Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (lim-FAN-je-o-LI-o-MI-o-ma-TO-sis), or LAM, is a rare lung disease that most commonly affects women in their early forties.

In LAM, an unusual type of cell begins to grow out of control throughout the body, including the lungs, lymph nodes and vessels, and kidneys. Over time, these LAM cells form [[cysts]] (fluid-filled sacs) and clusters of cells, which grow throughout the lungs and slowly block the airways. They also destroy the normal lung tissue and replace it with cysts. As a result, air cannot move freely in and out of the lungs, and the lungs cannot supply enough oxygen to the body's other organs.

People with LAM also may develop:

• Growths in other organs, including the liver and brain
• Large tumors on their lymph nodes

There currently is no cure for LAM.

Types

There are two forms of lymphangioleiomyomatosis (LAM):

Sporadic LAM

Sporadic LAM occurs for unknown reasons.

Tuberous sclerosis LAM

Tuberous sclerosis LAM is an often milder form that occurs in people with a rare inherited disease called tuberous sclerosis complex.

Signs and Symptoms

The signs and symptoms of lymphangioleiomyomatosis (LAM) are caused by the uncontrolled growth of the LAM cells.^[1] The most common signs and symptoms are:

• Shortness of breath, especially following exertion. At first, patients may feel short of breath only during strenuous activity. Over time, they may also have trouble breathing at all times, even when resting.
• Chest pain, usually caused by a collapsed lung (pneumothorax).
• Frequent cough, sometimes with bloody phlegm.

LAM also can lead to other serious conditions:^[2][3]

• About six of every seven women with LAM develop a collapsed lung (pneumothorax) at some point. Sometimes one lung will collapse over and over again. Both lungs can collapse too. This is a serious condition that can be life-threatening. A lung that is only partly collapsed may slowly re-expand without treatment, but treatment is often required.
• In one out of every three women with LAM, a fatty fluid called chyle, or lymph, leaks into the chest cavity and builds up.
• Nearly half of the women with LAM develop growths called angiomyolipomas in their kidneys.

Many patients with LAM also have:

• Blood or lymph in their sputum
• Blood in their urine
• Enlarged lymph nodes
• Abdominal swelling

Other diseases can cause many of these signs and symptoms and complications. It is thought that many more cases of LAM exist than are diagnosed, since the illness can mimic other conditions such as chronic obstructive pulmonary disease or bronchiectasis.

Causes

Researchers do not know what causes lymphangioleiomyomatosis (LAM), or why it affects mostly women. They have recently discovered that LAM has some of the same features as another rare disease called tuberous sclerosis complex (TSC).^[4] This discovery has begun to provide some valuable clues about what causes LAM.

The common features of LAM and TSC are:

• People with TSC develop growths in their kidneys that are the same as the angiomyolipomas that many people with LAM develop in their kidneys.
• About one out of every three women who has TSC develops cysts in her lungs that are the same as the ones women with LAM develop in their lungs.

TSC is a genetic disease. It is caused by abnormalities, or defects, in one of two genes. These genes are called TSC1 and TSC2. Normally, they make proteins that control the growth of the cells in the body. In people with TSC, the genes are abnormal, and the proteins that they make cannot control cell growth and movement.

LAM patients also have abnormal versions of the TSC1 and TSC2 genes, and researchers have discovered that these genes play a role in the development of LAM. More research on the TSC genes and the proteins that they make should shed new light on the causes of LAM.

Since LAM mostly affects women in their mid-forties, and the vast majority of women sufferers are pre-menopausal, many doctors think that estrogen also plays a role in causing LAM.

Diagnosis

Methods for diagnosing lymphangioleiomyomatosis (LAM) have improved, and it is now possible to diagnose the disease at an earlier stage. Many of the signs and symptoms of LAM can be caused by other diseases such as asthma, emphysema, and bronchitis. It is important to rule out those conditions before a final diagnosis is made.

• Chest x-ray. A chest x-ray takes a picture of the heart and lungs. It can show a collapsed lung or fluid in the chest cavity. In the early stages of LAM, the chest x-rays may look normal, but as the disease gets worse, they may show cysts in the lungs.
• Pulmonary function tests. For these tests, the patient breathes through a mouthpiece into a machine called a spirometer. The spirometer measures the amount of air inhaled and exhaled and how fast the lungs move it in and out. These tests also can provide an estimate of the amount of air that the lungs can hold, and how well they can take oxygen into the bloodstream.
• Exercise stress test. This test helps the doctor evaluate the effect of exercise on a patient's heart and lungs.
• Blood tests. The doctor takes a sample of blood from an artery in the arm and examines it to see whether the lungs are providing enough oxygen to the blood. These tests may show low oxygen levels in the blood even when patients are resting. The doctor also may take a blood sample from a vein in the arm to look at the blood cells and blood chemistry.
• Pulse oximetry. A small sensor attached to the fingertip also can give an estimate of the level of oxygen in a patient's blood.

