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Last updated: 04/23/2025
Years published: 1987, 1989, 1995, 1996, 1998, 2005, 2009, 2021, 2025
NORD gratefully acknowledges Feriel Rahmani, MDCM, McGill University School of Medicine, and Nishant Gupta MD, MS, The LAM Foundation Professor for LAM Research, Director, Interstitial and Rare Lung Disease Program, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, for assistance in the preparation of this report.
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Summary
Lymphangioleiomyomatosis (LAM) is a rare progressive multisystem disorder that mostly affects females of reproductive age. It is estimated to affect approximately 20/1,000,000 females worldwide. There are two main types of LAM: sporadic LAM and LAM associated with tuberous sclerosis complex (TSC), an inheritable genetic condition. LAM is characterized by the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle-like LAM cells) in certain organs of the body, especially the lungs, kidneys and lymphatics. The most common symptom associated with LAM is difficulty breathing (dyspnea), especially on exertion. Affected individuals may also have complications including lung collapse (pneumothorax) or fluid accumulation around the lungs (pleural effusion) and in the abdomen, and benign kidney tumors called angiomyolipomas (AMLs). The disorder is progressive and, in some people, may result in chronic respiratory failure. Fortunately, treatment with sirolimus slows disease progression and better management of complications. Further research leading to better understanding of this rare disease promises improved therapeutic options in the future.
The symptoms of LAM vary depending on the organs affected.
The abnormal LAM cells infiltrate tissues, form cysts and obstruct the affected airways (breathing tubes), blood vessels and lymphatic vessels. Consequently, pulmonary LAM can present with shortness of breath upon exertion, cough, wheezing and chest pain. Sometimes, individuals may cough up small amounts of blood (hemoptysis) and have bleeding in their lungs (pulmonary hemorrhage) due to obstructed blood vessels, especially in association with physical exercise and sexual activity. Infiltration of the lung with LAM cells results in progressive breathing difficulties, lung collapse and interference with the lung’s ability to deliver oxygen to the rest of the body.
About 50-60% of individuals with LAM experience a lung collapse (pneumothorax) at some point in their life. In about one third of these patients, the pneumothorax may be the first manifestation that brings the diagnosis of LAM to light. The symptoms of a collapsed lung may include sudden, sharp chest pain, difficult, rapid breathing (tachypnea), rapid heartbeat (tachycardia), low blood pressure (hypotension), profuse sweating (diaphoresis), dizziness and/or lack of normal chest movement on the affected side of the chest. This complication tends to recur in LAM, therefore management with a medical or surgical technique that adheres lungs to the chest wall (pleurodesis) is recommended.
About 10 to 20% of females with LAM have fluid (e.g. chyle) accumulation in the chest cavity around the lungs (pleural effusion). Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins where it mixes with blood. In some people with LAM, the lymphatic vessels may rupture or become blocked (obstructed) due to the infiltration of LAM cells, causing chyle to accumulate in the chest cavity (chylothorax). In some people, chyle may accumulate in the abdomen causing an increase in girth, a condition called chylous ascites. Involvement of the axial lymphatics may also lead to the formation of chyle-filled lymphatic cysts called lymphangioleiomyomas that are seen most commonly in the abdomen.
Approximately 30% of individuals with sporadic LAM and up to 80% of individuals with TSC-LAM develop angiomyolipomas (AMLs) which are benign tumors made up of fat, blood vessels and smooth muscle-like cells. These tumors most commonly affect the kidneys and often do not cause symptoms. In some people, they may cause flank pain, blood in the urine (hematuria) or bleeding into the abdomen.
Symptoms of LAM may become progressively worse as LAM cell proliferation continues and may result in chronic life-threatening respiratory failure.
LAM is associated with the genetic disorder tuberous sclerosis complex (TSC) as both diseases are caused by changes (variants) in one of two TSC genes known as the TSC1 or TSC2. There are two main types of LAM: sporadic LAM (or S-LAM that may occur without TSC) and LAM associated with TSC (called TSC-LAM). In both types, abnormal LAM cells circulate in blood and lymphatic vessels and deposit in the lungs, causing cysts and lung damage. In S-LAM, gene variants are thought to be somatic variants (e.g., variants that occur in peripheral tissues after conception and are not inherited). These variants are not found in the blood or the normal lung or normal kidney cells of affected individuals. On the contrary, in TSC-LAM, these gene variants may occur spontaneously (sporadically) for unknown reasons or be inherited in an autosomal dominant pattern. Most cases represent new (sporadic) gene variants with no family history of the disease.
Approximately one-third of females with TSC show evidence of pulmonary LAM; however, the prevalence of LAM in females with TSC increases with age and by the age of 40 years almost 80% of females with TSC have cystic changes consistent with LAM. Consequently, the TSC Guidelines recommend that females with TSC be screened for LAM upon reaching adulthood.
