What Is Lymphangioleiomyomatosis?

Pulmonary lymphangioleiomyomatosis (PLAM)

Lymphangioma

Lymphatic leiomyoma (LAM) is a systemic disease with an unknown etiology that causes the bronchial, lymphatic, and small blood vessels to become blocked due to abnormal smooth muscle proliferation.

Introduction to Lymphatic Leiomyoma

Pulmonary lymphangioleiomyomatosis (PLAM)

Occurs in women aged 16-68, especially women of childbearing age, with an incidence rate of about 0.029 to 1 per million. The lungs are the most susceptible and often manifest as diffuse interstitial lung disease, so LAM is often referred to as lymphangioleiomyomatosis. The disease mainly occurs in menopausal women. Clinically, there are often symptoms of dyspnea, spontaneous pneumothorax, and chylothorax. Typical chest imaging shows diffusely distributed thin-walled small cysts in the lungs.

Causes of Lymphangioma

unknown. Many studies have suggested that this disease is related to tuberous sclerosis syndrome.

The pathogenesis of lymphatic leiomyoma

Currently unknown

Lymphatic leiomyoma pathology

The naked eye shows that the lung tissue is often a diffuse honeycomb structure, which appears as cysts of varying sizes, with a diameter of about

Lymphangioma

About 1cm.

Microscopically, the early stage of the lesion was that immature smooth muscle cells accumulated on the outer bronchial epithelium, alveolar wall, and pleura. Alveolar capillaries were not involved.

In the late stage of the disease, due to the accumulation of muscle cells, collagen deposition increased and nodules were formed, and edema, bleeding, and macrophages decreased.

The damaged alveoli can fuse with each other to form a sac. The sac wall is lined with flat epithelium and ciliated epithelium, and the nodules can protrude into the sac, alveoli and bronchioles, making these walls thicker and structurally disordered.

Widely distributed cysts on the surface of the lungs are caused by dilated lymphatic vessels forming alveolar-like lesions on the muscular and parietal pleura. The new atypical smooth muscle cells mainly occur in the lymphatic vessels, bronchial vascular bundles, and small veins. They can also extend to the alveoli and the interstitial space of the lung, which can cause obstruction and expansion of the lumen. Form diffuse cysts that can be diffused by the terminal air cavity, with a diameter of 0.1cm to several centimeters. Atypical proliferating cells are similar to vascular smooth muscle, but are slightly shorter and polymorphic, which is a polyclonal nature. A certain level of hemosiderin was seen in the tissue, which was caused by a small amount of bleeding caused by dilated and distorted small veins. Lymphatic and ductal expansion and distortion, hilum. Lymph nodes of the mediastinum and posterior ventral wall are often involved and enlarged. The thoracic duct can thicken and expand, and chylous chest appears after obstruction. Vascular leiomyomas often occur at the same time in the thoracic organs such as the kidney, the posterior abdominal wall, the abdominal cavity and the pelvic cavity. Lymphatic leiomyomas can be divided into two phases: Early stage: atypical smooth muscle cells are present outside the terminal bronchioles, alveolar walls, and pleura. Macrophages; late stage: collagen-forming nodules appear, alveoli expand significantly. Smooth muscle hyperplasia is obvious, full spindle shape with round or oval nucleus, pale cytoplasm. At the same time, most of the horn cells were seen, and the cytoplasm was clearly epithelial cells.