High-resolution CT scan of the chest shows multiple bizarrely-shaped cysts. This is the typical appearance of lymphangioleiomyomatosis (LAM). Source: WikiMedia Commons.

• High-resolution CT scan (HRCT). This test shows a computer-generated picture of the lungs that has more detail than a chest x-ray. It is the most useful imaging test for diagnosing LAM. HRCT in patients with LAM can show cysts or shadows of cell clusters in the lungs, a collapsed lung, or enlarged lymph nodes. It also can show how much normal lung tissue has been replaced by the LAM cysts. HRCT scans of the abdomen and pelvis can show if there are growths in the kidneys, other abdominal organs, or lymph nodes.
• Lung biopsy. Although the tests mentioned above sometimes provide enough information to diagnose LAM, the most useful test involves removing samples of lung tissue so they can be looked at under a microscope. Several procedures can be used to obtain lung tissue:
  • Thoracoscopy. A doctor inserts a small, lighted tube (endoscope) into little incisions in the chest wall under anesthesia. This lets him or her see the insides of the chest and to cut out a few small pieces of lung tissue. This procedure is not major surgery, but it usually provides all the tissue a doctor needs for tests.
  • Open lung biopsy. In this more major procedure, a doctor removes a few small pieces of lung tissue through an incision in the chest wall between the ribs. This procedure also is done in the hospital, under general anesthesia. Recovery takes longer than recovery from thoracoscopy.
  • Transbronchial biopsy. A doctor inserts a long, narrow, flexible, lighted tube (bronchoscope) down the windpipe, or trachea, into the lungs. He or she then snips out bits of lung tissue with a tiny forceps from the inside of the lung rather than the outside like with the other two. This procedure is usually done in a hospital on an outpatient basis, and under local anesthesia or light (conscious) sedation. Doctors usually are not able to remove enough tissue to diagnose LAM with this procedure.

Some doctors recommend that patients who have recently been diagnosed with LAM should have magnetic resonance imaging (MRI) of the head. This test can show signs of tuberous sclerosis complex (TSC) or growths in the brain called [[meningioma]]s. About one out of every 20 patients with LAM has a meningioma. This type of growth also appears in people with TSC.

The National Institutes of Health is studying whether blood tests for the TSC1 and TSC2 genes may be helpful in diagnosing LAM patients.

Treatment

There is no treatment available yet to slow or stop the growth of the cell clusters and cysts that are the major feature of lymphangioleiomyomatosis (LAM).

Most treatments for LAM are aimed at relieving symptoms and preventing complications.

Doctors have learned a lot about LAM in recent years. They are now able to diagnose the condition earlier and provide support services that improve the quality of life. Not too long ago, doctors thought that the life expectancy for women with LAM was less than 10 years following diagnosis. It is now known that some patients with LAM may survive for more than 20 years. The most common cause of death from LAM is respiratory failure.

The main treatments for LAM are:

• Medication
• Oxygen therapy
• Procedures to remove fluid from the chest or abdominal cavities and prevent it from building up again
• Procedures to remove angiomyolipomas (AMLs) from positions where they cause distress or discomfort
• Lung transplantation

Medicines

Some medicines may help open up the air passages of the lungs so that patients with LAM-related respiratory complaints can breathe more easily.

• Bronchodilators are drugs that relax the muscles around the airways. As a result, the airways can open up, making it easier to breathe. About one out of five women with LAM improves with the use of bronchodilators.
• Octreotide and diuretics (water pills) are sometimes used to prevent the buildup of fluid in the chest cavity and abdomen. Octreotide may reduce leakage of lymph into the abdominal or chest cavity.

Women with LAM have a greater chance of developing osteoporosis (a condition that causes bones to become weak and brittle) than other women. In patients with LAM, the doctor might therefore measure a patient's bone density. If the bone density is found to be decreased, the doctor may prescribe drugs that prevent bone loss such as calcium and vitamin D supplements.

