Download PDF
Semin Respir Crit Care Med 2020; 41(02): 256-268
DOI: 10.1055/s-0040-1702195
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Lymphangioleiomyomatosis

Kai-Feng Xu
1   Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
2   Rare Diseases Research Center, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
,
Wenshuai Xu
1   Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
,
Song Liu
2   Rare Diseases Research Center, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
3   Central Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
,
Jane Yu
4   Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
,
Xinlun Tian
1   Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
,
Yanli Yang
1   Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
2   Rare Diseases Research Center, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
,
Shao-Ting Wang
1   Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
2   Rare Diseases Research Center, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
,
Weihong Zhang
5   Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
,
Ruie Feng
6   Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
,
Tengyue Zhang
1   Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
› Author Affiliations Funding This work was supported by the National Nature Science Foundation of China (81570061), the National Key Research and Development Program of China (2016YFC0901502), and Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (2017–12M-2–001).
Further Information

Publication History

Publication Date:
12 April 2020 (online)

    Permissions and Reprints

Abstract

Lymphangioleiomyomatosis (LAM) is a slow albeit progressive rare neoplastic disease featured with diffuse thin-walled cysts in lungs and angiomyolipomas in kidneys. LAM affects almost exclusively women and has one of the strongest gender predispositions of any extragenital human disease. Two forms of LAM present clinically, sporadic (S-LAM) and tuberous sclerosis complex-associated (TSC-LAM). TSC is an autosomal dominant genetic multisystems neoplastic disease. A high prevalence of LAM can be detected in adult female TSC patients. Tremendous progress has been made in our understanding and management of this rare disease. Both LAM and TSC are TSC2 or TSC1 mutated diseases that result in overactivation of the mechanistic target of rapamycin (mTOR) pathway. Sirolimus, an mTOR inhibitor, has been approved for LAM treatment in the United States and many other countries. Therapies targeting female sex hormones have shown preclinical efficacy in animal and cell culture-based experiments, but have not been properly investigated clinically. In this review, we summarize current recommendations in the diagnosis and treatment of LAM.

Keywords

lymphangioleiomyomatosis - tuberous sclerosis complex - diffuse cystic lung disease - vascular endothelial growth factor-D - sirolimus - estrogen - pneumothorax - chylothorax - angiomyolipoma
 

  • References

  • 1 Harknett EC, Chang WY, Byrnes S. , et al. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM 2011; 104 (11) 971-979
    CrossrefPubMedGoogle Scholar
  • 2 Gupta N, Lee HS, Ryu JH. , et al; NHLBI LAM Registry Group. The NHLBI LAM Registry: prognostic physiologic and radiologic biomarkers emerge from a 15-year prospective longitudinal analysis. Chest 2019; 155 (02) 288-296
    CrossrefPubMedGoogle Scholar
  • 3 Oprescu N, McCormack FX, Byrnes S, Kinder BW. Clinical predictors of mortality and cause of death in lymphangioleiomyomatosis: a population-based registry. Hai 2013; 191 (01) 35-42
    PubMedGoogle Scholar
  • 4 Cudzilo CJ, Szczesniak RD, Brody AS. , et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 2013; 144 (02) 578-585
    CrossrefPubMedGoogle Scholar
  • 5 Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, Zonnenberg BA, Prokop M. Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. Clin Radiol 2011; 66 (07) 625-628
