Lymphangiomyomatosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Jogeet Singh Sekhon, M.D. [2]

Synonyms and Keywords: Lymphangioleiomyomatosis; LAM; Pulmonary lymphangioleiomyomatosis; Pulmonary lymphangiomyomatosis

Overview

Lymphangiomyomatosis is a disorder resulting from proliferation of abnormal smooth muscle like cells, mostly in the lungs but can also occur in other body parts such as kidney, mediastinum or axial lymphatics. Lymphangiomyomatosis is characterized by small mediastinal or retro- peritoneal tumors which involve the thoracic duct and consist of numerous smooth muscle bundles interspersed with lymphatic channels. Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as asthma, spontaneous pneumothorax, emphysema, interstitial pulmonary fibrosis, eosinophilic granuloma (EG), Birt-Hogg-Dube syndrome, lymphangiomas, pulmonary lymphangiectasis, and leiomyosarcoma. Symptoms of lymphangiomyomatosis may include constipation, dyspnea, and cough. The mainstay of therapy for lymphangiomyomatosisis include sirolimus, medroxyprogesterone, gonadotropin-releasing hormone agonists, and tamoxifen. The most effective treatment is lung transplant.

Historical Perspective

It was first described by Van Stossel in the year 1937.

Classification

Lymphangiomyomatosis is classified into:

Pathophysiology

  • Lymphangiomyomatosis is a disorder resulting from proliferation of abnormal smooth muscle like cells, mostly in the lungs but can also occur in other body parts such as kidney, mediastinum or axial lymphatics[2][3][4].
  • Lymphangiomyomatosis is characterized by small mediastinal or retro- peritoneal tumors which involve the thoracic duct and consist of numerous smooth muscle bundles interspersed with lymphatic channels[5].
  • It can occur in a sporadic form, which only affects females, who are usually of childbearing age.
  • It can also occur in patients who have tuberous sclerosis..
  • Renal angiolipomas are present in 50 % of cases of sporadic lymphangiomyomatosis[6].
  • The tuberous sclerosis complex (TSC) gene mutation has been associated with the development of lymphangiomyomatosis.
  • TSC1 and TSC2 genes located on chromosome 9q34 and 16p13, are involved in the pathogenesis.
  • TSC1 gene is responsible for the production of hamartin protein and TSC2 for the production of tuberin protein.
  • The loss of these proteins along with the influence of estrogen allows the cell to grow and divide in an uncontrolled way, resulting in the tumors and cysts associated with lymphangiomyomatosis.
  • This proliferation of immature muscle cells starts covering alveolar walls, bronchioles, pleura and vessels, including lymphatic routes.
  • Excessive proteolytic activity from the proliferation of the smooth muscle cells result in lung destruction and formation of cysts.
  • These cysts are called lymphangioleiomyomas.
  • Obstruction of lymphatics may result in chylothorax, and chylous ascites[7][8].
  • As the cysts develop throughout the lungs, lymphangiomyomatosis causes breathing problems.
  • The abnormal proliferation and formation of cysts, causes obstructive pattern of lung disease[9].

Causes

  • Lymphangiomyomatosis is caused due to mutations in TSC1 and TSC2 genes.

Differentiating Lymphangiomyomatosis from other Diseases

  • Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as:

Epidemiology and Demographics

  • The incidence of lymphangiomyomatosis is 0.2 per 100000 individuals[10].

Age

  • Lymphangiomyomatosis is more commonly observed among female patients aged 15-45 years old.

Gender

  • Lymphangiomyomatosis affects women exclusively who are of reproductive age group.

Race

  • There is no racial predilection for lymphangiomyomatosis.

Natural History, Complications and Prognosis

Natural history

Patients will have a history of[2][11][12][13]:

Complications

Prognosis

  • The prognosis of lymphangiomyomatosis is poor, with 70% of patients not surviving more than 10 years after diagnosis.
  • Poor prognostic factors include:
    • Reduced FEV1.
    • Reduced diffusion lung capacity to carbon monoxide.
    • Formation of cysts in lungs.

Diagnosis

Symptoms

Physical Examination

  • Physical examination may be remarkable for:

Laboratory Findings

Imaging Findings

Other diagnostic studies

  • Transbronchial lung biopsy[9].
  • Surgical lung biopsy
  • On biopsy, the histopathological findings are:
    • Proliferation of spindle-shaped myoid cells that are arranged in short fascicles around arterioles, venules, and lymphatics which causes thickening of alveolar septa and formation of cysts.
    • The spindle cell proliferation can result in formation of nodules.
    • The tumor cells may invade lymphatics and blood vessels causing secondary hemorrhage and destruction of the septal wall.
  • Immunohistopathological results of the biopsy are:

Treatment

Medical Therapy

Surgery

  • Lung transplant is performed for patients with recurrent lymphangiomyomatosis resistant to medical therapy[21].

