Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Lymphangioleiomyomatosis

  • Author: Joel Moss, MD, PhD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
 
Updated: Jul 27, 2015
 

Background

Lymphangioleiomyomatosis (LAM) is a rare disorder resulting from proliferation in the lung, kidney, and axial lymphatics of abnormal smooth muscle–like cells (LAM cells) that exhibit features of neoplasia and neural crest origin.[1, 2, 3] Cystic destruction of the lung with progressive pulmonary dysfunction and the presence of abdominal tumors (eg, angiomyolipomas [AML], lymphangioleiomyomas) characterize the disease. LAM typically occurs in premenopausal women, suggesting the involvement of female hormones in disease pathogenesis. LAM can occur with increased frequency in patients with tuberous sclerosis complex (TSC), an autosomal dominant disorder due, in part, to mutations in the TSC1 or TSC2 gene. 

Next

Pathophysiology

Proliferation of lymphangioleiomyomatosis (LAM) cells may obstruct bronchioles,[1] possibly leading to airflow obstruction, air trapping, formation of bullae, and pneumothoraces. Obstruction of lymphatics may result in lymphangioleiomyomas, chylothorax, and chylous ascites. Excessive proteolytic activity, which relates to an imbalance of the elastase/alpha1-antitrypsin system or metalloprotease (MMPs) and their inhibitors (tissue inhibitors of metalloproteases [TIMPs]), may be important in lung destruction and formation of cysts.[4] Animal models suggest that estrogen may promote the metastasis of TSC2-deficient cells to the lungs.[5]

Previous
Next

Epidemiology

Frequency

United States

Lymphangioleiomyomatosis (LAM) may occur sporadically or in association with tuberous sclerosis complex (TSC). To date, more than 1500 cases of sporadic LAM exist in the United States; LAM may occur in approximately 30-40% of patients with TSC.[6]

International

The international frequency of lymphangioleiomyomatosis (LAM) is unknown, although Europe and Japan report case series.[7]

Race

No racial predilection has been reported for lymphangioleiomyomatosis (LAM).

Sex

Lymphangioleiomyomatosis (LAM) primarily is a disease of women; however, rare case reports describe LAM in men with TSC.

Age

Although primarily a disease of women of childbearing age, lymphangioleiomyomatosis (LAM) has also been reported in postmenopausal patients.

Previous
Next

Prognosis

Earlier reports indicated a grim prognosis for lymphangioleiomyomatosis (LAM), with progressive respiratory failure and death within 10 years of diagnosis. Recent reports, however, are more favorable, with 71% of affected patients alive at 10 years.[8] The statistics may improve further as patients are diagnosed earlier (lead-time bias) or with more benign disease.

Poor prognostic factors include the following:

  • Reduced forced expiratory volume in 1 second and/or diffusing capacity for carbon monoxide[25, 33]
  • A low LAM histology score, which quantifies the involvement of the lung with both LAM cells and cysts[8]
Previous
Next

Patient Education

Inform patients about their disease because education is an important issue in this condition. Excellent resources can be found at the LAM Foundation and the National Heart Lung and Blood Institute.

Previous
 
 
Contributor Information and Disclosures
Author

Joel Moss, MD, PhD Deputy Chief, Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health

Joel Moss, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American Society for Clinical Investigation, American Society for Biochemistry and Molecular Biology, American Thoracic Society, Association of American Physicians, Phi Beta Kappa

Disclosure: Nothing to disclose.

Coauthor(s)

Arnold S Kristof, MDCM, FRCPC Associate Professor of Medicine, Department of Medicine, Respiratory and Critical Care Divisions; Associate Member, Department of Microbiology and Immunology; Research Director, Meakins-Christie Laboratories, McGill University Faculty of Medicine; Attending Physician, Respiratory and Critical Care Divisions, McGill University Health Centre, Royal Victoria Hospital, Canada

Arnold S Kristof, MDCM, FRCPC is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Royal College of Physicians and Surgeons of Canada, American Society for Biochemistry and Molecular Biology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Harold L Manning, MD Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School

Harold L Manning, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Acknowledgements

John A Kelly, MB, BCh, MD † Assistant Professor of Medicine and Microbiology and Immunology, Dartmouth Medical School; Staff Pulmonologist, White River Junction Veterans Affairs Medical Center.

Acknowledgments

This work was supported in part by the Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute (J.M.) as well as National Institutes of Health R01-CA125436, Tuberous Sclerosis Alliance, LAM Foundation, LAM Canada (A.K.).

References
  1. Ferrans VJ, Yu ZX, Nelson WK, Valencia JC, Tatsuguchi A, Avila NA, et al. Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features. J Nihon Med Sch. 2000 Oct. 67(5):311-29. [Medline].

  2. Darling TN, Pacheco-Rodriguez G, Gorio A, Lesma E, Walker C, Moss J. Lymphangioleiomyomatosis and TSC2-/- cells. Lymphat Res Biol. 2010 Mar. 8(1):59-69. [Medline]. [Full Text].