    CrossrefPubMedGoogle Scholar
  • 6 Hirose M, Matsumuro A, Arai T. , et al. Serum vascular endothelial growth factor-D as a diagnostic and therapeutic biomarker for lymphangioleiomyomatosis. PLoS One 2019; 14 (02) e0212776
    CrossrefPubMedGoogle Scholar
  • 7 Gupta N, Lee HS, Young LR. , et al; NIH Rare Lung Disease Consortium. Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis. Eur Respir J 2019; 53 (04) 53
    CrossrefPubMedGoogle Scholar
  • 8 Kristof AS. mTOR signaling in lymphangioleiomyomatosis. Lymphat Res Biol 2010; 8 (01) 33-42
    CrossrefPubMedGoogle Scholar
  • 9 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 (04) 810-815
    CrossrefPubMedGoogle Scholar
  • 10 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) 6085-6090
    CrossrefPubMedGoogle Scholar
  • 11 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 (02) 166-173
    CrossrefPubMedGoogle Scholar
  • 12 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 (01) 20-28
    CrossrefPubMedGoogle Scholar
  • 13 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) 17462-17467
    CrossrefPubMedGoogle Scholar
  • 14 Badri KR, Gao L, Hyjek E. , et al. Exonic mutations of TSC2/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis. Am J Respir Crit Care Med 2013; 187 (06) 663-665
    CrossrefPubMedGoogle Scholar
  • 15 Fujita A, Ando K, Kobayashi E. , et al. Detection of low-prevalence somatic TSC2 mutations in sporadic pulmonary lymphangioleiomyomatosis tissues by deep sequencing. Hum Genet 2016; 135 (01) 61-68
    CrossrefPubMedGoogle Scholar
  • 16 Murphy SJ, Terra SB, Harris FR. , et al. Genomic rearrangements in sporadic lymphangioleiomyomatosis: an evolving genetic story. Modern pathology: an official journal of the United States and Canadian Academy of Pathology. Inc 2017; 30: 1223-1233
    PubMedGoogle Scholar
  • 17 Kim W, Giannikou K, Dreier JR. , et al. A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis. Eur Respir J 2019; 53 (06) 53
    CrossrefPubMedGoogle Scholar
  • 18 Zhang L, Wang MJ, Wang W. , et al. Identification of driver genes and somatic mutations in cell-free DNA of patients with pulmonary lymphangioleiomyomatosis. Int J Cancer 2020; 146 (01) 103-114
    CrossrefPubMedGoogle Scholar
  • 19 Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999; 160 (02) 628-633
    CrossrefPubMedGoogle Scholar
  • 20 Taveira-DaSilva AM, Pacheco-Rodriguez G, Moss J. The natural history of lymphangioleiomyomatosis: markers of severity, rate of progression and prognosis. Lymphat Res Biol 2010; 8 (01) 9-19
    CrossrefPubMedGoogle Scholar
  • 21 Prizant H, Hammes SR. Minireview: lymphangioleiomyomatosis (LAM): the “other” steroid-sensitive cancer. Endocrinology 2016; 157 (09) 3374-3383
    CrossrefPubMedGoogle Scholar
  • 22 Prizant H, Taya M, Lerman I. , et al. Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model. Endocr Relat Cancer 2016; 23 (04) 265-280
    CrossrefPubMedGoogle Scholar
  • 23 Chen Q, Gao S, He W. , et al. Xist repression shows time-dependent effects on the reprogramming of female somatic cells to induced pluripotent stem cells. Stem Cells 2014; 32 (10) 2642-2656
    CrossrefPubMedGoogle Scholar
  • 24 Logginidou H, Ao X, Russo I, Henske EP. Frequent estrogen and progesterone receptor immunoreactivity in renal angiomyolipomas from women with pulmonary lymphangioleiomyomatosis. Chest 2000; 117 (01) 25-30
    CrossrefPubMedGoogle Scholar
  • 25 McCormack FX, Gupta N, Finlay GR. , et al; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med 2016; 194 (06) 748-761
    CrossrefPubMedGoogle Scholar
  • 26 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) 23114-23122
    CrossrefPubMedGoogle Scholar
  • 27 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 (04) L694-L700
    CrossrefPubMedGoogle Scholar
  • 28 Yu JJ, Robb VA, Morrison TA. , et al. Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc Natl Acad Sci U S A 2009; 106 (08) 2635-2640
