Lymphangioleiomyomatosis (LAM) is a rare, low-grade, metastasizing neoplasm that arises from an unknown source, spreads via the lymphatics, and targets the lungs. All pulmonary structures become infiltrated with benign-appearing spindle and epithelioid cells (LAM cells) that express smooth-muscle and melanocyte-lineage markers, harbor mTOR-activating mutations in tuberous sclerosis complex (TSC) genes, and recruit abundant stromal cells. Elaboration of lymphangiogenic growth factors and matrix remodeling enzymes by LAM cells enables their access to lymphatic channels and likely drives the cystic lung remodeling that often culminates in respiratory failure. Dysregulated cellular signaling results in a shift from oxidative phosphorylation to glycolysis as the preferred mode of energy generation, to allow for the accumulation of biomass required for cell growth and tolerance of nutrient-poor, anaerobic environments. Symptomatic LAM occurs almost exclusively in females after menarche, highlighting the central but as yet poorly understood role for sex-restricted anatomical structures and/or hormones in disease pathogenesis. LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell—metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism and the pathogenesis of cancer.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Johnson SR, Cordier JF, Lazor R. 1.  et al. 2010. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur. Respir. J. 35:14–26 [Google Scholar]
  2. Young LR, Lee HS, Inoue Y. 2.  et al. 2013. Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet 1:445–52 [Google Scholar]
  3. Young LR, VanDyke R, Gulleman PM. 3.  et al. 2010. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 138:674–81 [Google Scholar]
  4. McCormack FX, Gupta N, Finlay GR. 4.  et al. 2016. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am. J. Respir. Crit. Care Med. 194748–61
  5. Henske EP, McCormack FX. 5.  2012. Lymphangioleiomyomatosis—a wolf in sheep's clothing. J. Clin. Investig. 122:3807–16 [Google Scholar]
  6. Smolarek TA, Wessner LL, McCormack FX. 6.  et al. 1998. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiolipomas and lymph nodes from women with lymphangiomyomatosis. Am. J. Hum. Genet. 62:810–15 [Google Scholar]
  7. Carsillo T, Astrinidis A, Henske EP. 7.  2000. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. PNAS 97:6085–90 [Google Scholar]
  8. Hammes SR, Krymskaya VP. 8.  2013. Targeted approaches toward understanding and treating pulmonary lymphangioleiomyomatosis (LAM). Horm. Cancer 4:70–77 [Google Scholar]
  9. Yu J, Astrinidis A, Henske EP. 9.  2001. Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am. J. Respir. Crit. Care Med. 164:1537–40 [Google Scholar]
  10. Seyama K, Kumasaka T, Kurihara M. 10.  et al. 2010. Lymphangioleiomyomatosis: a disease involving the lymphatic system. Lymphatic Res. Biol. 8:21–31 [Google Scholar]
  11. Knudson AG. 11.  2001. Two genetic hits (more or less) to cancer. Nat. Rev. Cancer 1:157–62 [Google Scholar]
  12. Juvet SC, McCormack FX, Kwiatkowski DJ, Downey GP. 12.  2006. Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans. Am. J. Respir. Cell Mol. Biol. 36:398–408 [Google Scholar]
  13. van Slegtenhorst M, Hoogt RD, Hermans C. 13.  et al. 1997. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–8 [Google Scholar]
  14. 14. European Chromosome 16 Tuberous Sclerosis Consortium 1993. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–15 [Google Scholar]
  15. Ito M, Rubin GM. 15.  1999. gigas, a Drosophila homolog of tuberous sclerosis complex gene product-2, regulates the cell cycle. Cell 96:529–39 [Google Scholar]
  16. Gao X, Pan D. 16.  2001. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 15:1383–92 [Google Scholar]
  17. Montagne J, Radimerski T, Thomas G. 17.  2001. Insulin signaling: lessons from the Drosophila tuberous sclerosis complex, a tumor suppressor. Science's STKE 105:PE36 [Google Scholar]
  18. Potter CJ, Huang H, Xu T. 18.  2001. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105:357–68 [Google Scholar]
  19. Tapon N, Ito N, Dickson BJ. 19.  et al. 2001. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105:345–55 [Google Scholar]
