Lymphangioleiomyomatosis (leiomyomatosis): causes, symptoms, diagnosis, treatment

Lymphangioleiomyomatosis (leiomyomatosis) is a benign proliferation of smooth muscle cells in all parts of the lung, including the pulmonary blood and lymphatic vessels, and the pleura. Lymphangioleiomyomatosis (leiomyomatosis) is a rare disease that occurs exclusively in young women. The cause is unknown. It manifests itself as shortness of breath, cough, chest pain, and hemoptysis; spontaneous pneumothorax often develops.

The disease is suspected based on clinical manifestations and chest X-ray results and is confirmed by high-resolution CT. The prognosis is unknown, but the disease progresses slowly and often leads to respiratory failure and death over a number of years. Radical treatment for lymphangioleiomyomatosis is lung transplantation.

Lymphangioleiomyomatosis (leiomyomatosis), disseminated - a pathological process characterized by tumor-like proliferation of smooth muscle fibers along the small bronchi, bronchioles, walls of blood and lymphatic vessels of the lungs, followed by microcystic transformation of the lung tissue. The disease affects only women aged 18-50 years.

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What causes lymphangioleiomyomatosis?

Lymphangioleiomyomatosis is a lung disease that affects exclusively women, predominantly between the ages of 20 and 40. Caucasians are at highest risk. Lymphangioleiomyomatosis occurs with an incidence of less than 1 in 1 million people and is characterized by benign proliferation of atypical smooth muscle cells in the chest, including the lung parenchyma, blood and lymphatic vessels, and pleura, leading to altered lung architecture, cystic emphysema, and progressive decline in lung function. This disorder is included in this chapter because patients with lymphangioleiomyomatosis are sometimes misdiagnosed as having IBLAR.

The cause of lymphangioleiomyomatosis is unknown. The attractive hypothesis that female sex hormones play a role in the pathogenesis of the disease remains unproven. Lymphangioleiomyomatosis usually occurs spontaneously and has many similarities to tuberous sclerosis. Lymphangioleiomyomatosis also occurs in some patients with TS; therefore, it has been suggested that it is a special form of TS. Mutations in the tuberous sclerosis complex-2 (TSC-2) gene complex have been described in lymphangioleiomyomatosis cells and in angiomyolipomas. These data suggest one of two possibilities:

1. Somatic mosaicism of TSC-2 mutations in the lungs and kidneys leads to the appearance of foci of disease among normal cells of these tissues (while the appearance of isolated areas of disease might be expected);
2. Lymphangioleiomyomatosis is the extension of angiomyolipoma tissue into the lung, similar to that seen in benign metastatic leiomyoma syndrome.

The following pathomorphological signs of the disease are characteristic:

• significant density of the lungs, many small nodules 0.3-0.7 cm in diameter, whitish, filled with fluid, they are located subpleurally;
• the presence of large air cavities in certain areas of the lungs;
• lymph node hyperplasia;
• diffuse proliferation of smooth muscle fibers in the interstitium of the lungs (interalveolar, perivascular, peribronchial, subpleural, along the lymphatic vessels);
• destructive changes in the walls of blood and lymphatic vessels, the walls of the bronchi, and alveoli;
• formation of microcystic "honeycomb" lung;
• development of pneumohemochylothrox due to destruction of the walls of blood and lymphatic vessels of the lungs and rupture of subpleural cysts.

The indicated pathomorphological manifestations are characteristic of the diffuse form of the disease.

The focal form (leiomyomatosis) is characterized by the development of tumor-like formations in the lung parenchyma - leiomyomas.

Symptoms of lymphangioleiomyomatosis

Initial manifestations include dyspnea and, less commonly, cough, chest pain, and hemoptysis. In general, manifestations are usually mild, but some patients may have wheezing or rales. Spontaneous pneumothorax is common. Manifestations of lymphatic duct obstruction, including chylothorax, chylous ascites, and chyluria, may also occur. Worsening is thought to occur during pregnancy and possibly with air travel; the latter is particularly contraindicated with new or worsening respiratory manifestations; history of pneumothorax or hemoptysis; and evidence of extensive subpleural bullous or cystic changes on HRCT. Renal angiomyolipomas (hamartomas composed of smooth muscle, blood vessels, and adipose tissue) occur in 50% of patients and, although usually asymptomatic, can cause bleeding, which, as it progresses, usually presents as hematuria or flank pain.

For a long time the disease is asymptomatic. In the advanced stage, the characteristic symptoms of lymphangioleiomyomatosis are:

• shortness of breath, at first it bothers only during physical exertion, later it becomes constant;
• chest pain that gets worse when breathing;
• hemoptysis (an intermittent symptom);
• recurrent spontaneous pneumothorax - observed in 1/3-1/2 of patients, manifested by sudden intense pain in the chest, shortness of breath, absence of vesicular breathing and a tympanic tone of percussion sound on the affected side;
• chylothorax - accumulation of chylous fluid in the pleural cavity (on one or both sides). As chylothorax develops, dyspnea increases, an intense dull sound appears on percussion over the area of effusion, there is no breathing in this area; chylous fluid accumulates again after its removal. It is characteristic that the development of pneumothorax and chylothorax coincides with menstruation;
• Chylopericarditis and chylous ascites develop as the disease progresses and their appearance also coincides with menstruation;
• development of chronic pulmonary heart disease (for symptoms, see “Pulmonary hypertension”).