  3. Moss J. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. 1st ed. New York, NY: Marcel Decker; 1999.

  4. Hayashi T, Fleming MV, Stetler-Stevenson WG, Liotta LA, Moss J, Ferrans VJ, et al. Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum Pathol. 1997 Sep. 28(9):1071-8. [Medline].

  5. Yu JJ, Robb VA, Morrison TA, Ariazi EA, Karbowniczek M, Astrinidis A, et al. Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc Natl Acad Sci U S A. 2009 Feb 24. 106(8):2635-40. [Medline]. [Full Text].

  6. Meraj R, Wikenheiser-Brokamp KA, Young LR, McCormack FX. Lymphangioleiomyomatosis: new concepts in pathogenesis, diagnosis, and treatment. Semin Respir Crit Care Med. 2012 Oct. 33(5):486-97. [Medline].

  7. Harknett EC, Chang WY, Byrnes S, Johnson J, Lazor R, Cohen MM, et al. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM. 2011 Nov. 104(11):971-9. [Medline].

  8. Matsui K, Beasley MB, Nelson WK, Barnes PM, Bechtle J, Falk R, et al. Prognostic significance of pulmonary lymphangioleiomyomatosis histologic score. Am J Surg Pathol. 2001 Apr. 25(4):479-84. [Medline].

  9. Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006 Jan 1. 173(1):105-11. [Medline].

  10. Oberstein EM, Fleming LE, Gomez-Marin O, Glassberg MK. Pulmonary lymphangioleiomyomatosis (LAM): examining oral contraceptive pills and the onset of disease. J Womens Health (Larchmt). 2003 Jan-Feb. 12(1):81-5. [Medline].

  11. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006 Sep 28. 355(13):1345-56. [Medline].

  12. 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 U S A. 2000 May 23. 97(11):6085-90. [Medline].

  13. Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EP. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am J Hum Genet. 1998 Apr. 62(4):810-5. [Medline].

  14. Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest. 2010 Sep. 138(3):674-81. [Medline]. [Full Text].

  15. Young L, Lee HS, Inoue Y, Moss J, Singer LG, et al. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013 Aug. 1(6):445-52. [Medline]. [Full Text].

  16. Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J. Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest. 2009 May. 135(5):1293-300. [Medline]. [Full Text].

  17. Moss J, DeCastro R, Patronas NJ, Taveira-DaSilva A. Meningiomas in lymphangioleiomyomatosis. JAMA. 2001 Oct 17. 286(15):1879-81. [Medline].

  18. Taveira-Dasilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J. Bone mineral density in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2005 Jan 1. 171(1):61-7. [Medline].

  19. Taylor JR, Ryu J, Colby TV, Raffin TA. Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med. 1990 Nov 1. 323(18):1254-60. [Medline].

  20. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, Kristof AS, Avila NA, Rabel A, et al. Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2003 Dec 15. 168(12):1427-31. [Medline].

  21. Harari S, Torre O, Cassandro R, Taveira-DaSilva AM, Moss J. Bronchoscopic diagnosis of Langerhans cell histiocytosis and lymphangioleiomyomatosis. Respir Med. 2012 Sep. 106(9):1286-92. [Medline]. [Full Text].

  22. Adema GJ, de Boer AJ, Vogel AM, Loenen WA, Figdor CG. Molecular characterization of the melanocyte lineage-specific antigen gp100. J Biol Chem. 1994 Aug 5. 269(31):20126-33. [Medline].

  23. [Guideline] Johnson, S.R.; Cordier, J.F.; Lazor, R.; Cottin, V.; Costabel, U.; Harari, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur.Respir J. 01/2010. 35:14-26. [Medline].

  24. Bonetti F, Pea M, Martignoni G, Zamboni G, Iuzzolino P. Cellular heterogeneity in lymphangiomyomatosis of the lung. Hum Pathol. 1991 Jul. 22(7):727-8. [Medline].

  25. Taveira-DaSilva AM, Hedin C, Stylianou MP, Travis WD, Matsui K, Ferrans VJ, et al. Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2001 Sep 15. 164(6):1072-6. [Medline].

  26. Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med. 1996 Oct 24. 335(17):1275-80. [Medline].

  27. Taveira-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 Dec. 126(6):1867-74. [Medline].

  28. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28. 364(17):1595-606. [Medline]. [Full Text].

  29. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10. 358(2):140-51. [Medline].

  30. Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med. 2011 Jun 21. 154(12):797-805, W-292-3. [Medline]. [Full Text].

  31. Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res. 2011 Jun 15. 17(12):4071-81. [Medline].

  32. Williams JM, Racadio JM, Johnson ND, Donnelly LF, Bissler JJ. Embolization of renal angiomyolipomata in patients with tuberous sclerosis complex. Am J Kidney Dis. 2006 Jan. 47(1):95-102. [Medline].

  33. Kitaichi M, Nishimura K, Itoh H, Izumi T. Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med. 1995 Feb. 151(2 Pt 1):527-33. [Medline].

  34. Kristof AS. mTOR signaling in lymphangioleiomyomatosis. Lymphat Res Biol. 2010 Mar. 8(1):33-42. [Medline]. [Full Text].

Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.