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Lymphangioleiomyomatosis

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Book cover Molecular Basis of Pulmonary Disease

Part of the book series: Respiratory Medicine ((RM))

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Abstract

Lymphangioleiomyomatosis is a rare, cystic lung disease of women that most commonly presents with progressive dyspnea on exertion and recurrent pneumothorax in the third or fourth decade of life (1). LAM can also be associated with abdominal and thoracic lymphadenopathy, renal and extrarenal angiomyolipomas, and chylous fluid collections in the abdomen, chest, or pericardium. LAM occurs almost exclusively in females, for reasons that are not understood, but biopsy-documented LAM in males has also been reported. Cystic changes consistent with LAM are found in about 30–40% of women who have the heritable disease tuberous sclerosis complex (TSC), a neurocutaneous tumor suppressor syndrome. TSC-associated LAM (TSC-LAM) is frequently asymptomatic. LAM also occurs in patients who do not have TSC, and despite an estimated prevalence that is 10-fold lower than that of TSC-LAM, these “sporadic LAM or S-LAM” patients generally outnumber TSC-LAM patients 6:1 in pulmonary clinics and registries around the world. S-LAM is also associated with TSC mutations, but they are found only in the neoplastic lesions in the lung, kidney, and lymphatics, and not in normal tissues or in the circulating blood cells. The histopathologic hallmark of LAM in the lung is interstitial expansion with benign-appearing smooth muscle cells, which infiltrate all lung structures, including alveolar septa, airways, blood vessels, lymphatics, and pleura. The origin of the invading cells is unknown, but available evidence suggests an extrapulmonary source. Two metastatic mechanisms have been proposed: dissemination from angiomyolipomas and pulmonary microvascular dissemination of LAM cell clusters originating in the lymphatics and gaining access to the venous circulation at the level of the thoracic duct. The prognosis in LAM depends on the mode of presentation and is more favorable in patients who are ascertained through screening, pneumothorax or incidental findings on studies obtained for other purposes rather than through shortness of breath. There are currently no treatments which are known to be effective. Antagonism of estrogen action, using progestins or GnRh agonists, is the most commonly employed empiric therapeutic strategy. Advances in our understanding of the molecular pathogenesis of LAM have far outstripped progress in the clinical arena, and clinical trials directed at molecular targets identified through basic investigation are underway in the United States and Europe.

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References

  1. McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008;133(2):507–16.

    Article  CAS  PubMed  Google Scholar 

  2. Lutembacher R. Dysembryomes metatypiques des reins; carcinose submiliaire aigue du poumon avec emphyseme generalise et double pneumothorax. Ann Med 1918;5:435–50.

    Google Scholar 

  3. von Stossel E. Uber muskulare Cirrhose der Lunge (Muscular cirrhosis of the lung). Beitr Klin Tuberk 1937;90:432–42.

    Article  Google Scholar 

  4. Cornog JL Jr., Enterline HT. Lymphangiomyoma, a benign lesion of chyliferous lymphatics synonymous with lymphangiopericytoma. Cancer 1966;19(12):1909–30.

    Article  PubMed  Google Scholar 

  5. Corrin B, Leibow AA, Friedman PJ. Pulmonary lymphangiomyomatosis: a review. Am J Pathol 1975;79:348–82.

    CAS  PubMed  Google Scholar 

  6. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006;173(1):105–11.

    Article  PubMed  Google Scholar 

  7. Hayashida M, Seyama K, Inoue Y, Fujimoto K, Kubo K. The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors. Respirology 2007;12(4):523–30.

    Article  PubMed  Google Scholar 

  8. Urban T, Lazor R, Lacronique J, et al. Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d‘Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P). Medicine (Baltimore) 1999;78(5):321–37.

    Article  CAS  Google Scholar 

  9. Johnson SR, Whale CI, Hubbard RB, Lewis SA, Tattersfield AE. Survival and disease progression in UK patients with lymphangioleiomyomatosis. Thorax 2004;59(9):800–3.

    Article  CAS  PubMed  Google Scholar 

  10. Johnson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK. Thorax 2000;55(12):1052–7.

    Article  CAS  PubMed  Google Scholar 

  11. 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;151:527–33.

