From Wikipedia, the free encyclopedia
Jump to: navigation, search
Figure A shows the location of the lungs and airways in the body. The inset image shows a cross-section of a healthy lung. Figure B shows a view of the lungs with LAM and a collapsed lung (pneumothorax). The inset image shows a cross-section of a lung with LAM.
Classification and external resources
ICD-9-CM 516.4
ICD-O 9174/1
OMIM 606690
DiseasesDB 30755
eMedicine med/1348 radio/415
MeSH D018192

Lymphangioleiomyomatosis (LAM) is a rare, progressive, systemic disease that typically results in cystic lung destruction and predominantly affects women, especially during child bearing years.[1] It occurs in more than 30% of women with tuberous sclerosis complex (TSC-LAM), a heritable syndrome that is associated with seizures, cognitive impairment and benign tumors in multiple tissues.[2][3][4][5] Most LAM patients who present for medical evaluation have the sporadic form of the disease (S-LAM), however, which is not associated with other manifestations of tuberous sclerosis complex. Mild cystic changes consistent with LAM have been described in 10-15% of men with TSC,[6][7] but symptomatic LAM in males is extremely rare.[8][9] Sporadic LAM occurs exclusively in women, with one published exception to date.[9] Both TSC-LAM and S-LAM are associated with mutations in tuberous sclerosis genes.[10] Lung destruction in LAM is a consequence of diffuse infiltration by neoplastic smooth muscle cells, which invade all lung structures including the lymphatics, airway walls, blood vessels, and interstitial spaces.[11] The consequence of obstruction of the vessels and airways include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. The typical disease course is characterized by progressive dyspnea on exertion, punctuated by recurrent pneumothoraces and, in some patients, chylous pleural effusions or ascites.[12] Modern estimates for median survival in LAM have varied from 10 to 30 years, based on whether hospital based or population based cohorts are studied.[13][14][15] Most patients have dyspnea on exertion with daily activities by 10 years after symptom onset and many will require supplemental oxygen over that interval.[16] An FDA approved therapy, sirolimus, is now available for stabilization of lung function decline.[17] Lung transplant remains the option of last resort for patients with advanced disease.

Signs and symptoms[edit]

The average age of onset of symptoms is in the early to mid 30s.[18][19][20][21] Exertional dyspnea and spontaneous pneumothorax have been reported as the initial presentation of the disease in 49% and 46% of patients, respectively.[21]

The diagnosis is typically delayed by 5 to 6 years,[18][19][20][21] often initially misdiagnosed as bronchial asthma, emphysema, chronic bronchitis, or chronic obstructive pulmonary disease. The first pneumothorax precedes the diagnosis of LAM in 82% of patients.[16][22] Other signs and symptoms of LAM that may present at onset or develop during the course of disease include:

  • Fatigue
  • Cough
  • Hemoptysis (rarely massive)
  • Chest pain
  • Chylous complications arising from lymphatic obstruction, including
  • Angiomyolipomas, fatty kidney tumors, are present in about 30% of patients with sporadic LAM and up to 90% of patients with TSC-LAM.[2][23] Angiomyolipomas can sometimes spontaneously bleed, causing pain or hypotension.
  • Cystic lymphangiomyomas or lymph nodes with hyodense centers, which mimic necrotizing lymphomas, ovarian or renal cancers, or other malignancies can occur in the retroperitoneum, pelvis or mediastinum.[24][25][26][27]


A variable percentage of cells within the LAM lesion contain mutational inactivation of the Tuberous Sclerosis Complex (TSC1 or TSC2) tumor suppressor genes.[28][29][30] TSC1 mutations cause a less severe clinical phenotype than do TSC2 mutations.[31] The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1)[32][33] led to successful use of rapamycin analog sirolimus in clinical trials[34][17] and FDA approval of sirolimus for treatment of LAM.

