lymphangioleiomyomatosis



OVERVIEW

A rare tumor characterized by diffuse cystic lesions in the lungs often presenting with cough, progressive dyspnea, hemoptysis, spontaneous pneumothorax, celiac disease, and chest painTreatment consists of general, pharmacological, and surgical therapyThe current prognosis is poor

Definition of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM), also known as lymphangioleiomyomatosis, is a rare, low-grade malignant, aggressive, metastatic tumor. It is most often characterized by diffuse cystic lesions in the lungs that cause patients to present with cough and dyspnea.

Almost all LAM occurs in females, especially predominantly in females of childbearing age, and cases of LAM in males are extremely rare [1-3].

Classification

Lymphangioleiomyomatosis is classified according to the presence or absence of a genetic background.

Spreading lymphangioleiomyomatosis (S-LAM): no genetic background, rare.

Tuberous sclerosis-associated lymphangioleiomyomatosis (TSC-LAM): may have multisystemic manifestations, such as neuropsychiatric and skin lesions.

Incidence

The incidence of lymphangioleiomyomatosis in the general population is 1 in a million.

Almost all patients with lymphangioleiomyomatosis are female and usually of childbearing age.

The average prevalence of S-LAM is approximately 4.9 per 1 million female population [4].

The prevalence of TSC in newborns is 1/6,000 to 1/10,000, and about 30% to 40% of adult female TSC patients have combined LAM, and there are also findings that 80% of female TSC patients over the age of 40 years present with cystic changes in the lungs [5-6].

Etiology

The etiology of lymphangioleiomyomatosis is unknown and may be related to genetic mutations.

Pathogenesis

The etiology of lymphangioleiomyomatosis is unknown, and it is hypothesized that estrogen plays a role in its development, but this is not well explained by current studies.

Risk Factors

The following people are at high risk for lymphangioleiomyomatosis:

Women of childbearing age.

Patients with tuberous sclerosis and their immediate family members.

Pathogenesis

The development of lymphangioleiomyomatosis may be associated with mutations in the tuberous sclerosis (TSC) gene.

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. TSC1 and TSC2 proteins act as a complex in vivo to inhibit rapamycin-targeted proteins (mTORs). mTORs are over-activated when TSC1/TSC2 are functionally defective due to genetic mutations, leading to cellular over-proliferation.

The overproliferating smooth muscle-like cells can metastasize to the lungs via the lymphatics and then through the blood circulation, forming LAM foci that are diffusely distributed throughout the lungs, or they can reach extrapulmonary tissues and involve extrapulmonary organs.

Estrogen plays an important role in both the proliferation and metastasis of smooth muscle-like cells. Other causes may include compression of the conducting airways by interstitial smooth muscle proliferation, imbalance of the elastase/α1-antitrypsin system, and metastasis or precursor cell migration of LAM cells that may originate from lymphangioleiomyolipomas.

Symptoms.

Lymphangioleiomyomatosis involves the lung parenchyma in nearly half of the cases and presents with progressive dyspnea (shortness of breath), cough, sputum, spontaneous pneumothorax, hemoptysis, and celiac disease.

Main Symptoms

Progressive dyspnea

The onset of dyspnea is usually insidious and may be preceded by symptoms such as poor activity tolerance. Dyspnea and shortness of breath appear as the disease progresses and worsen progressively.

Cough

The cough is usually mild, dry or with a small amount of white foamy sputum.

Hemoptysis

Common. Gastrointestinal small to moderate amount of hemoptysis, individual large amount can cause asphyxia.

Spontaneous pneumothorax symptoms

Pneumothorax symptoms are often the first symptom of lymphangioleiomyomatosis and can be recurrent.

It occurs in more than half of patients. The main manifestation is sudden chest pain, followed by chest tightness and dyspnea with an irritating dry cough.

Celiac Chest Symptoms

Celiac chest is also often the first symptom of lymphangioleiomyomatosis and is recurrent.

It is seen in 20% to 30% of LAM patients. It manifests as chest tightness, shortness of breath, dyspnea, palpitations, and weakness.

Chest pain.

Lymphangioleiomyomatosis may also present with symptoms such as chest pain.

Other symptoms

Extrapulmonary symptoms

Extrapulmonary manifestations of lymphangioleiomyomatosis mainly include angiosmooth muscle lipoma, extrapulmonary lymphangioleiomyoma, and lymphadenopathy.

Angio-smooth muscle lipomas are most commonly found in the kidneys, and a few patients may present with spleen and liver involvement.

Extrapulmonary lymphangio-smooth muscle tumors tend to present as retroperitoneal or pelvic masses, and a small number of patients may present with abdominal symptoms (e.g., bloating, abdominal pain, etc.) as their first symptom.

