LAM

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General Information About LAM

LAM

What is LAM?

Lymphangioleiomyomatosis is a rare disease that primarily affects women of childbearing age. An unusual type of muscle cell grows throughout the lungs, causing obstruction of airways, lymph vessels and blood vessels, preventing the lungs from providing oxygen to the body. Although classified as an interstitial lung disease, it is more like emphysema, with airway obstruction and formation of cysts. LAM occurs in two forms, sporadically, and associated with tuberous sclerosis complex (TSC), a distinct syndrome that also affects the central nervous system, eyes and skin.

What are the symptoms?

Progressive difficulty breathing, sometimes with a cough. Pneumothorax, partial collapse of a lung due to cyst rupture and leakage of air from the lung into the surrounding chest, is often the first event leading to diagnosis. Symptoms of pneumothorax are sudden shortness of breath and chest discomfort.

How serious is LAM?

LAM is debilitating and life-threatening, eventually causing respiratory failure. Early on, most people can live normally. Lung function gradually worsens, at an unpredictable rate. Physical activity becomes limited, and oxygen is required. There can be repeated pneumothoraces. Due to blockage or rupture of lymph vessels, fluid can leak into the chest cavity (chylous pleural effusions), causing more breathlessness.

How is LAM diagnosed?

Over half have airflow obstruction on pulmonary function tests; most have impaired oxygen exchange between the lungs and blood. Chest X-rays may be normal when cysts are small, or show over-inflation of the lungs. LAM can be mistaken for asthma or COPD. As disease progresses, opacities can be seen, and lymph nodes may be enlarged. Thin-walled cysts throughout the lungs on high-resolution CT scans can be diagnostic. Tissue samples are sometimes obtained for confirmation, by bronchoscopy, video-assisted thoracoscopic or open lung biopsy.

Are other areas of the body affected by LAM?

Benign masses of blood vessels, lymphatic material, muscle tissue and fat are often seen in the kidneys, abdomen, retroperitoneal space and pelvis. Symptoms include bloating, abdominal pain and leg edema.

What causes LAM?

Unknown. There is evidence for gene mutations, possibly in combination with environmental factors. Loss of cellular tumor suppression functions may contribute.

Who is at risk?

LAM almost exclusively afflicts women of childbearing age. Post-menopausal women can be affected, especially if taking estrogen; it is rarely seen in men. In the National Heart, Lung and Blood Institute (NHLBI) LAM registry, the average age of symptom onset was 37, with diagnosis at 41. Caucasians are at highest risk, with lower rates among Asians and those of African descent. LAM occurs in a third of people with tuberous sclerosis, often at a younger age and with less impaired lung function.

How common is LAM?

1,300 known people with LAM in North America. Based on TSC prevalence, 8,000-10,000 women probably have cystic lesions consistent with LAM, and over 250,000 worldwide.

Can LAM be prevented?

No. Earlier diagnosis, including screening people with TSC, may improve outcomes, through avoidance of tobacco smoke and estrogen-containing medications, and the potential for early treatment. Women are cautioned to avoid pregnancy, since there can be disease acceleration. Due to increased risk of pneumothorax, air travel should be avoided if there is new or worsening breathlessness or chest pain, prior pneumothorax or coughing up blood, or multiple cysts in the lung periphery.

How is LAM treated?

There is not yet a cure. Symptoms may improve with inhaled bronchodilators, such as ipratropium or albuterol, and oxygen is needed for advanced disease. Estrogen probably plays a central role in disease progression, and some respond to hormonal manipulation. While taking sirolimus, which affects cell growth and proliferation, participants in early trials showed improved quality of life, activity level and lung function. Sirolimus has long-term adverse effects, and research is necessary to determine optimal dosing and timing of therapy, and those likely to benefit. Lung transplant provides overall relief, although with a high complication rate.

Source: Dona Upson, MD, Past Chair , ATS Council of Chapter Representatives (CCR)

Chest Computed Tomography in Lymphangioleiomyomatosis (LAM)

Lymphangioleiomyomatosis (LAM) is one of a handful of cystic lung diseases for which chest computed tomography (CT) is a prerequisite to diagnosis. The typical CT findings include more than 10 thin walled cysts scattered diffusely throughout the lungs. Most often the cyst number is in the thousands and only a few alternative diagnoses are possible.

Radiologists commonly see individuals who have less than 10 cysts in the lung parenchyma; most of these are assumed to be congenital or developmental in origin with primary failure of alveolar formation. It is thought that these arborization defects occur in small lung segments which then become round if there is any air trapping. There is no evidence based approach to these patients, since serial CT scan usually does not change and because LAM is such a rare disease.

However, if symptoms develop, the approach to the CT scan is different. Hagaman, et. al. constructed a Markov decision model using available data to show that non-smoking women between the ages of 25-54 years with pneumothorax should get a Chest CT to screen for LAM1. Chest CT screening was cost effective in this model since 5% of this population has LAM. Younger ages more often have primary spontaneous pneumothorax and older ages often have other causes of secondary spontaneous pneumothoraces.

There are some other cystic lung diseases that should be considered in a patient with many cysts. The hallmark of a cyst is that it has a discernable wall, a finding that is absent in early emphysema. Some advanced cases of emphysema with bullae can have walls that look similar to cysts, since alveolar destruction can produce remnants of lung interstitial connective tissue that has no other place to go except to fall against the wall of an emphysematous bleb. This occurs most often in paraseptal emphysema in a distribution that abuts the pleural surfaces including the interlobular fissures.