TSC1 and TSC2 form a tumor suppressor complex that regulates activity of the mammalian target of rapamycin (mTOR) signaling complex by directly controlling the activity of the small GTPase Rheb via the GTPase activating protein (GAP) domain of TSC2. Rheb binds to Raptor and controls the activity of the mTOR complex 1 (mTORC1) that directly phosphorylates p70 S6 kinase (S6K1) and 4E-BP1. mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2.[35] The mTORC1 consists of five proteins including Raptor positively regulates mTOR activity.[36][37][38] The mTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2[39][40][41] and modulates the assembly of the actin cytoskeleton through Rho GTPases,[42][43][44] and Rac1 is required for mTOR activation.[45] In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival.[46][47][48] Loss of TSC1/TSC2 in LAM not only induces uncontrolled LAM cell growth but also increases LAM cell viability. Upregulation of STAT1 and STAT3[49][50][51][52] and autophagy[53] are known mediators of LAM cell viability and survival.

LAM cells behave, in many ways, like metastatic tumor cells.[54] Several studies have demonstrated that LAM cells appear to arise from an extrapulmonary source and migrate to the lung.[10] Although increased LAM cell migration and invasiveness is rescued by TSC2 re-expression in experimental studies,[47] the cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by LAM cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteases (MMPs) and their endogenous inhibitors TIMPs.[55] The invasive cell phenotype in LAM is associated with TIMP-3 downregulation[56] and TSC2-dependent upregulation of MMPs.[57][58][59][60]

Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM.[27][55][61][62][63][64][65][66] The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts.[55] VEGF-D serum levels are increased in LAM[67] compared to other cystic lung diseases including pulmonary Langerhans cell histiocytosis, emphysema, Sjögren syndrome, or Birt-Hogg-Dubé syndrome.[68] VEGF-D levels correlate with the severity of LAM, evaluated as a measure of CT grade, the abundance of chylous effusions and lymphatic involvement.[69] VEGF-D, a secreted homodimer glycoprotein and a member of the VEGF family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis.[70][71][72] Proteolytic processing of VEGF-D affects cognate binding to VEGFR3.[73] Histopathologically, LAM lesions are surrounded by cells that stain for VEGFR3, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin.[74][75] VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice.[76][77] Surprisingly, knock-out of VEGF-D in mice has little effect on development of lymphatic system.[78] During tumorigenesis, however, VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells.[79][80] Little is known, however, about a role of abnormal lymphatics and VEGF-D in LAM etiology and pathogenesis.


LAM occurs in two settings: in the disease tuberous sclerosis complex (TSC-LAM) and in a sporadic form, in women who do not have TSC (sporadic LAM).[81][82] In both settings, genetic evidence indicates that LAM is caused by inactivating or “loss of function” mutations in the TSC1 or TSC2 genes, which were cloned in 1997 and 1993 respectively.[83] The TSC1 gene is located on chromosome 9q34 and the TSC2 gene is located on chromosome 16p13. TSC-LAM occurs in women who have germline mutations in either the TSC1 or the TSC2 gene.[84]

Sporadic LAM is primarily associated with somatic TSC2 gene mutations.[10][85] Germline and somatic mutations in LAM include many types of mutations spread across the genes, with no clear “hot spots,” including missense changes, in-frame deletions, and nonsense mutations.[84][10][85] Because of the large size of the genes (together they have more than 60 exons) and because mutations can be located virtually anywhere within the genes, mutation detection is often challenging.

On a cellular basis, LAM cells carry bi-allelic inactivation of the TSC2 genes, consistent with the “two-hit” tumor suppressor gene model originally proposed by Alfred Knudson, MD, PhD.[86][87] The second hit event in LAM cells is often loss of the chromosomal region containing the wild-type copy of the TSC2 gene; this is referred to as loss of heterozygosity or LOH.[88] LOH can be detected in microdissected LAM cells,[10][89] in angiomyolipomas and lymph nodes from women with LAM,[28] and in LAM cells isolated from the blood and urine, referred to as circulating LAM cells.[90][91]

Interestingly, angiomyolipomas and pulmonary LAM cells from women with the sporadic form of LAM carry identical mutations in TSC2.[29] This, together with the fact that recurrent LAM after lung transplantation carries the same TSC2 mutations as the original LAM,[92] has led to the “benign metastasis” hypothesis that LAM cells can migrate or metastasize from one site to another.[81][82]


Micrograph of lymphangioleiomyomatosis. H&E stain.
CT scan of the lungs in a patient with lymphangioleiomyomatose showing numerous thin walled cysts within the lungs.