    CrossrefPubMedGoogle Scholar
  • 29 Sun Y, Gu X, Zhang E. , et al. Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells. Cell Death Dis 2014; 5: e1231
    CrossrefPubMedGoogle Scholar
  • 30 Li C, Lee PS, Sun Y. , et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med 2014; 211 (01) 15-28
    CrossrefPubMedGoogle Scholar
  • 31 Sun Y, Zhang E, Lao T. , et al. Progesterone and estradiol synergistically promote the lung metastasis of tuberin-deficient cells in a preclinical model of lymphangioleiomyomatosis. Horm Cancer 2014; 5 (05) 284-298
    CrossrefPubMedGoogle Scholar
  • 32 Terasaki Y, Yahiro K, Pacheco-Rodriguez G. , et al. Effects of prolactin on TSC2-null Eker rat cells and in pulmonary lymphangioleiomyomatosis. Am J Respir Crit Care Med 2010; 182 (04) 531-539
    CrossrefPubMedGoogle Scholar
  • 33 Howe SR, Everitt JI, Gottardis MM, Walker C. Estrogen/antiestrogen responsiveness in an in vivo/in vitro model for myometrial tumorigenesis. Ann N Y Acad Sci 1995; 761: 373-375
    CrossrefPubMedGoogle Scholar
  • 34 Liu F, Lunsford EP, Tong J. , et al. Real-time monitoring of tumorigenesis, dissemination, & drug response in a preclinical model of lymphangioleiomyomatosis/tuberous sclerosis complex. PLoS One 2012; 7 (06) e38589
    CrossrefPubMedGoogle Scholar
  • 35 Stovall DW. Clinical symptomatology of uterine leiomyomas. Clin Obstet Gynecol 2001; 44 (02) 364-371
    CrossrefPubMedGoogle Scholar
  • 36 Prizant H, Sen A, Light A. , et al. Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs. Mol Endocrinol 2013; 27 (09) 1403-1414
    CrossrefPubMedGoogle Scholar
  • 37 Ryu JH, Moss J, Beck GJ. , et al; NHLBI LAM Registry Group. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006; 173 (01) 105-111
    CrossrefPubMedGoogle Scholar
  • 38 Johnson SR, Cordier JF, Lazor R. , et al; Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010; 35 (01) 14-26
    CrossrefPubMedGoogle Scholar
  • 39 Harari S, Torre O, Cassandro R, Moss J. The changing face of a rare disease: lymphangioleiomyomatosis. Eur Respir J 2015; 46 (05) 1471-1485
    CrossrefPubMedGoogle Scholar
  • 40 Gupta R, Kitaichi M, Inoue Y, Kotloff R, McCormack FX. Lymphatic manifestations of lymphangioleiomyomatosis. Lymphology 2014; 47 (03) 106-117
    PubMedGoogle Scholar
  • 41 Uehara K, Kawakami F, Hirose T. , et al. Clinicopathological analysis of clinically occult extrapulmonary lymphangioleiomyomatosis in intra-pelvic and para-aortic lymph nodes associated with pelvic malignant tumors: A study of nine patients. Pathol Int 2019; 69 (01) 29-36
    CrossrefPubMedGoogle Scholar
  • 42 Kingswood JC, d'Augères GB, Belousova E. , et al; TOSCA consortium and TOSCA investigators. TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients. Orphanet J Rare Dis 2017; 12 (01) 2
    CrossrefPubMedGoogle Scholar
  • 43 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 (04) 669-671
    CrossrefPubMedGoogle Scholar
  • 44 Northrup H, Krueger DA. ; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 243-254
    CrossrefPubMedGoogle Scholar
  • 45 Han MK, Tyburczy ME, Darling TN. , et al. Apparent sporadic lymphangioleiomyomatosis in a man as a result of extreme mosaicism for a TSC2 mutation. Ann Am Thorac Soc 2017; 14 (07) 1227-1229
    PubMedGoogle Scholar
  • 46 Wakida K, Watanabe Y, Kumasaka T. , et al. Lymphangioleiomyomatosis in a Male. Ann Thorac Surg 2015; 100 (03) 1105-1107
    CrossrefPubMedGoogle Scholar
  • 47 Ryu JH, Sykes AM, Lee AS, Burger CD. Cystic lung disease is not uncommon in men with tuberous sclerosis complex. Respir Med 2012; 106 (11) 1586-1590
    CrossrefPubMedGoogle Scholar
  • 48 Aubry MC, Myers JL, Ryu JH. , et al. Pulmonary lymphangioleiomyomatosis in a man. Am J Respir Crit Care Med 2000; 162 (2 Pt 1): 749-752
    CrossrefPubMedGoogle Scholar