Physicians who think that estrogen may play a role in the development of LAM usually treat their patients with hormone therapy.^[5] This is still a matter of debate.

Oxygen therapy

Severe lung involvement of LAM may lead to a level of oxygen in the blood that is too low, and patients may need oxygen therapy. Oxygen is usually given through nasal prongs or a mask. At first, patients may need oxygen only while exercising and/or while sleeping. Over time, the disease may progress to the point where patients need full-time oxygen therapy.

After a diagnosis of LAM, a standard exercise stress test or a six-minute walk test may be performed to find out whether or not oxygen is needed during exercise.

Procedures

In LAM, fluid may build up in the chest as a chylothorax, and air may develop in the chest as a spontaneous pneumothorax. In both cases, the extra fluid or gas expands in the chest cavity, putting external pressure on the lungs and preventing them from inflating. This can cause a lack of oxygen and the feeling of breathlessness. Several procedures help remove air or fluid from the chest and abdominal cavities and prevent them from building up in the chest cavity.

• Removing fluid from the chest or abdominal cavities may help relieve abdominal discomfort and shortness of breath. A doctor can usually remove this fluid with a needle and syringe. If large amounts of fluid build up inside the chest cavity, a doctor may have to insert a larger tube into the chest and leave it there for several hours or days to completely remove it.
• Removing air from the chest cavity may relieve shortness of breath and chest pain caused by a collapsed lung. Usually the air is removed with a tube that is inserted into the chest cavity between the side ribs thoracocentesis. The tube is usually attached to a suction device or an underwater seal that allows air out of the chest but not back into it. If this procedure doesn't work, or the lungs continue to collapse frequently, patients are often advised to undergo surgery.
• If lymph and air leak continue to fill the chest cavity, doctors may perform a procedure to fuse the lung and chest wall together and remove space for leakage. This procedure is called pleurodesis. It involves injecting a chemical into the place where the leakage is happening. This can be either talcum powder suspension or the antibiotic tetracycline. Doctors can do this either at the bedside under local anesthesia, or in the operating room by video-assisted thoracoscopy surgery under general anesthesia. This procedure works relatively well. Because the procedure can cause some pain afterward, patients generally remain in the hospital for a day or so afterwards.

If there is ongoing severe pain or bleeding caused by angiomyolipomas (AMLs), surgery to remove some of the abdominal growths may be helpful. If the bleeding is not too severe, an experienced radiologist can often block the blood vessels feeding the AMLs. This may cause them to shrink. This is known as embolization.

Lung transplantation

Surgery to replace one or both of the lungs with healthy lungs from a human donor is often helpful to LAM patients.^[6] Survival after a lung transplant for LAM may be better than survival after a lung transplant for another condition, such as emphysema.^[7] Lung transplantation has a high risk of complications, so it is reserved for people with advanced illness.

In a few cases, doctors have found LAM cells in the new transplanted lungs and other parts of the body, but the LAM cells do not seem to prevent the transplanted lung from working.

Chances of Developing LAM

LAM mostly affects women in their mid-forties. More than seven out of every 10 patients are between the ages of 20 and 40 when they begin to have symptoms. But LAM may occur in women as old as 70 to 80. There are also a few reports of LAM occurring in men.

Today, about 675 women in the United States have been diagnosed with either LAM alone or LAM with tuberous sclerosis complex (about 15% have both conditions). Scientists believe that many more women have LAM, but they have been misdiagnosed with another more common lung disease, such as emphysema, asthma, or bronchitis.

Since LAM affects about three out of every 10 women with TSC, there may be as many as 10,000 women in the United States who have TSC and undiagnosed LAM. Many of these women may have mild cases of LAM that are not causing symptoms. Not all TSC patients who have LAM have lung problems.

Living with LAM

In the early stages of LAM, patients usually can go about their daily activities with minimal disruption, including attending school, going to work, and performing common physical activities such as walking up a hill. Later on, it may be harder for them to be active. After a while, patients may also require oxygen full-time.

Ongoing medical care is important. Treatment by a pulmonologist who specializes in LAM is recommended. These specialists are usually located at major medical centers.

It is especially important for patients with LAM to take good care of their general health. This means following the same healthy lifestyle that is recommended for all Americans, including eating a healthy diet, being as physically active as you can, and getting plenty of rest. Patients with LAM absolutely must avoid smoking, in order to preserve their residual lung function.