The abnormally proliferating smooth muscle cells have special cytological morphology and heterogeneous gene appearance. Three different cell types can be seen in LAM nodules: larger epithelioid cells are located on the periphery of the nodules, while smaller cells are centered. In addition to morphological differences, LAM cells can be stained with anti-human melanoma antibodies (HMB-45) and metalloproteinases (MMPs) to show different immunophenotypes. Different protein particles exist in these cells: smooth muscle-specific -actin, vimentin, and desmin show different immunohistochemical staining responses suggesting heterogeneity of smooth muscle origin. Under electron microscopy, LAM cells are also different from normal smooth muscle cells. The nucleus is round or oval, multi-notch, obvious nucleoli, contains dense body formed by microfilament matrix components and well-developed endoplasmic reticulum. A finely crystalline layered body is composed of many electron-bound film-bound particles. Similar cells are also found in angiomyolipoma of the kidney and liver, and clear cell tumors of the lung. Heterogeneity of LAM cells has led people to hypothesize that the pathogenesis of LAM may be related to blood vessel or vessel-related cell types like tumor-like abnormal differentiation and proliferation . HMB-45 is a monoclonal antibody purified from melanoma hybridomas. Pathology is used for the diagnosis of malignant melanoma. Positive staining in LAM cells. HMB-45 binds to 10kD glycoproteins (Pmel17 and GP100). HMB-45 positive is found in malignant melanoma and other cell line-derived melanomas, such as LAM, angiomyolipoma and clear lung tumors, and tuberous sclerosis syndrome (TSC), suggesting that it may originate from common precursor production Cross reaction. HBM-45 has been used in 5 cases of LAM known to be confirmed by histology, all of which have positive results, while 15 cases of primary spontaneous pneumothorax, emphysema, Langerhan histiocytosis, and IPF have negative results.

Clinical features of lymphatic leiomyoma

1. Dyspnea, which progresses slowly, is the main symptom of PLAM.

Lymphangioma

2. Repeated spontaneous pneumothorax can be unilateral and bilateral. It has been reported in the literature that about 95% of patients have spontaneous pneumothorax as the first symptom.

3. Dry cough, rare chest pain, chylothorax exudation, blood in sputum and wheezing.

4. Extrapulmonary symptoms include chyluria, chylopericardial effusion, and chylous ascites.

5. Others: Some patients can find uterine fibroids or renal angiomyolipoma, and changes in lung function: often obstructive ventilation dysfunction and diffuse dysfunction.

Lymphangioleiomyoma Epidemiology

No exact incidence has been reported outside China. The disease was first recorded from 1937 to 1997, with more than 300 cases reported worldwide. The Denver Interstitial Disease Research Center in the United States only reported 16 cases in 10 years, accounting for <1% of diffuse pulmonary interstitial disease, so LAM is considered a rare disease. There are scattered cases reported in China. Six cases of LAM were diagnosed pathologically from 1997 to 2000 in the Department of Respiratory Medicine, Drum Tower, Nanjing Hospital, and the disease may not be uncommon. The low diagnosis rate in the past was mainly related to insufficient understanding of its clinical characteristics and insufficient advanced diagnostic methods. Non-lymphatic leiomyomas occur almost exclusively in premenopausal women, 70% of them occur between the ages of 20 and 40, and only 5% occur after the age of 50. Very few cases occur after menopause, but how often do these patients receive estrogen therapy?

The pathogenesis of lymphatic leiomyoma

The cause of LAM is unknown, and many facts suggest that the disease may be related to estrogen. The disease does not occur before menarche, and it is rare after menopause. A small number of postmenopausal cases often have a history of estrogen supplementation. The disease worsens during pregnancy and decreases after oophorectomy. In cases of tuberous sclerosis with lung disease, women have a clear advantage, and living tissues have also confirmed that estrogen and progesterone are affected.

Lymphangioma

body. However, the results of anti-estrogen therapy, such as bilateral ovarian resection, radiation therapy, and progesterone, are not satisfactory, indicating that the pathogenesis of lymphatic leiomyomatosis is related to estrogen and other important factors. .

As for the formation of pulmonary cysts caused by pulmonary interstitial smooth muscle hyperplasia and the causes of similar emphysema, it is not clear. Some scholars believe that it is caused by smooth muscle compression and conduction of airways, but it is controversial. It is also considered that the "ball-valve" obstruction effect of smooth muscle hyperplasia in the airway is the main cause of terminal air cavity expansion. The imbalance of the elastin / 1-antitrypsin system, which leads to the degeneration of elastic fibers, may be the main cause of pulmonary cysts and emphysema-like changes.