    Google Scholar 

  12. Oh YM, Mo EK, Jang SH, et al. Pulmonary lymphangioleiomyomatosis in Korea. Thorax 1999;54(7):618–21.

    Article  CAS  PubMed  Google Scholar 

  13. Aubry MC, Myers JL, Ryu JH, et al. Pulmonary lymphangioleiomyomatosis in a man. Am J Respir Crit Care Med 2000;162(2 Pt 1):749–52.

    CAS  PubMed  Google Scholar 

  14. Miyake M, Tateishi U, Maeda T, et al. Pulmonary lymphangioleiomyomatosis in a male patient with tuberous sclerosis complex. Radiat Med 2005;23(7):525–7.

    PubMed  Google Scholar 

  15. Kim NR, Chung MP, Park CK, Lee KS, Han J. Pulmonary lymphangioleiomyomatosis and multiple hepatic angiomyolipomas in a man. Pathol Int 2003;53(4):231–5.

    Article  PubMed  Google Scholar 

  16. Schiavina M, Di Scioscio V, Contini P, et al. Pulmonary lymphangioleiomyomatosis in a karyotypically normal man without tuberous sclerosis complex. Am J Respir Crit Care Med 2007;176(1):96–8.

    Article  PubMed  Google Scholar 

  17. 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;164(4):669–71.

    CAS  PubMed  Google Scholar 

  18. Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000;75(6):591–4.

    Article  CAS  PubMed  Google Scholar 

  19. Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 2001;164(4):661–8.

    CAS  PubMed  Google Scholar 

  20. O’Callaghan FJ, Shiell AW, Osborne JP, Martyn CN. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 1998;351(9114):1490.

    Article  PubMed  Google Scholar 

  21. Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes Chromosomes Cancer 2003;38(4):376–81.

    Article  CAS  PubMed  Google Scholar 

  22. Juvet SC, McCormack FX, Kwiatkowski DJ, Downey GP. Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans. Am J Respir Cell Mol Biol 2007;36(4):398–408.

    Article  CAS  PubMed  Google Scholar 

  23. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75(7):1305–15.

    Google Scholar 

  24. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277(5327):805–8.

    Article  PubMed  Google Scholar 

  25. Casper KA, Donnelly LF, Chen B, Bissler JJ. Tuberous sclerosis complex: renal imaging findings. Radiology 2002;225(2):451–6.

    Article  PubMed  Google Scholar 

  26. Karbowniczek M, Yu J, Henske EP. Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and non-neoplastic vascular structures. Am J Pathol 2003;162(2):491–500.

    CAS  PubMed  Google Scholar 

  27. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001;1(2):157–62.

    Article  CAS  PubMed  Google Scholar 

  28. Henske EP, Scheithauer BW, Short MP, et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 1996;59(2):400–6.

    CAS  PubMed  Google Scholar 

  29. Yu J, Astrinidis A, Henske EP. Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am J Respir Crit Care Med 2001;164(8 Pt 1):1537–40.

    CAS  PubMed  Google Scholar 

  30. Strizheva GD, Carsillo T, Kruger WD, Sullivan EJ, Ryu JH, Henske EP. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am J Respir Crit Care Med 2001;163:253–8.

    CAS  PubMed  Google Scholar 

  31. Moss J, DeCastro R, Patronas NJ, Taveira-DaSilva A. Meningiomas in lymphangioleiomyomatosis. JAMA 2001;286(15):1879–81.

    Article  CAS  PubMed  Google Scholar 

  32. 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;97(11):6085–90.

    Article  CAS  PubMed  Google Scholar 

  33. Sato T, Seyama K, Fujii H, et al. Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. J Hum Genet 2002;47(1):20–8.

    Article  CAS  PubMed  Google Scholar 

  34. Sato T, Seyama K, Kumasaka T, et al. A patient with TSC1 germline mutation whose clinical phenotype was limited to lymphangioleiomyomatosis. J Intern Med 2004;256(2):166–73.

    Article  CAS  PubMed  Google Scholar 

  35. Astrinidis A, Khare L, Carsillo T, et al. Mutational analysis of the tuberous sclerosis gene TSC2 in patients with pulmonary lymphangioleiomyomatosis. J Med Genet 2000;37(1):55–7.

    Article  CAS  PubMed  Google Scholar 

  36. Avila NA, Kelly JA, Chu SC, Dwyer AJ, Moss J. Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology 2000;216(1):147–53.