Langerhans Cell Histiocytosis (LCH) is a disease seen almost exclusively in cigarette smokers in which the multiple cysts are interspersed with small stellate nodules. Typically the cysts are not as regularly shaped as in LAM and LCH tends to spare the lung bases and costophrenic sulci.

Other cystic lung diseases include Birt Hogg Dube, a rare autosomal dominant genetic disease with variable penetrance causing defects in folliculin. There is often a familial history of cancer, particularly renal adenocarcinoma. Lung cysts also occur in HIV and Sjӧgren's in association with lymphocytic interstitial pneumonitis (LIP). The mechanism by which small airways develop enlargement distal to proximal lymphocytic proliferation is not known. These small lymphocytic accumulations are seen as small ground glass nodules. Also unknown is whether the enormous cysts occasionally seen in Sjӧgren's syndrome are necessarily associated with LIP or associated lymphomas. Some of the Sjӧgren's patients can also develop pulmonary amyloidosis which has been associated with a rare cystic presentation. A very rare disease associated with an immunoglobulin G light chain non-amyloid deposition has been shown to produce lung cysts, likely by production of matrix metalloproteinases by macrophagic giant cells. Metastatic cancers, particularly sarcomas, Erdheim Chester disease, and infections such as Pneumocystis jiroveci are also on the differential diagnosis. Therefore,a definitivediagnosis of a cystic lung disease as LAM requires other features to be present.

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The European Respiratory Society published 2010 guidelines on LAM diagnosis in which they stratified LAM into possible, probable, and definite diagnoses2. A characteristic CT featured multiple thin walled cysts evenly distributed throughout the lung without other features.

LAM Diagnosis

Disease Features

Possible Characteristic or compatible HRCT

Probable

Characteristic CT+ compatible clinical features
Compatible CT + renal angiomyolipoma,or thoracic, or abdominal chylous effusion

Definite

Characteristic or compatible HRCT and lung biopsy fitting the pathological features of LAM, or
Characteristic CT and any of the following: renal angiomyolipoma, thoracic or abdominal chylous effusions, lymphangioleiomyoma or lymph node involved by LAM and definite or probable Tuberous Sclerosis Complex.

This scoring system has now been altered in clinical practice by acceptance of serum Vascular Endothelial Growth Factor D (VEGF-D) as a very specific biomarker for LAM when the value is >800 ng/dl. Furthermore, this blood test declines with use of rapamycin and might be able to power clinical trials in LAM with many fewer subjects3.

Since the CT scan features so prominently in LAM diagnosis, some work has been done to characterize whether quantitative CT grading can serve a similar function as VEGF-D as a biomarker of disease responsiveness. Cyst volume percent is calculated on either an inspiratory or expiratory CT as the ratio of very low density voxels (cysts) to low density voxels of the lung. Inspiratory cyst volume percent has been correlated with FEV1, residual volume, and DLCO, although the correlations are weak 4.

Newer algorithms are needed to measure cyst characteristics and the CT textures that surround the cysts. What is clear is that the cysts ventilate with a size that is different on inspiration than on expiration. What is unclear are the best ways to accurately count the cysts on automated software platforms to give reproducible and robust CT signatures that can suffice as primary outcomes for clinical trials.

As professional societies and insurers become more restrictive in CT recommendations, care should be taken to assure that we establish evidence to recommend the CT as a clinical diagnostic tool in the lung diseases for which it is essential. The CT has established this role in LAM.

Charlie Strange, MD
Immediate Past Chair, Clinical Problems Assembly

  1. Hagaman JT, Schauer DP, McCormack FX, Kinder BW. "Screening for Lymphangioleiomyomatosis by High-Resolution Computed Tomography in Young, Nonsmoking Women Presenting with Spontaneous Pneumothorax Is Cost-Effective", American Journal of Respiratory and Critical Care Medicine, Vol. 181, No. 12 (2010), pp. 1376-1382

  2. Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, Harari S, Reynaud-Gaubert M, Hoehler A, Brauner M, Popper H, Bonetti F, Kingswood C and the Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010; 35:14-26.

  3. Young LR, Lee HS, Inoue Y, Moss J, Singer LS, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP, Goldberg HJ, Downey GP, Swigris JJ, Taveira-DaSilva AM, Krischer JP, Trapnell BC, McCormack FX for the MILES Trial Group. Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: A prospective analysis of the MILES Trial. Lancet Resp Med 2013; 1(6): 445-452. PMID 24159565.

  4. Schmithorst VJ. Altes TA. Young LR, Franz DN, Bissler JJ, McCormack FX, Dardzinski BJ, Brody AS. Automated algorithm for quantifying the extent of cystic change on volumetric chest CT: Initial results in lymphangioleio-myomatosis. AJR Am J Roentgenol. 2009;192:1037–1044.


Four Facts About LAM

  1. Lymphangioleiomyomatosis (LAM) is a progressive disease that affects women, usually in their childbearing years. Symptoms may include shortness of breath, collapsed lung, chest pain, cough, fatigue and in 40% of patients one or more benign kidney tumors called angiomyolipoma.

  2. Women with LAM may be misdiagnosed with asthma, emphysema, or bronchitis. The diagnosis of LAM can most often be made without surgical lung biopsy using a combination of high resolution CT imaging of the lungs and abdomen, clinical signs and symptoms, serum VEGF-D levels and sometimes transbronchial biopsy.

  3. Sirolimus is a proven therapy for LAM and can stabilize lung function and improve some measures of quality of life and functional performance.

  4. The median survival of patients registered with The LAM Foundation is 29 years after the onset of symptoms — meaning half of all registered patients live 29 years after the first LAM symptoms develop.