Other factors affect the disease process in LAM but are not completely understood. For example, researchers have observed that estrogen and progesterone receptors are commonly expressed on LAM cells. In addition, LAM symptoms flare up during surges of female hormones, such as during pregnancy, with hormonal contraception, or during menstruation, and then symptoms stabilize post-menopause. The mechanism of action of female hormones in LAM on a molecular level is still not fully understood.
LAM is a rare disorder that is estimated to affect approximately 20/1,000,000 females worldwide. The US LAM clinic network follows ~1,500 people with LAM and there are ~3,000 people with LAM registered with The LAM Foundation. Current estimates suggest that there are over 50,000 people with sporadic LAM and 80,000–160,000 people with TSC-LAM worldwide. However, many researchers think that the disorder is under-diagnosed, making it difficult to determine the true frequency in the general population.
LAM predominantly affects females of reproductive age, with an average age at symptom onset of about 35 years of age. Two thirds of people who first present with symptoms of LAM are in their thirties or forties, but the age range can extend from adolescent to elderly.
The diagnosis of LAM may be confirmed by a thorough clinical evaluation that includes a detailed patient history and a variety of specialized tests.
High resolution CT scan (HRCT) shows characteristic thin-walled cysts in the lungs consistent with LAM and can help rule out other pulmonary conditions. HRCT may also reveal angiomyolipomas or lymphangioleiomyomas in the abdomen that support a diagnosis of LAM. Chest X-rays are not diagnostic for LAM and are often normal especially early in the disease course.
VEGF-D blood test is elevated in ~60-70% of individuals with LAM. In combination with a characteristic CT scan, the finding of elevated VEGF-D can establish the diagnosis of LAM without the need of a surgical lung biopsy, which is the gold standard for diagnosis but comes with its risks and complications.
Lung function tests are useful to obtain a baseline of the individual’s lung function and facilitate monitoring over time.
Currently, no test can accurately predict the course of the disease (prognosis), and progression seems to vary greatly from one person to another, though there has been a significant improvement in our understanding of LAM in the past decade. People with LAM have a favorable life expectancy with a transplant-free survival of more than 20 years from the time of diagnosis.
Treatment
Individuals with LAM are encouraged to lead a normal life with a healthy lifestyle as LAM is generally a chronic disease with slow progression over decades. LAM is a progressive disease with no cure but, in recent years, a medication called sirolimus has been shown to slow the decline in lung function in LAM. Sirolimus has been shown to slow the disease process, resolve fluid accumulation in the lungs (chylous effusions) and regress renal masses (angiomyolipomas). Sirolimus is approved by the U.S. Food and Drug Administration (FDA) as well as by the regulatory agencies in the European Union and multiple other countries across the world to treat LAM.
Fluid accumulation in the lungs (pleural effusion) should be first managed with a trial of sirolimus, and invasive procedures such as drainage should only be used in patients where sirolimus doesn’t have a satisfactory response. It is worth noting that it can sometimes take a few months for sirolimus to take full effect in the resolution of chylous fluids. Lung collapse (pneumothorax) may require the placement of a chest tube. Due to the high risk of recurrence, it is recommended that patients with LAM undergo a procedure called pleurodesis (a technique that adheres lungs to the chest wall) early to reduce the number of future pneumothoraces.
Drugs that temporarily widen the bronchial tubes (bronchodilators) may help to alleviate breathing difficulties (asthma-like symptoms) in some patients. Influenza, pneumococcal and COVID-19 vaccines are recommended due to the pulmonary vulnerability of individuals with LAM. Supplemental oxygen should be administered to qualifying patients as needed. As with other respiratory conditions, patients with LAM may benefit from pulmonary rehabilitation. In individuals with severe cases of LAM, lung transplantation may be considered.
Renal angiomyolipomas pose a risk for internal bleeding especially as they increase in size. Interventional radiology procedures such as embolization or treatment with sirolimus may be needed to reduce the risk of bleeding. Surgical resection is rarely needed and should be reserved as a last resort.
Because of the association between surges in female hormones and worsening of symptoms of LAM, estrogen-containing contraceptives are contraindicated. Postmenopausal patients and patients with reduced mobility should be tested for osteoporosis. Any loss of bone mineral density should be treated with vitamin D and calcium supplementation and/or bisphosphonates according to treatment guidelines for osteoporosis.
Although sirolimus is a safe and effective treatment of LAM, drug toxicity and development of resistance are potential problems related to therapy. Recent evidence suggests that low dose sirolimus (1mg daily) is effective at halting disease progression and offers a better safety profile. Sirolimus has been shown to reduce the rate of lung function decline, resolve chylous effusions, shrink angiomyolipomas and lymphangioleiomyomas, reduce the risk of future pneumothoraces and help people with LAM live longer. Research is ongoing to determine if sirolimus should be started early in the disease course in a preventative way to preserve lung function. Other ongoing research continues to explore the long-term safety and efficacy of sirolimus and develop new treatment options for LAM.
