prognosis for life largely depends on the patient’s compliance with medical recommendations and timely medical correction of complications. There is no primary prevention of the disease. Patients are advised to refrain from pregnancy and taking estrogens. It is undesirable to use air transport, since air travel can provoke relapses of pneumothorax. In order to prevent chylothorax, a low-fat diet is prescribed. Patients need to stop smoking, get vaccinated against influenza and pneumococcal infection.
Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis.PLoS One. 2014 Oct 27;9(10):e104809. doi: 10.1371/journal.pone.0104809. eCollection 2014.PMID: 25347447 Free PMC article. link
Mutational analysis of the tuberous sclerosis gene TSC2 in patients with pulmonary lymphangioleiomyomatosis.J Med Genet. 2000 Jan;37(1):55-7. doi: 10.1136/jmg.37.1.55.PMID: 10633137 Free PMC article. link
Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis.Proc Natl Acad Sci U S A. 2000 May 23;97(11):6085-90. doi: 10.1073/pnas.97.11.6085.PMID: 10823953 Free PMC article. link
Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2.Pathol Int. 2001 Aug;51(8):585-94. doi: 10.1046/j.1440-1827.2001.01242.x.PMID: 11564212 Review. link