  20. McManus EJ, Alessi DR. 20.  2002. TSC1-TSC2: a complex tale of PKB-mediated S6K regulation. Nat. Cell Biol. 4:E214–E216 [Google Scholar]
  21. Inoki K, Ouyang H, Li Y, Guan K-L. 21.  2005. Signaling by target of rapamycin proteins in cell growth control. Microbiol. Mol. Biol. Rev. 69:79–100 [Google Scholar]
  22. Zoncu R, Efeyan A, Sabatini DM. 22.  2011. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12:21–35 [Google Scholar]
  23. Guertin DA, Sabatini DM. 23.  2009. The pharmacology of mTOR inhibition. Sci. Signal. 2:pe24 [Google Scholar]
  24. Chantranupong L, Wolfson RL, Sabatini DM. 24.  2015. Nutrient-sensing mechanisms across evolution. Cell 161:67–83 [Google Scholar]
  25. Huang J, Dibble CC, Matsuzaki M, Manning BD. 25.  2008. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol. Cell Biol. 28:4104–15 [Google Scholar]
  26. Goncharova EA, Goncharov DA, Li H. 26.  et al. 2011. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol. Cell Biol. 31:2484–98 [Google Scholar]
  27. Guertin DA, Sabatini DM. 27.  2007. Defining the role of mTOR in cancer. Canc. Cell 12:9–22 [Google Scholar]
  28. Hanahan D, Weinberg Robert A. 28.  2011. Hallmarks of cancer: the next generation. Cell 144:646–74 [Google Scholar]
  29. Dibble CC, Cantley LC. 29.  2015. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 25:545–55 [Google Scholar]
  30. Inoki K, Corradetti MN, Guan K-L. 30.  2005. Dysregulation of the TSC-mTOR pathway in human disease. Nat. Genet. 37:19–24 [Google Scholar]
  31. Menon S, Dibble CC, Talbott G. 31.  et al. 2014. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771–85 [Google Scholar]
  32. Zhang Y, Gao X, Saucedo LJ. 32.  et al. 2003. Rheb is a direct target of the tuberous sclerosis tumor suppressor proteins. Nat. Cell Biol. 5:578–81 [Google Scholar]
  33. Tee AR, Manning BD, Roux PP. 33.  et al. 2003. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13:1259–68 [Google Scholar]
  34. Tabancay AP Jr., Gau C-L, Machado IMP. 34.  et al. 2003. Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J. Biol. Chem. 278:39921–30 [Google Scholar]
  35. Dibble CC, Manning BD. 35.  2013. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat. Cell Biol. 15:555–64 [Google Scholar]
  36. Tsun Z-Y, Bar-Peled L, Chantranupong L. 36.  et al. 2013. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol. Cell 52:495–505 [Google Scholar]
  37. Schmidt LS, Linehan WM. 37.  2015. Clinical features, genetics and potential therapeutic approaches for Birt-Hogg-Dubé syndrome. Expert Opin. Orphan Drugs 3:15–29 [Google Scholar]
  38. Goncharova EA, Goncharov DA, James ML. 38.  et al. 2014. Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK. Cell Rep 7:412–23 [Google Scholar]
  39. Harrington LS, Findlay GM, Gray A. 39.  et al. 2004. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166:213–23 [Google Scholar]
  40. Shah OJ, Wang Z, Hunter T. 40.  2004. Inappropiate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14:1650–56 [Google Scholar]
  41. Hsu PP, Kang SA, Rameseder J. 41.  et al. 2011. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317–22 [Google Scholar]
  42. Yea SS, Fruman DA. 42.  2011. New mTOR targets Grb attention. Science 332:1270–71 [Google Scholar]
  43. Yu Y, Yoon S-O, Poulogiannis G. 43.  et al. 2011. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332:1322–26 [Google Scholar]
  44. Ding M, Bruick RK, Yu Y. 44.  2016. Secreted IGFBP5 mediates mTORC1-dependent feedback inhibition of IGF-1 signalling. Nat. Cell Biol. 18:319–27 [Google Scholar]
  45. Manning BD, Logsdon MN, Lipovsky AI. 45.  et al. 2005. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 19:1773–78 [Google Scholar]
  46. DeNicola GM, Cantley LC. 46.  2015. Cancer's fuel choice: new flavors for a picky eater. Mol. Cell 60:514–23 [Google Scholar]
  47. Vander Heiden MG, Cantley LC, Thompson CB. 47.  2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–33 [Google Scholar]
  48. Brugarolas J, Kaelin JWG. 48.  2004. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6:7–10 [Google Scholar]
  49. Brugarolas JB, Vazquez F, Reddy A. 49.  et al. 2003. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4:147–58 [Google Scholar]
  50. Prabhakar NR, Semenza GL. 50.  2012. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Phys. Rev. 92:967–1003 [Google Scholar]