  • 49 Kang HW, Kim CJ, Kang SK, Lee KS, Lee CS, Kim YH. Pulmonary lymphangioleiomyomatosis in a male. J Korean Med Sci 1991; 6 (01) 83-85
    CrossrefPubMedGoogle Scholar
  • 50 Miyake M, Tateishi U, Maeda T. , et al. Pulmonary lymphangioleiomyomatosis in a male patient with tuberous sclerosis complex. Radiat Med 2005; 23 (07) 525-527
    PubMedGoogle Scholar
  • 51 Yamanaka S, Mizobuchi T, Kurihara M. Two kinds of cystic lung lesions with pulmonary lymphangioleiomyomatosis in a male. Ann Thorac Cardiovasc Surg 2017; 23 (01) 36-39
    CrossrefPubMedGoogle Scholar
  • 52 Hancock E, Tomkins S, Sampson J, Osborne J. Lymphangioleiomyomatosis and tuberous sclerosis. Respir Med 2002; 96 (01) 7-13
    CrossrefPubMedGoogle Scholar
  • 53 Avila NA, Dwyer AJ, Rabel A, Moss J. Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features. Radiology 2007; 242 (01) 277-285
    CrossrefPubMedGoogle Scholar
  • 54 Xu KF, Feng R, Cui H. , et al. Diffuse cystic lung diseases: diagnostic considerations. Semin Respir Crit Care Med 2016; 37 (03) 457-467
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Wataya-Kaneda M, Tanaka M, Hamasaki T, Katayama I. Trends in the prevalence of tuberous sclerosis complex manifestations: an epidemiological study of 166 Japanese patients. PLoS One 2013; 8 (05) e63910
    CrossrefPubMedGoogle Scholar
  • 56 Konno S, Shigemura M, Ogi T. , et al. Clinical course of histologically proven multifocal micronodular pneumocyte hyperplasia in tuberous sclerosis complex: a case series and comparison with lymphangiomyomatosis. Respiration 2018; 95 (05) 310-316
    CrossrefPubMedGoogle Scholar
  • 57 Issaka RB, Oommen S, Gupta SK. , et al. Vascular endothelial growth factors C and D induces proliferation of lymphangioleiomyomatosis cells through autocrine crosstalk with endothelium. Am J Pathol 2009; 175 (04) 1410-1420
    CrossrefPubMedGoogle Scholar
  • 58 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; 135 (05) 1293-1300
    CrossrefPubMedGoogle Scholar
  • 59 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 (03) 143-152
    CrossrefPubMedGoogle Scholar
  • 60 Xu KF, Zhang P, Tian X. , et al. The role of vascular endothelial growth factor-D in diagnosis of lymphangioleiomyomatosis (LAM). Respir Med 2013; 107 (02) 263-268
    CrossrefPubMedGoogle Scholar
  • 61 McCormack FX, Inoue Y, Moss J. , et al; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364 (17) 1595-1606
    CrossrefPubMedGoogle Scholar
  • 62 Young L, Lee HS, Inoue Y. , et al; MILES Trial Group. 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; 1 (06) 445-452
    CrossrefPubMedGoogle Scholar
  • 63 Zhan Y, Shen L, Xu W. , et al. Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study. Orphanet J Rare Dis 2018; 13 (01) 34
    CrossrefPubMedGoogle Scholar
  • 64 Xu KF, Lo BH. Lymphangioleiomyomatosis: differential diagnosis and optimal management. Ther Clin Risk Manag 2014; 10: 691-700
    PubMedGoogle Scholar
  • 65 Gonano C, Pasquier J, Daccord C. , et al. Air travel and incidence of pneumothorax in lymphangioleiomyomatosis. Orphanet J Rare Dis 2018; 13 (01) 222
    CrossrefPubMedGoogle Scholar
  • 66 Taveira-DaSilva AM, Burstein D, Hathaway OM. , et al. Pneumothorax after air travel in lymphangioleiomyomatosis, idiopathic pulmonary fibrosis, and sarcoidosis. Chest 2009; 136 (03) 665-670
    CrossrefPubMedGoogle Scholar
  • 67 Hu X, Cowl CT, Baqir M, Ryu JH. Air travel and pneumothorax. Chest 2014; 145 (04) 688-694
    CrossrefPubMedGoogle Scholar
  • 68 Hayney MS, Welter DL, Francois M, Reynolds AM, Love RB. Influenza vaccine antibody responses in lung transplant recipients. Prog Transplant 2004; 14 (04) 346-351
    CrossrefPubMedGoogle Scholar
  • 69 Willcocks LC, Chaudhry AN, Smith JC. , et al. The effect of sirolimus therapy on vaccine responses in transplant recipients. Am J Transplant 2007; 7 (08) 2006-2011
    CrossrefPubMedGoogle Scholar