Lymphadenopathy most often presents with multiple enlarged lymph nodes in the thoracic and abdominal cavities.

Symptoms associated with tuberous sclerosis

LAM associated with tuberous sclerosis (TSC) has other multisystemic clinical features of TSC.

Neurologic changes: e.g. epilepsy, neurodevelopmental delay and autism.

Skin changes: e.g., depigmentation, facial angiofibromas, cutaneous shark leather spots, and perinail fibromas.

Seek medical attention

Symptoms related to lymphangioleiomyomatosis require active medical attention. Doctors will ask about clinical manifestations, medical history, previous examinations and medications.

Department of Medicine

Respiratory Medicine

When symptoms such as progressive dyspnea, chest tightness and coughing occur, it is recommended to consult a respiratory physician promptly.

Emergency Department

When symptoms such as dyspnea and severe chest pain occur, consult the Emergency Department.

Preparation

How to prepare for your visit: registering, preparing documents, and common problems.

Tips for medical treatment

Chest X-ray or chest CT is often needed, so avoid wearing underwear made of metal, and inform your doctor if you are pregnant or planning to become pregnant.

Preparation List

Symptom list

Pay special attention to the time of onset of symptoms, special manifestations, etc.

Is there wheezing, chest tightness? Cough?

How long have the symptoms been present?

Under what circumstances do the symptoms worsen or lessen?

Is there chest pain or hemoptysis?

Is there abdominal pain?

Is there any abnormality in the urine? Is there celiac disease?

Are there skin changes?

Are there seizures?

Are there neuropsychiatric changes?

Medical History Checklist

Is there a history of tuberous sclerosis?

Are there any members of the immediate family with tuberous sclerosis?

Checklist

Test results from the last 6 months, which can be brought to the doctor’s office

Laboratory tests: routine blood tests, arterial blood gas analysis, serum vascular endothelial growth factor-D (VEGF-D). Anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, blood sedimentation.

Imaging examination: chest CT examination, abdominal CT examination.

Pulmonary function tests: pulmonary ventilation function test, peak expiratory flow rate (PEF) and its variability determination, bronchodilator test.

List of medications used

Medication used in the last 3 months, if available in boxes or packages, carry with you to the doctor’s office

Bronchodilators: salbutamol, terbutaline, aminophylline, ipratropium bromide, etc.

Diagnosis

Diagnosis of lymphangioleiomyomatosis can be made on the basis of history, clinical presentation, serum vascular endothelial cell growth factor-D, and high-resolution CT of the chest.

Diagnosis is based on

Medical history

Female of childbearing age.

Self or immediate family members with tuberous sclerosis.

Clinical manifestations

Progressively worsening dyspnea and recurrent pneumothorax, celiac chest and occasional hemoptysis are present.

Abdominal pain, abdominal distension, celiac ascites, and abdominal masses are present with abdominal involvement.

Laboratory Tests

Serum vascular endothelial growth factor-D (VEGF-D): has diagnostic value, and serum VEGF-D ≥ 800 ng/L is now considered one of the diagnostic criteria.

Imaging

Chest high-resolution CT (HRCT)

The most diagnostically suggestive manifestation is diffuse thin-walled cystic changes in both lungs on high-resolution CT (HRCT) of the chest.

The shape, size, and contour are quite variable, ranging from 2 to 5 mm in diameter and occasionally up to 30 mm. the sacs are usually round, evenly distributed throughout the lungs, and spaced from normal lung parenchyma. The thickness of the sac wall fluctuates to 2 mm in the majority of cases.

Abdominal CT

CT scanning of the abdomen may reveal angiomyolipomas, lymphovascular smooth muscle tumors, or enlarged lymph nodes and is used to support the diagnosis, guide treatment, and provide follow-up.

Cranial magnetic resonance imaging

Sporadic lymphangioleiomyomatosis increases the risk of developing meningiomas and therefore needs to be screened for exclusion.

Progesterone promotes meningioma growth, and the presence of meningiomas should be confirmed in patients receiving progesterone therapy.

Lung Function Tests

Lung function assessment is important to understand the changes in the patient’s condition, and patients are usually advised to have their lung function checked regularly, including lung volume, ventilation, diastolic test and diffusion function.

Early lung function is not significantly impaired. Decrease in diffusion function occurs earlier, and as the disease progresses obstructive ventilatory dysfunction and increased residual air volume can occur.

The absolute value and annual rate of decline of first-second forced expiratory lung volume (FEV1) are of great clinical value in determining the severity of the disease and assessing the response to treatment.