  51. Düvel K, Yecies JL, Menon S. 51.  et al. 2010. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39:171–83 [Google Scholar]
  52. Keith B, Johnson RS, Simon MC. 52.  2012. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12:9–22 [Google Scholar]
  53. Bertout JA, Patel SA, Simon MC. 53.  2008. The impact of O2 availability on human cancer. Nat. Rev. Cancer 8:967–75 [Google Scholar]
  54. Bhat M, Robichaud N, Hulea L. 54.  et al. 2015. Targeting the translation machinery in cancer. Nat. Rev. Drug Discov. 14:261–78 [Google Scholar]
  55. Morita M, Gravel S-P, Chénard V. 55.  et al. 2013. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metabol 18:698–711 [Google Scholar]
  56. Goncharova EA, Goncharov DA, Eszterhas A. 56.  et al. 2002. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis. J. Biol. Chem. 277:30958–67 [Google Scholar]
  57. Kwiatkowski DJ, Zhang H, Bandura JL. 57.  et al. 2002. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11:525–34 [Google Scholar]
  58. Ma EH, Jones RG. 58.  2016. (TORC)ing up purine biosynthesis. Science 351:670–71 [Google Scholar]
  59. Ben-Sahra I, Hoxhaj G, Ricoult SJH. 59.  et al. 2016. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351:728–33 [Google Scholar]
  60. Ben-Sahra I, Howell JJ, Asara JM, Manning BD. 60.  2013. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339:1323–28 [Google Scholar]
  61. French JB, Jones SA, Deng H. 61.  et al. 2016. Spatial colocalization and functional link of purinosomes with mitochondria. Science 351:733–37 [Google Scholar]
  62. Laplante M, Sabatini DM. 62.  2013. Regulation of mTORC1 and its impact on gene expression at a glance. J. Cell Sci. 126:1713–19 [Google Scholar]
  63. Russell RC, Yuan H-X, Guan K-L. 63.  2014. Autophagy regulation by nutrient signaling. Cell Res 24:42–57 [Google Scholar]
  64. Mihaylova MM, Shaw RJ. 64.  2011. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13:1016–23 [Google Scholar]
  65. Parkhitko A, Myachina F, Morrison TA. 65.  et al. 2011. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. PNAS 108:12455–60 [Google Scholar]
  66. Inoki K, Kim J, Guan K-L. 66.  2012. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52:381–400 [Google Scholar]
  67. Jacinto A, Hall MN. 67.  2003. TOR signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell Biol. 4:117–26 [Google Scholar]
  68. Wullschleger S, Loewith R, Hall MN. 68.  2006. TOR signaling in growth and metabolism. Cell 124:471–84 [Google Scholar]
  69. Goncharova EA, Goncharov DA, Damera G. 69.  et al. 2009. Signal transducer and activator of transcription 3 is required for abnormal proliferation and survival of TSC2-deficient cells: relevance to pulmonary lymphangioleiomyomatosis. Mol. Pharmacol. 76:766–77 [Google Scholar]
  70. El-Hashemite N, Kwiatkowski DJ. 70.  2005. Interferon-γ-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target. Am. J. Respir. Cell Mol. Biol. 33:227–30 [Google Scholar]
  71. Palm W, Park Y, Wright K. 71.  et al. 2015. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162:259–70 [Google Scholar]
  72. Csibi A, Fendt S-M, Li C. 72.  et al. 2013. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153:840–54 [Google Scholar]
  73. Choo AY, Kim SG, Vander Heiden MG. 73.  et al. 2010. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol. Cell 38:487–99 [Google Scholar]
  74. Parkhitko AA, Priolo C, Coloff JL. 74.  et al. 2014. Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Mol. Cancer Res. 12:48–57 [Google Scholar]
  75. Pusapati RV, Daemen A, Wilson C. 75.  et al. 2016. mTORC1-dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. Cancer Cell 29:548–62 [Google Scholar]
  76. McCormack FX, Inoue Y, Moss J. 76.  et al. 2011. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N. Engl. J. Med. 364:1595–606 [Google Scholar]
  77. Franz DN, Leonard J, Tudor C. 77.  et al. 2006. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 59:490–98 [Google Scholar]
  78. Bissler JJ, McCormack FX, Young LR. 78.  et al. 2008. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 358:140–51 [Google Scholar]
  79. Barnes EA, Kenerson HL, Mak BC, Yeung RS. 79.  2010. The loss of tuberin promotes cell invasion through the β-catenin pathway. Am. J. Respir. Cell Mol. Biol. 43:617–27 [Google Scholar]