  • 70 Spruit MA, Singh SJ, Garvey C. , et al; ATS/ERS Task Force on Pulmonary Rehabilitation. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013; 188 (08) e13-e64
    CrossrefPubMedGoogle Scholar
  • 71 Araujo MS, Baldi BG, Freitas CS. , et al. Pulmonary rehabilitation in lymphangioleiomyomatosis: a controlled clinical trial. Eur Respir J 2016; 47 (05) 1452-1460
    CrossrefPubMedGoogle Scholar
  • 72 Chu SC, Horiba K, Usuki J. , et al. Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest 1999; 115 (04) 1041-1052
    CrossrefPubMedGoogle Scholar
  • 73 Baldi BG, de Albuquerque AL, Pimenta SP, Salge JM, Kairalla RA, Carvalho CR. A pilot study assessing the effect of bronchodilator on dynamic hyperinflation in LAM. Respir Med 2013; 107 (11) 1773-1780
    CrossrefPubMedGoogle Scholar
  • 74 Johnson J, Johnson SR. Cross-sectional study of reversible airway obstruction in LAM: better evidence is needed for bronchodilator and inhaled steroid use. Thorax 2019; 74 (10) 999-1002
    CrossrefPubMedGoogle Scholar
  • 75 Le K, Steagall WK, Stylianou M. , et al. Effect of beta-agonists on LAM progression and treatment. Proc Natl Acad Sci U S A 2018; 115 (05) E944-E953
    CrossrefPubMedGoogle Scholar
  • 76 Hardinge M, Annandale J, Bourne S. , et al; British Thoracic Society Home Oxygen Guideline Development Group; British Thoracic Society Standards of Care Committee. British Thoracic Society guidelines for home oxygen use in adults. Thorax 2015; 70 (Suppl. 01) i1-i43
    CrossrefPubMedGoogle Scholar
  • 77 Xu KF, Tian X, Yang Y, Zhang H. Rapamycin for lymphangioleiomyomatosis: optimal timing and optimal dosage. Thorax 2018; 73 (04) 308-310
    CrossrefPubMedGoogle Scholar
  • 78 Zhou L, Ouyang R, Luo H. , et al. Efficacy of sirolimus for the prevention of recurrent pneumothorax in patients with lymphangioleiomyomatosis: a case series. Orphanet J Rare Dis 2018; 13 (01) 168
    CrossrefPubMedGoogle Scholar
  • 79 Interstitial Lung Disease Group; Chinese Thoracic Society, Chinese Medical Association; Expert Consensus Group of Lymphangioleiomyomatosis; Rare Diseases Research Center, Chinese Academy of Medical Sciences; Rare Diseases Society, Chinese Research Hospital Association. [Consensus Statement: sirolimus (rapamycin) as therapy for lymphangioleiomyomatosis (2018)]. Zhonghua Jie He He Hu Xi Za Zhi 2019; 42 (02) 92-97
    PubMedGoogle Scholar
  • 80 Bissler JJ, McCormack FX, Young LR. , et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358 (02) 140-151
    CrossrefPubMedGoogle Scholar
  • 81 Krueger DA, Northrup H. ; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 255-265
    CrossrefPubMedGoogle Scholar
  • 82 Hu S, Wu X, Xu W. , et al. Long-term efficacy and safety of sirolimus therapy in patients with lymphangioleiomyomatosis. Orphanet J Rare Dis 2019; 14 (01) 206
    CrossrefPubMedGoogle Scholar
  • 83 Harari S, Cassandro R, Chiodini I, Taveira-DaSilva AM, Moss J. Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis. Chest 2008; 133 (02) 448-454
    CrossrefPubMedGoogle Scholar
  • 84 Lu C, Lee HS, Pappas GP. , et al; Trial of an Aromatase Inhibitor in Lymphangioleiomyomatosis Group. A phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis. Ann Am Thorac Soc 2017; 14 (06) 919-928
    CrossrefPubMedGoogle Scholar
  • 85 Hayashi T, Fleming MV, Stetler-Stevenson WG. , et al. Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum Pathol 1997; 28 (09) 1071-1078
    CrossrefPubMedGoogle Scholar
  • 86 Odajima N, Betsuyaku T, Yoshida T, Hosokawa T, Nishimura M. High levels of extracellular matrix metalloproteinase inducer are expressed in lymphangioleiomyomatosis. Hum Pathol 2010; 41 (07) 935-943
    CrossrefPubMedGoogle Scholar
  • 87 Pimenta SP, Baldi BG, Kairalla RA, Carvalho CR. Doxycycline use in patients with lymphangioleiomyomatosis: biomarkers and pulmonary function response. J Bras Pneumol 2013; 39 (01) 5-15
    CrossrefPubMedGoogle Scholar