Prevention

  • Lymphangiomyomatosis cannot be prevented as it is caused due to gene mutations, mechanism of which is unknown.
  • However, the lung damage can be reduced by using the following measures[22]:

References

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  2. 2.0 2.1 Sullivan EJ (1998). "Lymphangioleiomyomatosis: a review.". Chest. 114 (6): 1689–703. PMID 9872207. 
  3. 3.0 3.1 Johnson S (1999). "Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms.". Thorax. 54 (3): 254–64. PMC 1745441Freely accessible. PMID 10325903. 
  4. Matsui K, Tatsuguchi A, Valencia J, Yu Zx, Bechtle J, Beasley MB; et al. (2000). "Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases.". Hum Pathol. 31 (10): 1242–8. PMID 11070117. 
  5. Kebria M, Black D, Borelli C, Modica I, Hensley M, Chi DS (2007). "Primary retroperitoneal lymphangioleiomyomatosis in a postmenopausal woman: a case report and review of the literature.". Int J Gynecol Cancer. 17 (2): 528–32. PMID 17362325. doi:10.1111/j.1525-1438.2007.00785.x. 
  6. Hancock E, Osborne J (2002). "Lymphangioleiomyomatosis: a review of the literature.". Respir Med. 96 (1): 1–6. PMID 11863203. 
  7. Richter MJ, Baumgartner R, Leuchte HH (2013). "[Chylothorax in an 87-year-old patient].". Internist (Berl). 54 (1): 105–9. PMID 23111591. doi:10.1007/s00108-012-3158-7. 
  8. Ryu JH, Doerr CH, Fisher SD, Olson EJ, Sahn SA (2003). "Chylothorax in lymphangioleiomyomatosis.". Chest. 123 (2): 623–7. PMID 12576391. 
  9. 9.0 9.1 Crausman RS, Jennings CA, Mortenson RL, Ackerson LM, Irvin CG, King TE (1996). "Lymphangioleiomyomatosis: the pathophysiology of diminished exercise capacity.". Am J Respir Crit Care Med. 153 (4 Pt 1): 1368–76. PMID 8616568. doi:10.1164/ajrccm.153.4.8616568. 
  10. Hayashida M, Seyama K, Inoue Y, Fujimoto K, Kubo K, Respiratory Failure Research Group of the Japanese Ministry of Health, Labor, and Welfare (2007). "The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors.". Respirology. 12 (4): 523–30. PMID 17587419. doi:10.1111/j.1440-1843.2007.01101.x. 
  11. Baldi BG, Freitas CS, Araujo MS, Dias OM, Pereira DA, Pimenta SP; et al. (2014). "Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre.". Sarcoidosis Vasc Diffuse Lung Dis. 31 (2): 129–35. PMID 25078640. 
  12. Nagy B, Nábrády Z, Nemes Z (1998). "Pulmonary lymphangiomyomatosis in a preadolescent girl.". N Engl J Med. 338 (7): 473–4. PMID 9463158. doi:10.1056/NEJM199802123380715. 
  13. Johnson SR, Tattersfield AE (2000). "Clinical experience of lymphangioleiomyomatosis in the UK.". Thorax. 55 (12): 1052–7. PMC 1745654Freely accessible. PMID 11083892. 
  14. "NHLBI Workshop Summary. Report of workshop on lymphangioleiomyomatosis. National Heart, Lung, and Blood Institute.". Am J Respir Crit Care Med. 159 (2): 679–83. 1999. PMID 9927387. doi:10.1164/ajrccm.159.2.9803107. 
  15. Taveira-DaSilva AM, Steagall WK, Rabel A, Hathaway O, Harari S, Cassandro R; et al. (2009). "Reversible airflow obstruction in lymphangioleiomyomatosis.". Chest. 136 (6): 1596–1603. PMC 2818851Freely accessible. PMID 19447921. doi:10.1378/chest.09-0624. 
  16. Warren SE, Lee D, Martin V, Messink W (1993). "Pulmonary lymphangiomyomatosis causing bilateral pneumothorax during pregnancy.". Ann Thorac Surg. 55 (4): 998–1000. PMID 8466360. 
  17. Corrin B, Liebow AA, Friedman PJ (1975). "Pulmonary lymphangiomyomatosis. A review.". Am J Pathol. 79 (2): 348–82. PMC 1912658Freely accessible. PMID 1146965. 
  18. Taylor JR, Ryu J, Colby TV, Raffin TA (1990). "Lymphangioleiomyomatosis. Clinical course in 32 patients.". N Engl J Med. 323 (18): 1254–60. PMID 2215609. doi:10.1056/NEJM199011013231807. 
  19. Lama A, Ferreiro L, Golpe A, Gude F, Álvarez-Dobaño JM, González-Barcala FJ; et al. (2016). "Characteristics of Patients with Lymphangioleiomyomatosis and Pleural Effusion: A Systematic Review.". Respiration. 91 (3): 256–64. PMID 26938102. doi:10.1159/000444264. 
  20. Zanella A, Toppan P, Nitti D, Lise M (1996). "Pulmonary lymphangioleiomyomatosis: a case report in postmenopausal woman treated with pleurodesis and progesterone (medroxyprogesterone acetate).". Tumori. 82 (1): 96–8. PMID 8623516. 
  21. Almoosa KF, Ryu JH, Mendez J, Huggins JT, Young LR, Sullivan EJ; et al. (2006). "Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications.". Chest. 129 (5): 1274–81. PMID 16685019. doi:10.1378/chest.129.5.1274. 
  22. Yen KT, Putzke JD, Staats BA, Burger CD (2005). "The prevalence of acute response to bronchodilator in pulmonary lymphangioleiomyomatosis.". Respirology. 10 (5): 643–8. PMID 16268919. doi:10.1111/j.1440-1843.2005.00762.x. 

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