    CAS  PubMed  Google Scholar 

  37. Bernstein SM, Newell JD, Jr., Adamczyk D, Mortensen R, King TE, Jr., Lynch DA. How common are renal angiomyolipomas in patients with pulmonary lymphangiomyomatosis? Am J Respir Crit Care Med 1995;152:2138–43.

    CAS  PubMed  Google Scholar 

  38. 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;62:810–5.

    Article  CAS  PubMed  Google Scholar 

  39. Karbowniczek M, Astrinidis A, Balsara BR, et al. Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med 2003;167(7):976–82.

    Article  PubMed  Google Scholar 

  40. Bittmann I, Rolf B, Amann G, Lohrs U. Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis. Hum Pathol 2003;34(1):95–8.

    Article  PubMed  Google Scholar 

  41. Crooks DM, Pacheco-Rodriguez G, DeCastro RM, et al. Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc Natl Acad Sci U S A 2004;101(50):17462–7.

    Article  CAS  PubMed  Google Scholar 

  42. El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 2003;361(9366):1348–9.

    Article  CAS  PubMed  Google Scholar 

  43. Robb VA, Astrinidis A, Henske EP. Frequent [corrected] hyperphosphorylation of ribosomal protein S6 [corrected] in lymphangioleiomyomatosis-associated angiomyolipomas. Mod Pathol 2006;19(6):839–46.

    Article  CAS  PubMed  Google Scholar 

  44. Ito N, Rubin GM. gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 1999;96(4):529–39.

    Article  CAS  PubMed  Google Scholar 

  45. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14(14):1296–302.

    Article  CAS  PubMed  Google Scholar 

  46. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6(11):1122–8.

    Article  CAS  PubMed  Google Scholar 

  47. Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002;10(3):457–68.

    Article  CAS  PubMed  Google Scholar 

  48. Plank TL, Yeung RS, Henske EP. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res 1998;58(21):4766–70.

    CAS  PubMed  Google Scholar 

  49. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4(9):648–57.

    Article  CAS  PubMed  Google Scholar 

  50. Gao X, Zhang Y, Arrazola P, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002;4(9):699–704.

    Article  CAS  PubMed  Google Scholar 

  51. Jaeschke A, Hartkamp J, Saitoh M, et al. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J Cell Biol 2002;159(2):217–24.

    Article  CAS  PubMed  Google Scholar 

  52. Kozma SC, Thomas G. Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays 2002;24(1):65–71.

    Article  CAS  PubMed  Google Scholar 

  53. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001;411(6835):355–65.

    Article  CAS  PubMed  Google Scholar 

  54. Stocker H, Radimerski T, Schindelholz B, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 2003;5(6):559–65.

    Article  CAS  PubMed  Google Scholar 

  55. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 2003;5(6):566–71.

    Article  CAS  PubMed  Google Scholar 

  56. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 2003;5(6):578–81.

    Article  CAS  PubMed  Google Scholar 

  57. Garami A, Zwartkruis FJ, Nobukuni T, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003;11(6):1457–66.

    Article  CAS  PubMed  Google Scholar 

  58. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 2003;13(15):1259–68.

    Article  CAS  PubMed  Google Scholar 

  59. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003;17(15):1829–34.

    Article  CAS  PubMed  Google Scholar 

  60. Ma RY, Tong TH, Cheung AM, Tsang AC, Leung WY, Yao KM. Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. J Cell Sci 2005;118(Pt 4):795–806.

    Article  CAS  PubMed  Google Scholar 

  61. Li Y, Inoki K, Vacratsis P, Guan KL. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. J Biol Chem 2003;278(16):13663–71.

    Article  CAS  PubMed  Google Scholar 

  62. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002;10(1):151–62.

    Article  CAS  PubMed  Google Scholar 

  63. Dan HC, Sun M, Yang L, et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2002;277(38):35364–70.

    Article  CAS  PubMed  Google Scholar 

  64. Marygold SJ, Leevers SJ. Growth signaling: TSC takes its place. Curr Biol 2002; 12(22):R785–7.

    Article  CAS  PubMed  Google Scholar 

  65. Astrinidis A, Senapedis W, Coleman TR, Henske EP. Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. J Biol Chem 2003;278(51):51372–9.

    Article  CAS  PubMed  Google Scholar 

  66. Goncharova EA, Goncharov DA, Eszterhas A, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002;277(34):30958–67.

    Article  CAS  PubMed  Google Scholar 

  67. El-Hashemite N, Walker V, Zhang H, Kwiatkowski DJ. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res 2003;63(17):5173–7.