LAM can come to medical attention in several different ways, most of which involve triggering scanning of the chest by CT. Thin walled cystic change in the lungs may be found incidentally on CT scans of the heart, chest or abdomen (on the cuts that include lung bases) obtained for other purposes. Screening of women with TSC with HRCT reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40.[5] LAM is sometimes revealed by chest CT scan in patients who present with an apparent primary spontaneous pneumothorax but more often CT scanning is not ordered (in the United States) until recurrences occur. Progressive dyspnea on exertion without the exacerbations and remissions that are characteristic of asthma or COPD sometimes prompt the astute clinician to order a chest CT. Chylothorax can also bring LAM to attention.

In some cases, the diagnosis of LAM can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma, lymphangioleiomyoma, chylothorax or serum VEGF-D > 800 pg/ml.[93][68]

If none of these clinical features are present, a biopsy may be necessary to make the diagnosis. Video-assisted thoracoscopic lung biopsy is the most definitive and widely used technique, but transbronchial biopsy has a yield of over 50% and can also be effective.[94][95] The safety of the latter procedure in patients with diffuse cystic disease and the profusion of cystic change that predicts an informative biopsy are incompletely understood, however. Cytology of chylous fluids, aspirated abdominal nodes or lymphatic masses can also yield the diagnosis.[96][97][98][99] In all cases, review by an expert pathologist who is familiar with LAM is advised.


Sirolimus is an mTOR inhibitor that stabilizes lung function and improves some measures of life in patients with LAM.[17] It is was FDA approved for use in LAM in May 2015. The MILES data supports the use of sirolimus in patients who have abnormal lung function (i.e. FEV1<70% predicted). Whether the benefits of treatment outweigh the risks for asymptomatic LAM patients with normal lung function is not clear, but some physicians consider treatment for rapidly declining patients who are approaching the abnormal range for FEV1. Sirolimus also appears to be effective for the treatment chylous effusions and lymphangioleiomyomas. The benefits of sirolimus only persist while treatment continues, so the safety of long term therapy must be addressed in future studies.

Potential side effects from mTOR inhibitors include swelling in the ankles, acne, oral ulcers, dyspepsia, diarrhea, elevation of cholesterol and triglycerides, hypertension, and headache. Sirolimus pneumonitis and latent malignancy are more serious concerns, but occur infrequently. Sirolimus inhibits wound healing. It is important to stop therapy with the drug for 1-2 weeks before and after elective procedures that require optimal wound healing. Proper precautions must be taken to avoid prolonged sun exposure because sirolimus enhances the risk of skin cancer.

Serum VEGF-D concentration has also been shown to useful predictive and prognostic biomarker.[69] A higher baseline VEGF-D levels predicts more rapid disease progression and a more robust treatment response.

Hormonal approaches to treatment have never been tested in proper trials. In the absence of proven benefit, therapy with progesterone, GnRh agonists (Lupron, goserelin) and tamoxifen are not rountinely recommended.

Doxycycline had no effect on the rate of lung function decline in a double blind trial.[100] Although the study was underpowered, the absence of any evidence for a beneficial effect suggests the drug should not be used to treat LAM.

Sirolimus is often effective as first line management for chylothorax.[101] If chylous leakage or accumulations persist despite medical treatment, imaging with heavy T2 weighted MRI, MRI lymphangiography or thoracic duct lymphangiography should be considered. Pleural fusion procedures can be considered in refractory cases.