Arterial Blood Gas Analysis

Patients with lymphangioleiomyomatosis frequently present with arterial hypoxemia. Arterial blood gas analysis is useful in determining the indications for oxygen therapy, for preoperative evaluation of lung transplantation, and for ruling out hypercapnia.

Pathologic Diagnosis

Pulmonary or extrapulmonary pathologic diagnosis is the gold standard for diagnosing lymphangioleiomyomatosis. However, not all patients require pathologic confirmation of the diagnosis, and the diagnosis can be made with typical clinical syndromes and presenting features.

Pathologic features in the lungs show multiple air sac cavities and abnormally proliferating spindle-shaped smooth muscle-like cells (also known as LAM tumor cells) under the microscope.

Immunohistochemistry shows positive staining for anti-smooth muscle actin (SMA) antibodies and positive melanoma-associated antigen HMB45, often accompanied by estrogen and progesterone receptor positivity.

Diagnostic criteria

Clinical history consistent with lymphangioleiomyomatosis and characteristic high-resolution CT features of the chest with one or more of the following:

Tuberous sclerosis (TSC).

Renal angio-smooth muscle lipoma (AML); and

Serum vascular endothelial cell growth factor-D (VEGF-D) ≥ 800 ng/ L;

Celiac chest or celiac ascites;

Lymphangioleiomyoma;

Atypical smooth muscle-like cells or clusters of atypical smooth muscle-like cells found in the plasma lumen fluid or lymph nodes;

Histopathologically confirmed lymphangioleiomyomatosis (lung, retroperitoneal or pelvic tumor).

Differential diagnosis

Lymphangioleiomyomatosis should be differentiated from the following diseases:

Pulmonary Langerhans cell histiocytosis

Similarities: both may have cystic lesions in the lungs.

Differences: pulmonary Langerhans’ cell histiocytosis occurs in young and middle-aged male smokers, and the lung lesions are predominantly located in the middle and upper lobes of the lungs, with irregular sac sizes and combined nodular shadows.

Lymphocytic interstitial pneumonia

Similarities: both may present with progressive dyspnea and cough.

Differences: Lymphocytic interstitial pneumonia occurs more often in middle-aged and elderly women and is associated with immune dysfunction. It can be differentiated by imaging.

Centralized lobar emphysema

Similarities: Both may present with cough and dyspnea after activity.

Differences: Centralized lobar emphysema is characterized by dilated alveoli of the respiratory bronchioles. Most of the patients have a history of long-term, heavy smoking combined with chronic bronchitis. It can be differentiated by imaging.

Pulmonary fibrosis

Similarity: both may present with dyspnea.

Differences: Pulmonary fibrosis refers to a type of lung disease caused by the accumulation of fibroblasts and a large amount of extracellular matrix in the lung tissue, accompanied by inflammatory damage and destruction of the tissue structure. Imaging manifests as diffuse shadows in both lungs, either striated or ground glass [7].

Bronchiectasis

Similarities: Both may present with cough and dyspnea.

Differences: Bronchiectasis is the deformation and persistent dilatation of the bronchial tubes due to chronic suppurative inflammation and fibrosis of the bronchial tubes and their surrounding tissues, which destroys the muscular and elastic tissues of the bronchial walls. It can be differentiated by imaging.

Treatment

Treatment aims: to prevent disease progression and further development of pulmonary symptoms.

Treatment principle: mainly general treatment, drug treatment and surgical treatment.

General treatment

Treatment of dyspnea

Symptoms of dyspnea also gradually worsen during disease progression.

If the patient has a therapeutic response to bronchodilators, they should be recommended.

Oxygen therapy should be given if significant hypoxemia is present.

Management of Pneumothorax, Celiac Chest and Renal Vascular Myolipoma

Pneumothorax is one of the common symptoms of lymphangioleiomyomatosis, and pleural fixation is feasible at presentation.

Patients with celiac disease should be put on a low-fat diet, and medium-chain triacylglycerol + growth inhibitors can be used to treat celiac disease.

Asymptomatic renal angioleiomyolipomas <4 cm in diameter do not require treatment but should be examined by ultrasound annually; if the tumor is >4 cm in diameter or the renal arterial aneurysm is >5 mm in diameter, there is an increased risk of hemorrhage, and ultrasound should be performed twice a year to assess growth. Arterial embolization is the first-line treatment for renal angiomyolipoma bleeding.

Drug therapy

mTOR inhibitors

Abnormal activation of the mTOR pathway is one of the pathogenetic mechanisms of lymphangioleiomyomatosis, and therefore inhibition of the mTOR pathway has become a treatment for LAM [8].