    CAS  PubMed  Google Scholar 

  68. Yu J, Astrinidis A, Howard S, Henske EP. Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am J Physiol Lung Cell Mol Physiol 2004;286(4):L694–700.

    Article  CAS  PubMed  Google Scholar 

  69. Goncharova EA, Goncharov DA, Spaits M, et al. Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: Role for tumor suppressor TSC2. Am J Respir Cell Mol Biol 2006;34(5):561–72.

    Article  CAS  PubMed  Google Scholar 

  70. Goncharova EA, Goncharov DA, Lim PN, Noonan D, Krymskaya VP. Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2006;34(4):473–80.

    Article  CAS  PubMed  Google Scholar 

  71. Seyama K, Kumasaka T, Souma S, et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol 2006;4(3):143–52.

    Article  CAS  PubMed  Google Scholar 

  72. Kumasaka T, Seyama K, Mitani K, et al. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol 2005;29(10):1356–66.

    Article  PubMed  Google Scholar 

  73. Kumasaka T, Seyama K, Mitani K, et al. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol 2004;28(8):1007–16.

    Article  PubMed  Google Scholar 

  74. Castro M, Shepherd CW, Gomez MR, Lie JT, Ryu JH. Pulmonary tuberous sclerosis. Chest 1995;107(1):189–95.

    Article  CAS  PubMed  Google Scholar 

  75. Davydov MI, Matveev VB, Lukianchenko AB, Kudashev BV, Petrovichev NN. Renal angiomyolipoma extending into the right atrium. Urol Int 2001;67(2):168–9.

    Article  CAS  PubMed  Google Scholar 

  76. Finlay GA, Malhowski AJ, Liu Y, Fanburg BL, Kwiatkowski DJ, Toksoz D. Selective inhibition of growth of tuberous sclerosis complex 2 null cells by atorvastatin is associated with impaired Rheb and Rho GTPase function and reduced mTOR/S6 kinase activity. Cancer Res 2007;67(20):9878–86.

    Article  CAS  PubMed  Google Scholar 

  77. Lim SD, Stallcup W, Lefkove B, et al. Expression of the neural stem cell markers NG2 and L1 in human angiomyolipoma: are angiomyolipomas neoplasms of stem cells? Mol Med 2007;13(3–4):160–5.

    CAS  PubMed  Google Scholar 

  78. Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 2005;29(12):1558–75.

    Article  PubMed  Google Scholar 

  79. Bonetti F, Pea M, Martignoni G, et al. Clear cell (“sugar”) tumor of the lung is a lesion strictly related to angiomyolipoma – the concept of a family of lesions characterized by the presence of the perivascular epithelioid cells (PEC). Pathology 1994;26(3):230–6.

    Article  CAS  PubMed  Google Scholar 

  80. Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology 2006;48(1):75–82.

    Article  CAS  PubMed  Google Scholar 

  81. Henry KW, Yuan X, Koszewski NJ, Onda H, Kwiatkowski DJ, Noonan DJ. Tuberous sclerosis gene 2 product modulates transcription mediated by steroid hormone receptor family members. J Biol Chem 1998;273(32):20535–9.

    Article  CAS  PubMed  Google Scholar 

  82. Noonan DJ, Lou D, Griffith N, Vanaman TC. A calmodulin binding site in the tuberous sclerosis 2 gene product is essential for regulation of transcription events and is altered by mutations linked to tuberous sclerosis and lymphangioleiomyomatosis. Arch Biochem Biophys 2002;398(1):132–40.

    Article  CAS  PubMed  Google Scholar 

  83. Finlay GA, York B, Karas RH, et al. Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-beta and ERK-1/2. J Biol Chem 2004;279(22):23114–22.

    Article  CAS  PubMed  Google Scholar 

  84. York B, Lou D, Panettieri RA Jr., Krymskaya VP, Vanaman TC, Noonan DJ. Cross-talk between tuberin, calmodulin, and estrogen signaling pathways. Faseb J 2005;19(9): 1202–4.