Other activities that can be altered by LAM include traveling by air, traveling to places at altitude, or traveling to remote areas where medical attention is not readily available.

In terms of pregnancy, when lung function is normal, pregnancy may be an option. In advanced disease, pregnancy can be dangerous.

Most doctors do not recommend oral contraceptives (birth control pills) containing estrogen because of the theoretical association between LAM and endogenous estrogen exposure. Patients also should avoid estrogen-rich foods. Progesterone may be used as a contraceptive instead, as there is no proven link between progestogens and LAM.

Clinical Trials

• The LAM foundation has information on the Miles trial, a study to determine if lung function is improved by a drug called rapamycin or sirolimus in LAM patients.
• Information on government-sponsored clinical trials on LAM is available at ClinicalTrials.gov.
• Clinical trials are also listed on the National Heart, Lung, and Blood Institute LAM Patient Recruitment Web site.

Research

Researchers are now studying several medicines as possible treatments for LAM, including rapamycin.

Rapamycin (sirolimus) is the first drug to show promise as a treatment that will slow or stop the development and growth of the LAM cell clusters. Doctors now use it to prevent the immune system from rejecting kidney transplants. Researchers are looking into whether this medicine can reduce the size of kidney AMLs in patients with LAM and tuberous sclerosis complex (TSC). They also are planning a larger study of the effects of rapamycin, or another drug like it, on TSC and LAM patients. This study will test whether the drug can prevent or reverse the growth of the LAM cell clusters and cysts in other organs and slow the decline of lung function.

Expected Outcome

Lung function declines rapidly in many LAM patients, but this is widely variable. One study reviewing this suggests that progesterone treatment can slow this decline.^[8]

Interesting Facts

The term lymphangioleiomyomatosis comes from the Greek. Lymph- and angio- refer to the lymph vessels, and leiomyoma refers to the type of cells involved in LAM.

Public Health

Knowledge of LAM has improved significantly since the formation of The LAM Foundation in 1995 by the mother of a patient with LAM, and the develoment of a national U.S. LAM registry by the National Heart, Lung, and Blood Institute in 1997. Patients with LAM who wish to be seen at one of six participating centers and are able to attend annually can enroll. This registry is designed to further characterize the clinical and laboratory features and natural history of LAM, and to be a resource for research and clinical trials.^[9]

Other Resources

Joining a LAM support group is helpful for many patients. Information about patient support groups is available from the National Institutes of Health/National Heart, Lung, and Blood Institute Pulmonary-Critical Care Branch at 1-877-NIH-LUNG (1-877-644-5864), extension 3, or from the LAM Foundation.

References

1. ↑ Taveira-DaSilva AM, Steagall WK, Moss J. Lymphangioleiomyomatosis. Cancer Control. 2006 Oct;13(4):276-85. Abstract
2. ↑ Ferrans VJ, Yu ZX, Nelson WK et al. Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features. J Nippon Med Sch. 2000 Oct;67(5):311-29. Abstract | Full Text
3. ↑ Ryu JH, Moss J, Beck GJ et al; NHLBI LAM Registry Group. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006 Jan 1;173(1):105-11. Epub 2005 Oct 6. Abstract | Full Text
4. ↑ Moss J, Avila NA, Barnes PM et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 2001 Aug 15;164(4):669-71. Abstract | Full Text
5. ↑ Johnson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK. Thorax. 2000 Dec;55(12):1052-7. Abstract | Full Text
6. ↑ Maurer JR, Ryu J, Beck G et al; National Heart, Lung, and Blood Institute LAM Registry Study Group. Lung transplantation in the management of patients with lymphangioleiomyomatosis: baseline data from the NHLBI LAM Registry. J Heart Lung Transplant. 2007 Dec;26(12):1293-9. Abstract | Full Text
7. ↑ Kpodonu J, Massad MG, Chaer RA, Caines A, Evans A, Snow NJ, Geha AS. The US experience with lung transplantation for pulmonary lymphangioleiomyomatosis. J Heart Lung Transplant. 2005 Sep;24(9):1247-53. Abstract
8. ↑ Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med. 1999 Aug;160(2):628-33. Abstract
9. ↑ Tattersfield AE, Glassberg MK. Lymphangioleiomyomatosis: a national registry for a rare disease. Am J Respir Crit Care Med. 2006 Jan 1;173(1):2-4. Full Text

External Links

LAM Treatment Alliance

The LAM Foundation

National Organization for Rare Disorders: Lymphangioleiomyomatosis