Imaging Features of Lymphatic Leiomyoma

CT Lymphatic leiomyoma CT

The lungs are diffusely uniformly distributed, with well-defined circular or polygonal thin-walled uniformly spaced airbag cavities, with clear edges, and the normal lung leaflet structure is submerged by the sac cavity. Most sacs are a few millimeters to 5cm in size, often about 1cm in thickness. Uniform, without obvious interstitial fibrosis and nodular shadows, may have mediastinal lymphadenopathy, may be accompanied by pneumothorax, chylothorax, evenly distributed in the lung parenchyma, there is no tendency to occur in the periphery of the lung, and the sac wall is smooth. The density is slightly higher.

X Lymphatic leiomyoma chest x-ray

The chest radiographs of patients with lymphatic leiomyomas show great differences, and there may be no obvious abnormalities at early stages, or they may show ground glass shadow. With the development of the disease, diffuse small nodules gradually appear, ranging from miliform to medium-sized nodular or reticular nodules. At the same time, there are irregular reticles and line-shaped shadows, which are distributed uniformly. These shadows may be caused by multiple cystic cavity compression of hypertrophic smooth muscle. Early lung volume is normal. With the development of the disease, a small number of cystic changes can be seen in the lung field. Generally, chest radiographs can be displayed when the cyst diameter is> 1 cm. The formation of a large number of lung cysts can significantly increase the lung volume, similar to emphysema, and lymphatic obstruction can form the KeleyB line. At the same time, unilateral or bilateral pleural fluid can be seen, often chylous, with large amounts and repeated occurrences. Chylous pleural fluid can also occur in the case of uninvolved lungs, with a high incidence of spontaneous pneumothorax, and lymphangiography can detect retroabdominal wall lesions.

CTHRCT CT and HRCT of lymphatic leiomyoma

It is an important method for the diagnosis of lymphangioma. Chest CT, especially HRCT, can clearly show pulmonary cysts that are unclear on ordinary chest radiographs. The pulmonary cysts of lymphatic leiomyomas have significant characteristics. They are thin-walled cysts of uniform size distributed throughout the lung, with a diameter of 0.5 to 5 cm, and the thickness of the cyst wall is generally <2 mm. Early cysts are small and become larger as the disease progresses. The incidence of this type of cyst is 100%, which is an important basis for the diagnosis of lymphangioma. About 50% of patients have ground-glass shadows at an early stage. Only about 5% of those who can see the nodular shadow on CT are caused by the enlarged cysts compressing the surrounding smooth muscle cells. If there are flaky shadows, bleeding is indicated. In 8 of the 8 patients with LAM reported by Sherrier et al., Mediastinal lymphadenopathy was found. The quantitative measurement of cyst area by HRCT is consistent with the measurement of lung volume, diffuse function, and severity of disease evaluated by exercise tests, so HRCT can be used for diagnosis and prognosis. CT or HRCT can detect lesions in the posterior abdominal wall, abdominal cavity, kidney, and pelvis.

Lymphatic leiomyoma lung function test

LAM is one of the few interstitial lung diseases with reticulated nodules, increased lung volume, and obstructive or mixed ventilation dysfunction. LAM lung function manifests as an increase in total lung capacity (TLC), an increase in residual gas (RV) and RV / TLC, a common limitation of airflow, a decrease in forced ventilation (FEV1), vital capacity, and FEV1 / FVC in the first second. Pulmonary mechanics manifests as a decrease in the average elastic retraction force and an increase in upstream resistance. Loss of elastic retraction force and increased pulmonary resistance can cause airflow restriction.

Gas exchange abnormalities often occur in LAM, Dlco is significantly reduced, and PA-aO2 is increased. Most patients have reduced exercise work, reduced oxygen consumption, and reduced anaerobic domains. Exercise can lead to faster breathing rates, increased minute ventilation, and decreased respiratory reserve. Exercise restriction also has a significant impact on athletic ability. Due to restricted airflow (decreased ventilation) and pulmonary vascular dysfunction or damage, many LAM patients have severely impaired motor performance.