  • 88 Chang WY, Cane JL, Kumaran M, Lewis S, Tattersfield AE, Johnson SR. A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis. Eur Respir J 2014; 43 (04) 1114-1123
    CrossrefPubMedGoogle Scholar
  • 89 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) 9878-9886
    CrossrefPubMedGoogle Scholar
  • 90 Lee N, Woodrum CL, Nobil AM, Rauktys AE, Messina MP, Dabora SL. Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol 2009; 9: 8
    PubMedGoogle Scholar
  • 91 Goncharova EA, Goncharov DA, Li H. , et al. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol 2011; 31 (12) 2484-2498
    CrossrefPubMedGoogle Scholar
  • 92 Atochina-Vasserman EN, Goncharov DA, Volgina AV, Milavec M, James ML, Krymskaya VP. Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling. Am J Respir Cell Mol Biol 2013; 49 (05) 704-709
    CrossrefPubMedGoogle Scholar
  • 93 Yu J, Parkhitko A, Henske EP. Autophagy: an ‘Achilles’ heel of tumorigenesis in TSC and LAM. Autophagy 2011; 7 (11) 1400-1401
    CrossrefPubMedGoogle Scholar
  • 94 Parkhitko A, Myachina F, Morrison TA. , et al. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 2011; 108 (30) 12455-12460
    CrossrefPubMedGoogle Scholar
  • 95 El-Chemaly S, Taveira-Dasilva A, Goldberg HJ. , et al. Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: results of a Phase I Clinical Trial. Chest 2017; 151 (06) 1302-1310
    CrossrefPubMedGoogle Scholar
  • 96 Gupta N, Finlay GA, Kotloff RM. , et al; ATS Assembly on Clinical Problems. 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
    CrossrefPubMedGoogle Scholar
  • 97 Almoosa KF, Ryu JH, Mendez J. , et al. Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 2006; 129 (05) 1274-1281
    CrossrefPubMedGoogle Scholar
  • 98 Kurihara M, Mizobuchi T, Kataoka H. , et al. A total pleural covering for lymphangioleiomyomatosis prevents pneumothorax recurrence. PLoS One 2016; 11 (09) e0163637
    CrossrefPubMedGoogle Scholar
  • 99 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; 154 (12) 797-805 , W-292–W-293
    PubMedGoogle Scholar
  • 100 Taveira-DaSilva AM, Hathaway OM, Sachdev V, Shizukuda Y, Birdsall CW, Moss J. Pulmonary artery pressure in lymphangioleiomyomatosis: an echocardiographic study. Chest 2007; 132 (05) 1573-1578
    CrossrefPubMedGoogle Scholar
  • 101 Wu X, Xu W, Wang J, Tian X, Tian Z, Xu K. Clinical characteristics in lymphangioleiomyomatosis-related pulmonary hypertension: an observation on 50 patients. Front Med 2019; 13 (02) 259-266
    CrossrefPubMedGoogle Scholar
  • 102 Cottin V, Harari S, Humbert M. , et al; Groupe d'Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients. Eur Respir J 2012; 40 (03) 630-640
    CrossrefPubMedGoogle Scholar
  • 103 Dabora SL, Franz DN, Ashwal S. , et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One 2011; 6 (09) e23379
    CrossrefPubMedGoogle Scholar
  • 104 Bissler JJ, Kingswood JC, Radzikowska E. , et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381 (9869): 817-824
    CrossrefPubMedGoogle Scholar
  • 105 Khawar MU, Yazdani D, Zhu Z, Jandarov R, Dilling DF, Gupta N. Clinical outcomes and survival following lung transplantation in patients with lymphangioleiomyomatosis. J Heart Lung Transplant 2019; 38 (09) 949-955
    CrossrefPubMedGoogle Scholar
  • 106 Xu KF, Tian X, Ryu JH. Recent advances in the management of lymphangioleiomyomatosis. F1000 Res 2018; 7: 7
    CrossrefPubMedGoogle Scholar
  • 107 Hagaman JT, Schauer DP, McCormack FX, Kinder BW. Screening for lymphangioleiomyomatosis by high-resolution computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is cost-effective. Am J Respir Crit Care Med 2010; 181 (12) 1376-1382
    CrossrefPubMedGoogle Scholar
  • 108 Gupta N, Langenderfer D, McCormack FX, Schauer DP, Eckman MH. Chest computed tomographic image screening for cystic lung diseases in patients with spontaneous pneumothorax is cost effective. Ann Am Thorac Soc 2017; 14 (01) 17-25
    CrossrefPubMedGoogle Scholar