Survival estimates vary widely, appear to be dependent on mode of presentation or ascertainment, and have generally trended upward over the past few decades, probably due to earlier recognition through more widespread use of CT scanning. In a recent population based cohort ascertained by surveying patients registered with the LAM Foundation, the median survival was found to be 29 years.[14] Data from earlier, large case series indicated that 38% to 78% of patients were alive at 8.5 years from the time of disease onset.[19][18][21][102]

Patients with LAM typically develop progressive airflow obstruction. In a cohort of patients in the United Kingdom, 10 years after symptom onset, 55% of 77 patients were breathless walking on flat ground and 10% were housebound.[103] The average annual rate of decline in FEV1 and DLCO in 275 patients studied in a single pulmonary function laboratory at the NHLBI was 75 ± 9 mL, and 0.69 ± 0.07 mL/min/mm Hg, respectively.[104] In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr. [21][105][106] In the MILES trial, patients in the placebo group lost 134 cc/yr. [17] There was some evidence in these studies that rate of decline in lung function correlates with initial DLCO, with menopausal status, and high baseline VEGF-D.


LAM almost always affects women, with only a handful of cases reported in men.[citation needed] The first of these was in a man with tuberous sclerosis, reported in 2000 from the Mayo Clinic by a team led by Henry Tazelaar[107]

See also[edit]