The focal form of the disease is asymptomatic and is detected radiologically. In some cases, the disease becomes systemic - leiomyomas develop in the abdominal cavity, retroperitoneal space, uterus, intestines, kidneys.

Pregnancy, childbirth, and taking contraceptives contribute to the activation of the disease.

Diagnosis of lymphangioleiomyomatosis

Lymphangioleiomyomatosis is suspected in young women with dyspnea, interstitial changes, normal or increased lung capacity on chest radiography, spontaneous pneumothorax, and/or chylous effusion. Confirmation of the diagnosis is possible by biopsy, but HRCT should always be performed first. The detection of multiple small, diffusely distributed cysts is pathognomonic for lymphangioleiomyomatosis.

Biopsy is performed only if HRCT results are in doubt. Histologic detection of abnormal smooth muscle cell proliferation (lymphangioleiomyomatosis cells) associated with cystic changes confirms the presence of the disease.

The results of pulmonary function tests also support the diagnosis and are especially useful in monitoring the dynamics of the process. Typical changes include the appearance of obstructive or mixed (obstructive and restrictive) types of disorders. The lungs are usually hyper-aerated, with an increase in total lung capacity (TLC) and chest airiness. Air retention is usually observed (an increase in residual volume (RV) and RV/TLC ratio). PaO2 and diffusion capacity for carbon monoxide are also usually reduced _. Most patients also show a decrease in performance.

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Laboratory diagnostics of lymphangioleiomyomatosis

1. General blood analysis - no significant changes. Some patients have eosinophilia, ESR often increases, especially with the development of pneumo-chylothorax.
2. General urine analysis - minor proteinuria may be observed (symptom is non-specific and inconstant);
3. Biochemical blood test - hypercholesterolemia is sometimes observed, possibly an increase in the level of alpha2- and gamma-globulins, aminotransferases, total lactate dehydrogenase, angiotensin-converting enzyme.
4. Pleural fluid examination. Chylothorax is extremely characteristic of lymphangioleiomyomatosis. Pleural fluid has the following characteristic features:
   • color milky white;
   • the turbidity of the liquid remains after centrifugation;
   • triglyceride content greater than 110 mg%;
   • contains chylomicrons, which are detected by electrophoresis of lipoproteins in polyacrylamide gel.

Instrumental diagnostics of lymphangioleiomyomatosis

1. X-ray examination of the lungs. In the diffuse form of the disease, characteristic X-ray signs are an increase in the pulmonary pattern due to the development of interstitial fibrosis and diffuse multiple small-focal (miliary) darkening. Subsequently, due to the formation of multiple small cysts, a picture of "honeycomb lung" appears.

The focal form is characterized by darkened areas from 0.5 to 1.5 cm in diameter with clear boundaries.

With the development of pneumothorax, a collapsed lung compressed by air is determined; with the development of chylothorax, an intense homogeneous shadow (due to effusion) with an oblique upper border is determined.

2. Computed tomography of the lungs reveals the same changes, but much earlier, including cystic and bullous formations.
3. Study of the ventilation capacity of the lungs. Characteristically, the residual volume of the lungs increases due to the formation of multiple cysts. Most patients also have an obstructive type of respiratory failure (reduced FEV1). As the disease progresses, restrictive respiratory failure (reduced VC) also occurs.
4. Blood gas analysis. As respiratory failure develops, arterial hypoxemia appears, partial oxygen tension decreases, especially after physical exertion.
5. ECG. As the disease progresses, signs of myocardial hypertrophy of the right atrium and right ventricle are revealed (see "Pulmonary hypertension").
6. Lung biopsy. A lung tissue biopsy is performed to verify the diagnosis. Only an open lung biopsy is informative. The biopsy reveals diffuse proliferation of smooth muscle fibers in the pulmonary interstitium.

Screening program for lymphangioleiomyomatosis

1. General blood and urine tests.
2. Biochemical blood test - determination of cholesterol, triglycerides, total protein, protein fractions, bilirubin, transaminases.
3. X-ray examination of the lungs.
4. Pleural fluid examination - assessment of color, transparency, density, cytology, biochemical analysis (determination of cholesterol, triglycerides, glucose).
5. ECG.
6. Ultrasound of abdominal organs and kidneys.
7. Open lung biopsy followed by histological examination of biopsy specimens.

Treatment of lymphangioleiomyomatosis

Standard treatment for lymphangioleiomyomatosis is lung transplantation, but the disease may recur in the graft. Alternative treatments, such as progestin hormonal therapy, tamoxifen, and oophorectomy, are generally ineffective. Pneumothorax can also be problematic because it can recur frequently, be bilateral, and be resistant to standard therapy. Recurrent pneumothoraces require lung decortication, pleurodesis (with talc or other substances), or pleurectomy. In the United States, patients can receive psychological support from the Lymphangioleiomyomatosis Foundation.

What is the prognosis for lymphangioleiomyomatosis?

Lymphangioleiomyomatosis has an unclear prognosis due to the extreme rarity of the disease and the significant variability in the clinical status of patients with lymphangioleiomyomatosis. In general, the disease progresses slowly, eventually leading to respiratory failure and death, but life expectancy varies widely among sources. Patients should be aware that disease progression may accelerate during pregnancy. Median survival is approximately 8 years from diagnosis.