    CAS  PubMed  Google Scholar 

  85. Levin ER. Cellular functions of plasma membrane estrogen receptors. Steroids 2002;67(6):471–5.

    Article  CAS  PubMed  Google Scholar 

  86. Kousteni S, Bellido T, Plotkin LI, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001;104(5):719–30.

    CAS  PubMed  Google Scholar 

  87. Razandi M, Pedram A, Levin ER. Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Mol Endocrinol 2000;14(9):1434–47.

    Article  CAS  PubMed  Google Scholar 

  88. Razandi M, Pedram A, Levin ER. Estrogen signals to the preservation of endothelial cell form and function. J Biol Chem 2000;275(49):38540–6.

    Article  CAS  PubMed  Google Scholar 

  89. Flores-Delgado G, Bringas P, Buckley S, Anderson KD, Warburton D. Nongenomic estrogen action in human lung myofibroblasts. Biochem Biophys Res Commun 2001;283(3):661–7.

    Article  CAS  PubMed  Google Scholar 

  90. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000;407(6803):538–41.

    Article  CAS  PubMed  Google Scholar 

  91. Simoncini T, Rabkin E, Liao JK. Molecular basis of cell membrane estrogen receptor interaction with phosphatidylinositol 3-kinase in endothelial cells. Arterioscler Thromb Vasc Biol 2003;23(2):198–203.

    Article  CAS  PubMed  Google Scholar 

  92. Castoria G, Migliaccio A, Bilancio A, et al. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. Embo J 2001;20(21):6050–9.

    Article  CAS  PubMed  Google Scholar 

  93. Duan R, Xie W, Li X, McDougal A, Safe S. Estrogen regulation of c-fos gene expression through phosphatidylinositol-3-kinase-dependent activation of serum response factor in MCF-7 breast cancer cells. Biochem Biophys Res Commun 2002;294(2):384–94.

    Article  CAS  PubMed  Google Scholar 

  94. Pedram A, Razandi M, Aitkenhead M, Hughes CC, Levin ER. Integration of the non-genomic and genomic actions of estrogen. Membrane-initiated signaling by steroid to transcription and cell biology. J Biol Chem 2002;277(52):50768–75.

    Article  CAS  PubMed  Google Scholar 

  95. Yu J, Astrinidis A, Howard S, Henske EP. Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am J Physiol Lung Cell Mol Physiol 2004;286(4):L694–700.

    Article  CAS  PubMed  Google Scholar 

  96. Govindarajan B, Mizesko MC, Miller MS, Ouda H, Nunnelley M, Casper K, Brat D, Coheu C, Arbiser JL. Tuberous-sclerosis associated neoplasms express activated p42/44 mitogen-activated protein (MAP) Kinase and inhibition of MAP Kinase signaling results in decreased in vivo tumor growth. Clin Cancer Res 2003;9(9); 3469–75.

    Article  Google Scholar 

  97. Matsui K, Takeda K, Yu ZX, Travis WD, Moss J, Ferrans VJ. Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis. Arch Pathol Lab Med 2000;124(2):267–75.

    CAS  PubMed  Google Scholar 

  98. Zhe X, Yang Y, Schuger L. Imbalanced plasminogen system in lymphangioleiomyomatosis: potential role of serum response factor. Am J Respir Cell Mol Biol 2005;32(1):28–34.

    Article  CAS  PubMed  Google Scholar 

  99. Zhe X, Yang Y, Jakkaraju S, Schuger L. Tissue inhibitor of metalloproteinase-3 downregulation in lymphangioleiomyomatosis: potential consequence of abnormal serum response factor expression. Am J Respir Cell Mol Biol 2003;28(4):504–11.

    Article  CAS  PubMed  Google Scholar 

  100. Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977;113(12):1674–7.

    Article  CAS  PubMed  Google Scholar 

  101. Toro JR, Glenn G, Duray P, et al. Birt–Hogg–Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999;135(10):1195–202.

    Article  CAS  PubMed  Google Scholar 

  102. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt–Hogg–Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002;11(4):393–400.

    PubMed  Google Scholar 

  103. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt–Hogg–Dube syndrome. Cancer Cell 2002;2(2):157–64.

    Article  CAS  PubMed  Google Scholar 

  104. van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, Henske EP. The Birt–Hogg–Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe. J Biol Chem 2007;282(34):24583–90.

    Article  PubMed  CAS  Google Scholar 

  105. Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 2006;103(42):15552–7.