  1. ^ McCormack FX, FX (2008). "Lymphangioleiomyomatosis: a clinical update". Chest 133: 507–516. 
  2. ^ a b Franz, DN; Brody, A; Meyer, C; Leonard, J; Chuck, G; Dabora, S; Sethuraman, G; Colby, TV; Kwiatkowski, DJ; McCormack, FX (2001). "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 164: 661–668. 
  3. ^ Costello, LC; Hartman, TE; Ryu, JH (2000). "High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex". Mayo Clin Proc 75: 591–594. 
  4. ^ Moss, J; Avila, NA; Barnes, PM; Litzenberger, RA; Bechtle, J; Brooks, PG; Hedin, CJ; Hunsberger, S; Kristof, AS (2001). "Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex". Am J Respir Crit Care Med 164: 669–671. 
  5. ^ a b Cudzilo, CJ; Szczesniak, RD; Brody, AS; Rattan, MS; Krueger, DA; Bissler, JJ; Franz, DN; McCormack, FX; Young, LR (2013). "Lymphangioleiomyomatosis screening in women with tuberous sclerosis". Chest 144: 578–585. 
  6. ^ Muzykewicz, DA; Sharma, A; Muse, V; Numis, AL; Rajagopal, J; Thiele, EA (2009). "TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex". J Med Genet 46: 465–468. 
  7. ^ Adriaensen, ME; Schaefer-Prokop, CM; Duyndam, DA; Zonnenberg, BA; Prokop, M (2011). "Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex". Clin Radiol 66: 625–628. 
  8. ^ Aubry, MC; Myers, JL; Ryu, JH; Henske, EP; Logginidou, H; Jalal, SM; Tazelaar, HD (2000). "Pulmonary lymphangioleiomyomatosis in a man". Am J Respir Crit Care Med 162: 749–754. 
  9. ^ a b Schiavina, M; Di Scioscio, V; Contini, P; Cavazza, A; Fabiani, A; Barberis, M; Bini, A; Altimari, A; Cooke, RM; Grigioni, WF; D'Errico-Grigioni, A (2007). "Pulmonary lymphangioleiomyomatosis in a karyotypically normal man without tuberous sclerosis complex". Am J Respir Crit Care Med 176: 96–98. 
  10. ^ a b c d e Carsillo, T; Astrinidis, A; Henske, EP (2000). "Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis". Proc Natl Acad Sci U S A 97: 6085–6090. 
  11. ^ Ferrans, VJ; Yu, ZX; Nelson, WK; Valencia, JC; Tatsuguchi, A; Avila, NA; Riemenschn, W; Matsui, K; Travis, WD; Moss, J (2000). "Lymphangioleiomyomatosis (LAM) (A review of clinical and morphological features)". J Nippon Med 67: 311–329. 
  12. ^ Taveira-DaSilva, AM; Steagall, WK; Moss, J (2006). "Lymphangioleiomyomatosis". Cancer Control 13: 276–285. 
  13. ^ Hayashida, M; Seyama, K; Inoue, Y; Fujimoto, K; Kubo, K (2007). "The epidemiology of lymphangioleiomyomatosis in Japan: A nationwide cross-sectional study of presenting features and prognostic factors". Resirology 12: 523–530. 
  14. ^ a b Oprescu, N; McCormack, FX; Byrnes, S; Kinder, BW (2013). "Clinical Predictors of Mortality and Cause of Death in Lymphangioleiomyomatosis: A Population-based Registry". Lung 191 (1): 35-42. 
  15. ^ Johnson, SR; Whale, CI; Hubbard, RB; Lewis, SA; Tattersfield, AE (2004). "Survival and disease progression in UK patients with lymphangioleiomyomatosis". Thorax 59: 800–803. 
  16. ^ a b Johnson, SR; Tattersfield, AE (2000). "Clinical experience of lymphangioleiomyomatosis in the UK". Thorax 55: 1052–1057. 
  17. ^ a b c d McCormack, FX; Inoue, Y; Moss, J; Singer, LG; Strange, C; Nakata, K; Barker, AF; Chapman, JT; Brantly, ML; Stocks, JM; Brown, KK; Lynch, JP, 3rd; Goldberg, HI; Young, LR; Kinder, BW; Downey, GP; Sullivan, EJ; Colby, TV; McKay, RT; Cohen, MM; Korbee, L; Taveira-DaSilva, AM; Lee, HS; Krischer, JP; Trapnell, BC (2011). "Efficacy and safety of sirolimus in lymphangioleiomyomatosis". N Engl J Med 364: 1595–1606. 
  18. ^ a b c Kitaichi, M; Nishimura, K; Itoh, H; Izumi, T (1995). "Pulmonary lymphangioleiomyomatosis: A report of 46 patients including a clinicopathologic study of prognostic factors". Am J Respir Crit Care Med 151: 527–533. 
  19. ^ a b c Taylor, JR; Ryu, J; Colby, TV; Raffin, TA (1990). "Lymphangioleiomyomatosis. Clinical course in 32 patients". N Engl J Med 323: 1254-1260. 
  20. ^ a b Chu, SC; Horiba, K; Usuki, J; Avila, NA; Chen, CC; Travis, WD; Ferrans, VJ; Moss, J (1999). "Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis". Chest 115: 1041–1052. 
  21. ^ a b c d e Urban, T; Lazor, R; Lacronique, J; Murris, M; Labrune, S; Valeyre, D; Cordier, JF (1999). "Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P)". Medicine (Baltimore) 78: 321–337. 
  22. ^ Almoosa, KF; Ryu, JH; Mendez, J; Huggins, JT; Young, LR; Sullivan, EJ; Maurer, J; McCormack, FX; Sahn, SA (2006). "Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications". Chest 129: 1274–1281. 