Scientists are also investigating the role of hormone therapy in the onset, development and treatment of LAM. No beneficial outcomes have been consistently seen in patients with LAM who received hormonal therapy, although available studies are limited and provide low-quality evidence. Randomized controlled trials of hormonal agents, either alone or in combination with sirolimus, are needed to better assess the impact of hormonal manipulation on the course of LAM. Until then, routine use of hormonal treatment in patients with LAM is discouraged.
Hereditary factors are also being studied to help determine whether a genetic predisposition is essential to the development of LAM. Similarly, research is ongoing to identify better biomarkers to improve the non-invasive diagnosis of LAM.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Kristof AS, Moss J. Lymphangioleiomyomatosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:395-6.
JOURNAL ARTICLES
Gupta N, Johnson SR. Lymphangioleiomyomatosis: No longer ultra-rare. Am J Respir Crit Care Med. 2024; 209(4):358-359. PubMed PMID: 38190704
Lynn E, Forde SH, Franciosi AN, et al. Updated prevalence of lymphangioleiomyomatosis in Europe. Am J Respir Crit Care Med. 2024;209(4):456-459. doi:10.1164/rccm.202310-1736LE
Rubin R, Baldi BG, Shaw BM, Kopras E, Kingsberg S, Larkin L, McCormack FX, and Gupta N. Hemoptysis associated with sexual activity in lymphangioleiomyomatosis. Ann Am Thorac Soc. 2024; 21(12):1784-1787
Palipana AK, Gecili E, Song S, Johnson SR, Szczesniak RD, and Gupta N. Predicting individualized lung disease progression in treatment naïve patients with lymphangioleiomyomatosis. Chest. 2023;163:1458-70
Xu W, Yang C, Cheng C, et al. Determinants of progression and mortality in lymphangioleiomyomatosis. Chest. 2023;164(1):137-148. doi:10.1016/j.chest.2023.02.026
Cortinas N, Liu J, Kopras EJ, Memon H, Burkes R, and Gupta N. Impact of age, menopause and sirolimus on spontaneous pneumothoraces in Lymphangioleiomyomatosis. Chest. 2022;162:1324-1327.
Shaw B, Kopras EJ, and Gupta N. Menstrual cycle-related respiratory symptom variability in patients with lymphangioleiomyomatosis. Ann Am Thorac Soc. 2022;19:1619-1621.
McCarthy C, Gupta N, Johnson SR, Yu J, McCormack FX. Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis and management. Lancet Respir Med. 2021;9:1313-1327
Northrup H, Aronow ME, Bebin EM, et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021;123:50-66. doi:10.1016/j.pediatrneurol.2021.07.011
Gupta N, Lee HS, Ryu JH, et al. The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis. Chest. 2019;155(2):288-296. doi:10.1016/j.chest.2018.06.016
Gupta N, Lee HS, Young LR, et al. Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis. Eur Respir J. 2019;53(4):1802066. Published 2019 Apr 4. doi:10.1183/13993003.02066-2018
Hu S, Wu X, Xu W, et al. Long-term efficacy and safety of sirolimus therapy in patients with lymphangioleiomyomatosis. Orphanet Journal of Rare Diseases. 2019;14(1). doi:10.1186/s13023-019-1178-2.
Gupta N, Finlay GA, Kotloff RM, et al. Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017;196(10):1337-1348. doi:10.1164/rccm.201709-1965ST
Singla A, Gupta N, Apewokin S, McCormack FX. Sirolimus for the treatment of lymphangioleiomyomatosis. Expert Opinion on Orphan Drugs. 2017;5(11):907-921
McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese respiratory society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 2016;194(6):748-761. doi:10.1164/rccm.201607-1384ST
Cudzilo C et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest.2013 Aug;144(2):578-585.
Johnson SR, Cordier JF, Lazor R, et al. European respiratory society guidelines for the diagnosis and management of lymphangioleiomyomatosis. European Respiratory Journal. 2009;35(1):14-26. doi:10.1183/09031936.00076209.
Taviera-DaSilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J. Bone mineral density in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2005;171:61-7.
Taviera-DaSilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest. 2004;126:1867-74.
Johnson SR, Whale CI, Hubbard RB, Lewis SA, Tattersfield AE. Survival and disease progression in UK patients with lymphangioleiomyomatosis. Thorax. 2004;59:800-3.
Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000;97:6085-90.
Urban T, Lazor R, Lacronique J, et al., Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Medicine (Baltimore). 1999;78:321-37.
Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EP. Evidence that lymphangioleiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangioleiomyomatosis. Am J Hum Genet. 1998;62:810-5.
INTERNET
Islam A. Lymphangioleiomyomatosis Imaging and Diagnosis. Medscape. Updated Jan 3, 2021. https://www.emedicine.com/radio/topic415.htm Accessed April 8, 2025.
Moss J. Lymphangioleiomyomatosis.Medscape. Updated December 22, 2019. https://www.emedicine.com/med/topic1348.htm Accessed April 8, 2025.
American Thoracic Society. General Information about LAM.2018. https://www.thoracic.org/patients/patient-resources/resources/lymphangioleiomyomatosis-lam.pdf Accessed April 8, 2025.
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