    Article  CAS  PubMed  Google Scholar 

  106. Baba M, Furihata M, Hong SB, et al. Kidney-targeted Birt–Hogg–Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst 2008;100(2):140–54.

    Article  CAS  PubMed  Google Scholar 

  107. McCormack FX. Lymphangioleiomyomatosis; a clinical update. Chest 2008;133(2): 507–16.

    Article  CAS  PubMed  Google Scholar 

  108. Almoosa KF, Ryu JH, Mendez J, et al. Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 2006;129(5):1274–81.

    Article  PubMed  Google Scholar 

  109. Avila NA, Dwyer AJ, Rabel A, Moss J. Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features. Radiology 2007;242(1):277–85.

    Article  PubMed  Google Scholar 

  110. Bense L, Eklund G, Wiman LG. Smoking and the increased risk of contracting spontaneous pneumothorax. Chest 1987;92(6):1009–12.

    Article  CAS  PubMed  Google Scholar 

  111. Koyama M, Johkoh T, Honda O, et al. Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients. AJR Am J Roentgenol 2003;180(3):827–35.

    PubMed  Google Scholar 

  112. Leslie KO, Gruden JF, Parish JM, Scholand MB. Transbronchial biopsy interpretation in the patient with diffuse parenchymal lung disease. Arch Pathol Lab Med 2007;131(3):407–23.

    PubMed  Google Scholar 

  113. Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med 2008;358(2):199–200.

    Article  CAS  PubMed  Google Scholar 

  114. Carrington CB, Cugell DW, Gaensler EA, et al. Lymphangioleiomyomatosis. Physiologic–pathologic–radiologic correlations. Am Rev Respir Dis 1977;116(6):977–95.

    CAS  PubMed  Google Scholar 

  115. Matsumoto Y, Horiba K, Usuki J, Chu SC, Ferrans VJ, Moss J. Markers of cell proliferation and expression of melanosomal antigen in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 1999;21(3):327–36.

    CAS  PubMed  Google Scholar 

  116. Hoon V, Thung SN, Kaneko M, Unger PDHMB-. 45 reactivity in renal angiomyolipoma and lymphangioleiomyomatosis. Arch Pathol Lab Med 1994;118(7):732–4.

    CAS  PubMed  Google Scholar 

  117. McCarty KS Jr., Mossler JA, McLelland R, Sieker HO. Pulmonary lymphangiomyomatosis responsive to progesterone. N Engl J Med 1980;303(25):1461–5.

    Article  PubMed  Google Scholar 

  118. Colley MH, Geppert E, Franklin WA. Immunohistochemical detection of steroid receptors in a case of pulmonary lymphangioleiomyomatosis. Am J Surg Pathol 1989;13(9):803–7.

    Article  CAS  PubMed  Google Scholar 

  119. Berger U, Khaghani A, Pomerance A, Yacoub MH, Coombes RC. Pulmonary lymphangioleiomyomatosis and steroid receptors. An immunocytochemical study. Am J Clin Pathol 1990;93(5):609–14.

    CAS  PubMed  Google Scholar 

  120. Matsui K, Riemenschneider W, Hilbert SL, et al. Hyperplasia of type II pneumocytes in pulmonary lymphangioleiomyomatosis. Arch Pathol Lab Med 2000;124(11):1642–8.

    CAS  PubMed  Google Scholar 

  121. Muir TE, Leslie KO, Popper H, et al. Micronodular pneumocyte hyperplasia. Am J Surg Pathol 1998;22:465–72.

    Article  CAS  PubMed  Google Scholar 

  122. Valensi QJ. Pulmonary lymphangiomyoma, a probable forme frust of tuberous sclerosis. A case report and survey of the literature. Am Rev Respir Dis 1973;108(6):1411–5.

    Google Scholar 

  123. Itami M, Teshima S, Asakuma Y, Chino H, Aoyama K, Fukushima N. Pulmonary lymphangiomyomatosis diagnosed by effusion cytology. A case report. Acta Cytol 1997;41(2):522–8.

    Google Scholar 

  124. Taveira-DaSilva AM, Hedin C, Stylianou MP, 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;164(6): 1072–6.

    CAS  PubMed  Google Scholar 

  125. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, et al. Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2003;168(12):1427–31.