Differential diagnosis of lymphangioma

Mainly from clinical manifestations (reproductive age women, recurrent pneumothorax history, LAM often accompanied by abdominal changes) + cystic shadow characteristics (similar in size, no knot outside the capsule, no artery inside the capsule, normal lung between the capsule, thin wall, more uniform distribution ) + Less interstitial fibrosis performance

(1) Fibroalveolar inflammation and end-stage fibrosis (honeycomb lung): The diameter of the cystic air cavity is 1mm ~ 2.5mm, the distribution is irregular, the wall is thick and the irregular lobular interval thickens. The lung volume was reduced, the branches expanded and the structure was obviously deformed, and the peripheral subpleural changes were obvious.

(2) Neurofibromatosis: cystic airspace can also be seen in this disease, but its distribution is different from LAM. The cystic airspace is located at the tip of the lung with enhanced basal line texture.

(3) Bronchiectasis: The cystic cavity is distributed along the bronchus, and the wall is thick and often fluid. The cystic shadow is rare around the lungs, which is enough to distinguish it from LAM.

(4) Pulmonary histiocytosis X: Similar to LAM, but there are multiple nodular shadows at the same time as cystic shadows, there are holes in the nodules, nodules in the lung interstitial, reticular changes, and nodules and sac-like The lesions were mostly located in the upper lobe of both lungs, without chylous pleural effusion.

(5) Emphysema: Similar to LAM, it is more difficult to identify. However, emphysema lacks thickening of the lobular septum, and the residual lobular structure can be seen in the center of most cystic low-density areas.

The wall, vascular shadow is located outside the edge of the cystic shadow, and generally has no extra large cystic cavity (similar to a bullosa-like change). Combining clinical history, age, and gender can help

do not.

(6) Nodular sclerosis: It is a systemic disease. When it invades the lungs, it has pathological features in common with LAM. It is reported in the literature that it can coexist with LAM, and some people think that LAM is a frustrating type of tuberous sclerosis. The pulmonary manifestations of the two are similar, but some authors believe that they are two different diseases, but they cannot be distinguished by imaging. Nodular sclerosis mainly involves vascular smooth muscle and rarely invades lymphatic vessels and lymph nodes. Therefore, chyle Chest is rare. In addition, the disease has a genetic predisposition to extrapulmonary multitubular lesions.

Lymphatic leiomyoma treatment

No specific treatment is currently available.

(1) Symptomatic and supportive treatment

(2) hormone therapy

(3) Lung transplant

There is no satisfactory treatment for this disease. Glucocorticoids and cytotoxic agents are not effective. Angonin progesterone is 400 mg per month or 400 mg intramuscularly every 2 months, and 10 to 20 mg per day is optional, but the effect is not ideal. Tamoxifen and progesterone-releasing hormone have also been used in the treatment of this disease, but the effect is not certain. Ovariectomy combined with progestin has a positive effect over single treatment. Lung transplantation has been used to treat this disease in more than 60 cases worldwide, and 50% of patients can survive for 3 years. LAM has also been reported in transplanted lungs. The natural course of the disease is progressive and the prognosis is poor. The median survival time is 8 to 10 years. Most of the patients die of respiratory failure. Occasionally, they survive for 20 years. In the later stages of the disease, there may be acute exacerbations, and pregnancy and estrogen can make the disease worse. Pulmonary function and histopathology can suggest prognosis. An increase in total lung volume and a decrease in FEV1 / FVC indicate a short survival time. Histopathology of a cystic to a major muscle type is worse than a prognosis.

Lymphatic leiomyoma prognosis

The prognosis of this disease is poor. Most patients develop progressive pulmonary dysfunction within 1-2 years after diagnosis, and eventually die of respiratory failure.

The imaging manifestations of pulmonary lymphangioleiomyomatosis and histiocytosis X are similar. The former is more common in women of childbearing age and is often accompanied by chylothorax.

treatment:

1: symptomatic treatment;

2: Hormonal therapy. Progesterone is reportedly the first choice, followed by glucocorticoids;

3: ovary removal;

4: lung transplantation

The prognosis is poor and most are related to death within 10 years of the onset of symptoms.