The main mTOR inhibitor is sirolimus.

The main side effects of sirolimus include hyperlipidemia, elevated liver enzymes, fever, stomatitis, lung infections, acne, diarrhea, headache, edema, vaginal bleeding, and urinary tract infections, which need to be strictly used under medical supervision.

In cases of surgery, pregnancy and severe infections, it is recommended to temporarily discontinue the use of sirolimus.

Other drugs

Clinical trials of the aromatase inhibitor letrozole are underway in patients with postmenopausal lymphangioleiomyomatosis, and may be expected to lead to new advances in the treatment of the disease.

Recent studies have found that statins such as simvastatin, autophagy inhibitors such as chloroquine and hydroxychloroquine, and tyrosine kinase inhibitors such as axitinib and doxycycline may have a role in lymphangioleiomyomatosis, but further basic and clinical studies are still needed [9].

Surgical treatment

Lung transplantation is an effective treatment for patients with advanced disease, and surgical treatment with lung transplantation may be necessary for patients with end-stage severe lymphangioleiomyomatosis.

Indications

Lung transplantation should be considered for patients with cardiac function class III or IV according to the New York Heart Association (NYHA) with hypoxia at rest and severe pulmonary function and exercise tolerance impairment (maximal oxygen uptake less than 50% of predicted value).

Precautions.

Patients presenting with renal angiomyolipoma should seek preoperative evaluation and those at risk for bleeding should be treated prior to transplantation.

The same immunosuppressive drug regimen should be used postoperatively as for patients receiving lung transplantation for other indications.

Treatment Considerations

Patients with lymphangioleiomyomatosis also need to be careful:

Maintain a normal work life as much as possible.

Maintain a balanced diet.

Maintain a normal weight.

Avoid smoking.

Flu and pneumonia vaccinations can help reduce the incidence of lung infections.

Air travel: Air travel is allowed for patients with mild or stable symptoms; if you have had a recent pneumothorax or have not fully recovered from chest surgery (which usually takes several weeks), you will need to avoid air travel for a while.

Avoid estrogenic medications, including oral contraceptives and hormone replacement therapy. Exogenous estrogens may accelerate disease progression in some patients.

Prognosis

There is no cure for lymphangioleiomyomatosis and most patients will continue to have a decline in lung function.

Cure

The prognosis for lymphangioleiomyomatosis is generally poor and there is currently no cure [10].

The 10-year survival rate is 80% to 90% from the onset of symptoms and approximately 70% from the date of diagnosis on lung biopsy.

Hazards.

Because there is no effective treatment for lymphangioleiomyomatosis, most patients have a persistent decline in lung function, and as the disease progresses, dyspnea becomes more severe and may eventually lead to life-threatening respiratory failure.

The risk of exacerbation and complications increases with pregnancy, and the decision to become pregnant requires individualized assessment and consideration. Lymphangioleiomyomatosis is not a contraindication to pregnancy, but a thorough evaluation of the patient’s condition, treatment status, risk of complications (pneumothorax, celiac disease, renal or retroperitoneal tumor bleeding), and appropriate countermeasures are required.

Daily routine

Patients with lymphangioleiomyomatosis need to stay away from smokers and estrogen products in their daily lives, avoid lung infections, closely monitor their condition, and follow their doctor’s instructions for regular follow-up.

Daily management

Smoking cessation can slow down the progression of the disease and relieve symptoms, in addition, should stay away from smokers.

Infections such as influenza, pneumonia and COVID-19 can seriously damage the lungs and should always be prevented by vaccination.

Lymphangioleiomyomatosis is prevalent in women of childbearing age and is prone to negative feelings of depression and anxiety. Patients need to be helped to relieve them effectively. Adequately give patients affirmation and encouragement to improve their self-confidence and motivation to cooperate with nursing care [11].

Avoid the use of high levels of estrogen (present in many contraceptive products).

Patients at risk of pneumothorax should avoid deep-sea diving and air travel.

Disease monitoring

If symptoms such as dyspnea worsen, seek prompt medical attention.

Follow-up review

Timing of review: Evaluation every 6 to 12 months; immediate consultation is recommended if symptoms such as coughing and sudden onset of dyspnea occur on a daily basis.

HRCT and abdominal ultrasound will be performed to assess disease progression, lung function, quality of life, and treatment options.

Prevention

There is no effective method of prevention for this disease. Disseminated lymphangioleiomyomatosis is not a genetic disease, but tuberous sclerosis is a hereditary disease. Patients with tuberous sclerosis need to receive appropriate genetic counseling and guidance on prenatal diagnosis before pregnancy.