  80. Pacheco-Rodriguez G, Kumaki F, Steagall WK. 80.  et al. 2009. Chemokine-enhanced chemotaxis of lymphangioleiomyomatosis cells with mutations in the tumor suppressor TSC2 gene. J. Immunol. 182:1270–77 [Google Scholar]
  81. Goncharova EA, Goncharov DA, Fehrenbach M. 81.  et al. 2012. Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Sci. Transl. Med. 4:154ra34 [Google Scholar]
  82. Lamb RF, Roy C, Diefenbach TJ. 82.  et al. 2000. The TSC1 tumor suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat. Cell Biol. 2:281–87 [Google Scholar]
  83. Hodges AK, Li S, Maynard J. 83.  et al. 2001. Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Hum. Mol. Genet. 10:2899–905 [Google Scholar]
  84. van Slegtenhorst MA, Nellist M, Nagelkerken B. 84.  et al. 1998. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet. 7:1053–57 [Google Scholar]
  85. Benvenuto G, Li S, Brown SJ. 85.  et al. 2000. The tuberous sclerosis-1 (TSC-1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquination. Oncogene 19:6306–16 [Google Scholar]
  86. Goncharova E, Goncharov D, Noonan D, Krymskaya VP. 86.  2004. TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. J. Cell Biol. 167:1171–82 [Google Scholar]
  87. Goncharova EA, Goncharov DA, Lim PN. 87.  et al. 2006. Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis. Am. J. Respir. Cell Mol. Biol. 34:473–80 [Google Scholar]
  88. Goncharova EA, James ML, Kudryashova TV. 88.  et al. 2014. Tumor suppressors TSC1 and TSC2 differentially modulate actin cytoskeleton and motility of mouse embryonic fibroblasts. PLoS ONE 9:e111476 [Google Scholar]
  89. Matsumoto Y, Horiba K, Usuki J. 89.  et al. 1999. Markers of cell proliferation and expression of melanosomal antigen in lymphangioleiomyomatosis. Am. J. Respir. Cell Mol. Biol. 21:327–36 [Google Scholar]
  90. Kumasaka T, Seyama K, Mitani K. 90.  et al. 2004. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Am. J. Surg. Pathol. 28:1007–16 [Google Scholar]
  91. Young LR, Inoue Y, McCormack FX. 91.  2008. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N. Engl. J. Med. 358:199–200 [Google Scholar]
  92. Baluk P, Tammela T, Ator E. 92.  et al. 2005. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J. Clin. Investig. 115:247–57 [Google Scholar]
  93. Karpanen T, Bry M, Ollila HM. 93.  et al. 2008. Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ. Res. 103:1018–26 [Google Scholar]
  94. Baldwin ME, Halford MM, Roufail S. 94.  et al. 2005. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol. Cell Biol. 25:2441–49 [Google Scholar]
  95. Sun S, Schiller JH, Gazdar AF. 95.  2007. Lung cancer in never smokers—a different disease. Nat. Rev. Cancer 7:778–90 [Google Scholar]
  96. Hammes SR, Krymskaya VP. 96.  2012. Targeted approaches toward understanding and treating pulmonary lymphangioleiomyomatosis (LAM). Horm. Cancer 4:70–77 [Google Scholar]
  97. Yu J, Astrinidis A, Howard S, Henske EP. 97.  2004. Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am. J. Physiol. Lung Cell Mol. Physiol. 286:L694–700 [Google Scholar]
  98. Gu X, Yu JJ, Ilter D. 98.  et al. 2013. Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis. PNAS 110:14960–65 [Google Scholar]
  99. Finlay GA, York B, Karas RH. 99.  et al. 2004. 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. 279:23114–22 [Google Scholar]
  100. Yu JJ, Robb VA, Morrison TA. 100.  et al. 2009. Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. PNAS 106:2635–40 [Google Scholar]
  101. Prizant H, Taya M, Lerman I. 101.  et al. 2016. Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model. End Relat. Cancer 23:265–80 [Google Scholar]
  102. Ohori N, Yousem SA, Sonmez-Alpan E, Colby TV. 102.  1991. Estrogen and progesterone receptors in lymphangioleiomyomatosis, epithelial hemangioendothelioma, and sclerosing hemangioma of the lung. Am. J. Clin. Pathol. 96:529–635 [Google Scholar]
  103. Taveira-DaSilva AM, Stylianou MP, Hedin CJ. 103.  et al. 2004. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest 126:1867–74 [Google Scholar]
  104. Ingelfinger JR, Drazen JM. 104.  2011. Patient organizations and research on rare diseases. N. Engl. J. Med. 364:1670–71 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error