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Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults

Authors
Talmadge E King, Jr, MD
Elizabeth Henske, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editors
Helen Hollingsworth, MD
Geraldine Finlay, MD

INTRODUCTION

Tuberous sclerosis complex (TSC) is a disorder characterized by multiple benign tumors, and rarely malignant neoplasms of the skin, brain, eyes, heart, lung, liver, and kidney [1,2]. TSC is caused by mutations in the TSC1 or TSC2 gene and is transmitted as an autosomal dominant trait in one-third of cases while nonfamilial cases represent either spontaneous mutations or mosaicism. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Genetics'.)

Lymphangioleiomyomatosis (LAM) is a multisystem disorder that primarily affects the lung. It can occur sporadically (sporadic-LAM) or in association with TSC (TSC-LAM). Many clinical, radiologic, and pathologic features are shared between TSC and sporadic variants. This review will focus on the elements of LAM that are specific to TSC. The epidemiology, diagnosis, and management of sporadic-LAM and TSC are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis" and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis" and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".)

EPIDEMIOLOGY

Sporadic lymphangioleiomyomatosis (sporadic-LAM) is rare and almost exclusively affects women, with estimates of up to 8 cases per million women (see "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Epidemiology'). In contrast, TSC, an autosomal dominant genetic disorder, has an incidence of approximately 1 in 5000 to 10,000 live births with a high prevalence of LAM among adults. Obtaining exact prevalence rates of TSC-LAM is challenging since data are derived from small retrospective observational studies that mostly utilize computed tomographic (CT) evidence of cystic lung disease for diagnosis:

Several studies report prevalence rates in women with TSC (mostly TSC2 mutations) that range from 26 to 50 percent [3-8]. Rates increase with age after 15 years with the highest rates (up to 80 percent) reported in women over the age of 40 years and lowest rates (27 percent) in those <21 years [7,9]. Estimates based upon the worldwide prevalence of TSC of one million people and the conservative projection that 30 percent of women with TSC develop cystic changes consistent with LAM, the number of women with TSC-LAM on earth is predicted to be approximately 100,000.

Unlike sporadic-LAM, which is extremely rare in men, LAM occurs in males with TSC with rates ranging from 10 to 38 percent [8,10,11].

                         
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Literature review current through: Sep 2017. | This topic last updated: Aug 04, 2017.
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References
Top
  1. von Ranke FM, Zanetti G, e Silva JL, et al. Tuberous Sclerosis Complex: State-of-the-Art Review with a Focus on Pulmonary Involvement. Lung 2015; 193:619.
  2. Henske EP, Jóźwiak S, Kingswood JC, et al. Tuberous sclerosis complex. Nat Rev Dis Primers 2016; 2:16035.
  3. Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000; 75:591.
  4. 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; 164:661.
  5. 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; 164:669.
  6. Muzykewicz DA, Sharma A, Muse V, et al. TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J Med Genet 2009; 46:465.
  7. Cudzilo CJ, Szczesniak RD, Brody AS, et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 2013; 144:578.
  8. Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, et al. Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. Clin Radiol 2011; 66:625.
  9. Kristof AS, Li PZ, Major P, Landry JS. Lymphangioleiomyomatosis and Tuberous Sclerosis Complex in Quebec: Prevalence and Health-care Utilization. Chest 2015; 148:444.
  10. Ryu JH, Sykes AM, Lee AS, Burger CD. Cystic lung disease is not uncommon in men with tuberous sclerosis complex. Respir Med 2012; 106:1586.
  11. 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; 49:243.
  12. Di Marco F, Terraneo S, Imeri G, et al. Women with TSC: Relationship between Clinical, Lung Function and Radiological Features in a Genotyped Population Investigated for Lymphangioleiomyomatosis. PLoS One 2016; 11:e0155331.
  13. Seibert D, Hong CH, Takeuchi F, et al. Recognition of tuberous sclerosis in adult women: delayed presentation with life-threatening consequences. Ann Intern Med 2011; 154:806.
  14. Harris PC. The TSC2/PKD1 contiguous gene syndrome. Contrib Nephrol 1997; 122:76.
  15. Avila NA, Dwyer AJ, Rabel A, Moss J. Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features. Radiology 2007; 242:277.
  16. Ryu JH, Doerr CH, Fisher SD, et al. Chylothorax in lymphangioleiomyomatosis. Chest 2003; 123:623.
  17. Tobino K, Johkoh T, Fujimoto K, et al. Computed tomographic features of lymphangioleiomyomatosis: evaluation in 138 patients. Eur J Radiol 2015; 84:534.
  18. Seaman DM, Meyer CA, Gilman MD, McCormack FX. Diffuse cystic lung disease at high-resolution CT. AJR Am J Roentgenol 2011; 196:1305.
  19. Kobashi Y, Sugiu T, Mouri K, et al. Clinicopathological analysis of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis in Japan. Respirology 2008; 13:1076.
  20. 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; 173:105.
  21. Young LR, Vandyke R, Gulleman PM, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138:674.
  22. McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med 2016; 194:748.
  23. Radzikowska E, Jaguś P, Sobiecka M, et al. Correlation of serum vascular endothelial growth factor-D concentration with clinical presentation and course of lymphangioleiomyomatosis. Respir Med 2015; 109:1469.
  24. Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010; 35:14.
  25. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364:1595.
  26. Goldberg HJ, Harari S, Cottin V, et al. Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. Eur Respir J 2015; 46:783.
  27. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant 2016; 31:111.
  28. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363:1801.
  29. 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; 49:255.
  30. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991; 66:792.
  31. Muir TE, Leslie KO, Popper H, et al. Micronodular pneumocyte hyperplasia. Am J Surg Pathol 1998; 22:465.
  32. Popper HH, Juettner-Smolle FM, Pongratz MG. Micronodular hyperplasia of type II pneumocytes--a new lung lesion associated with tuberous sclerosis. Histopathology 1991; 18:347.
  33. Maruyama H, Ohbayashi C, Hino O, et al. Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2. Pathol Int 2001; 51:585.
  34. Hayashi T, Kumasaka T, Mitani K, et al. Loss of heterozygosity on tuberous sclerosis complex genes in multifocal micronodular pneumocyte hyperplasia. Mod Pathol 2010; 23:1251.
  35. Muzykewicz DA, Black ME, Muse V, et al. Multifocal micronodular pneumocyte hyperplasia: computed tomographic appearance and follow-up in tuberous sclerosis complex. J Comput Assist Tomogr 2012; 36:518.
  36. Flieder DB, Travis WD. Clear cell "sugar" tumor of the lung: association with lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia in a patient with tuberous sclerosis. Am J Surg Pathol 1997; 21:1242.