    Article  PubMed  Google Scholar 

  126. Taveira-DaSilva AM, Steagall WK, Moss J. Lymphangioleiomyomatosis. Cancer Control 2006;13(4):276–85.

    PubMed  Google Scholar 

  127. Lazor R, Valeyre D, Lacronique J, Wallaert B, Urbane T, Cordier JF. Low initial KCO predicts rapid FEV1 decline in pulmonary lymphangioleiomyomatosis. Respir Med 2004;98(6):536–41.

    Article  PubMed  Google Scholar 

  128. Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999;160(2):628–33.

    CAS  PubMed  Google Scholar 

  129. De Luca S, Terrone C, Rossetti SR. Management of renal angiomyolipoma: a report of 53 cases. BJU Int 1999;83(3):215–8.

    Google Scholar 

  130. Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kid Intl 2004;66(3):924–34.

    Article  Google Scholar 

  131. Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 1996;335(17):1275–80.

    Article  CAS  PubMed  Google Scholar 

  132. Ryu JH, Doerr CH, Fisher SD, Olson EJ, Sahn SA. Chylothorax in lymphangioleiomyomatosis. Chest 2003;123(2):623–7.

    Article  PubMed  Google Scholar 

  133. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13(12):624–8.

    Article  CAS  PubMed  Google Scholar 

  134. 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;126(6):1867–74.

    Article  CAS  PubMed  Google Scholar 

  135. Harari S, Cassandro R, Chiodini J, Taveira-DaSilva AM, Moss J. Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis. Chest 2008;133(2):448–54.

    Article  CAS  PubMed  Google Scholar 

  136. Seyama K, Kira S, Takahashi H, et al. Longitudinal follow-up study of 11 patients with pulmonary lymphangioleiomyomatosis: diverse clinical courses of LAM allow some patients to be treated without anti-hormone therapy. Respirology 2001;6(4):331–40.

    Article  CAS  PubMed  Google Scholar 

  137. Schiavina M, Contini P, Fabiani A, et al. Efficacy of hormonal manipulation in lymphangioleiomyomatosis. A 20-year-experience in 36 patients. Sarcoidosis Vasc Diffuse Lung Dis 2007;24(1):39–50.

    PubMed  Google Scholar 

  138. Banner AS, Carrington CB, Emory WB, et al. Efficacy of oophorectomy in lymphangioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med 1981;305(4):204–9.

    Article  CAS  PubMed  Google Scholar 

  139. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358(2):140–51.

    Article  CAS  PubMed  Google Scholar 

  140. Bando K, Paradis IL, Keenan RJ, et al. Comparison of outcomes after single and bilateral lung transplantation for obstructive lung disease. J Heart Lung Transplant 1995;14(4):692–8.

    CAS  PubMed  Google Scholar 

  141. Nine JS, Yousem SA, Paradis IL, Keenan R, Griffith BP. Lymphangioleiomyomatosis: Recurrence after lung transplantation. J Heart Lung Trans 1994;13:714–9.

    CAS  Google Scholar 

  142. O’Brien JD, Lium JH, Parosa JF, Deyoung BR, Wick MR, Trulock EP. Lymphangioleiomyomatosis recurrence in the allograft after single lung transplantation. Am J Respir Crit Care 1995;151:2033–6.

    Google Scholar 

  143. Lee L, Sudentas P, Dabora SL. Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex. Genes Chromosomes Cancer 2006;45(10):933–44.

    Article  PubMed  CAS  Google Scholar 

  144. Lee L, Sudentas P, Donohue B, et al. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer 2005;42(3):213–27.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Elizabeth P. Henske MD, PhD

  2. Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA

    Francis X. McCormack MD

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  1. Elizabeth P. Henske MD, PhD
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  1. Div. Pulmonary & Critical Care, University of Cincinnati, Albert Sabin Way 231, Cincinnati, 45267, USA

    Francis X. McCormack

  2. Div. Pulmonary & Critical Care, University of Cincinnati, Albert Sabin Way 231, Cincinnati, 45267, USA

    Ralph J. Panos

  3. Medical Center, Cincinnati Children's Hospital, Burnet Ave. 3333, Cincinnati, 45229, USA

    Bruce C. Trapnell

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Henske, E.P., McCormack, F.X. (2010). Lymphangioleiomyomatosis. In: McCormack, F., Panos, R., Trapnell, B. (eds) Molecular Basis of Pulmonary Disease. Respiratory Medicine. Humana Press. https://doi.org/10.1007/978-1-59745-384-4_4

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