  23. ^ Ryu, JH; Moss, J; Beck, GJ; Lee, JC; Brown, KK; Chapman, JT; Finlay, GA; Olson, EJ; Ruoss, SJ; Maurer, JR; Raffin, TA; Peavy, HH; McCarthy, K; Taveira-Dasilva, A; McCormack, FX; Avila, NA; Decastro, RM; Jacons, SS; Stylianou, M; Fanburg, BL (2006). "The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment". Am J Respir Crit Care Med 173: 105–111. 
  24. ^ Avila, NA; Bechtle, J; Dwyer, AJ; Ferrans, VJ; Moss, J (2001). "Lymphangioleiomyomatosis: CT of diurnal variation of lymphangioleiomyomas". Radiology 221: 415–421. 
  25. ^ Avila, NA; Dwyer, AJ; Rabel, A; Moss, J (2007). "Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features". Radiology 242: 277–285. 
  26. ^ Avila, NA; Kelly, JA; Chu, SC; Dwyer, AJ; Moss, J (2000). "Lymphangioleiomyomatosis: abdominopelvic CT and US findings". Radiology 216: 147–153. 
  27. ^ a b Matsui, K; Tatsuguchi, A; Valencia, J; Yu, Z; Bechtle, J; Beasley, MB; Avila, NA; Travis, WD; Moss, J; Ferrans, VJ (2000). "Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases". Hum Pathol 31: 1242–1248. 
  28. ^ a b Smolarek, TA; Wessner, LL; McCormack, FX; Mylet, JC; Menon, AG; Henske, EP (1998). "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 62 (4): 810-815. 
  29. ^ a b Carsillo, T; Astrinidis, A; Henske, EP (2000). "Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis". Proc Natl Acad Sci U S A 97: 6085-6090. 
  30. ^ Sato, T; Seyama, K; Fujii, H; Maruyama, H; Setoguchi, Y; Iwakami, S; Fukuchi, Y; Hino, O (2002). "Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis". J Hum Genet 47 (1): 20-28. 
  31. ^ Dabora, SL; Jozwiak, S; Franz, DN; Roberts, PS; Nieto, A; Chung, J; Choy, YS; Reeve, MP; Thiele, E; Egelhoff, JC; Kasprzyk-Obara, J; Domanska-Pakiela, D; Kwiatkowski, DJ (2001). "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs". Am J Hum Genet 68 (1): 64-80. 
  32. ^ Goncharova, EA; Goncharov, DA; Eszterhas, A; Hunter, DS; Glassberg, MK; Yeung, RS; Walker, CL; Noonan, D; Kwiatkowski, DJ; Chou, MM; Panettieri, RA Jr; Krymskaya, VP (2002). "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 277 (34): 30958-30967. 
  33. ^ Kwiatkowski, DJ; Zhang, H; Bandura, JL; Heiberger, KM; Glogauer, M; el-Hashemite, N; Onda, H (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 (5): 525-534. 
  34. ^ Bissler, JJ; McCormack, FX; Young, LR; Elwing, JM; Chuck, G; Leonard, JM; Schmithorst, VJ; Laor, T; Brody, AS; Bean, J; Salisbury, S; Franz, DN (2008). "Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis". N Eng J Med 358 (2): 140-151. 
  35. ^ Guertin, DA; Sabatini, DM (2007). "Defining the role of mTOR in cancer". Cancer Cell 12 (1): 9-22. 
  36. ^ Hara, K; Maruki, Y; Long, X; Yoshino, K; Oshiro, N; Hidayat, S; Tokunaga, C; Avruch, J; Yonezawa, K (2002). "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action". Cell 110 (2): 177-189. 
  37. ^ Kim, DH; Sarbassov, DD; Ali, SM; King, JE; Latek, RR; Erdjument-Bromage, H; Tempst, P; Sabatini, DM (2002). "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery". Cell 100 (2): 163-175. 
  38. ^ Schalm, SS; Fingar, DC; Sabatini, DM; Blenis, J (2003). "TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function". Curr Biol 13 (10): 797-806. 
  39. ^ Frias, MA; Thoreen, CC; Jaffe, JD; Schroder, W; Sculley, T; Carr, SA; Sabatini, DM (2006). "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Curr Biol 16 (18): 1865-1870. 
  40. ^ Jacinto, E; Facchinetti, V; Liu, D; Soto, N; Wei, S; Jung, SY; Huang, Q; Qin, J; Su, B (2006). "SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity". Cell 127 (1): 125-137. 
  41. ^ Laplante, M; Sabatini, DM (2009). "mTOR signaling at a glance". J Cell Sci 122 (Pt 20): 3589-3594. 
  42. ^ Jacinto, E; Loewith, R; Schmidt, A; Lin, S; Rüegg, MA; Hall, A; Hall, MN (2004). "Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive". Nat Cell Biol 6 (11): 1122-1128. 
  43. ^ Sarbassov, DD; Ali, SM; Kim, DH; Guertin, DA; Latek, RR; Erdjument-Bromage, H; Tempst, P; Sabatini, DM (2004). "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton". Curr Biol 14 (14): 1296-1302. 
  44. ^ Zoncu, R; Efeyan, A; Sabatini, DM (2011). "mTOR: from growth signal integration to cancer, diabetes and ageing". Nat Rev Mol Cell Biol 12 (1): 21-35. 
  45. ^ Saci, A; Cantley, LC; Carpenter, CL (2011). "Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size". Mol Cell 42 (1): 50-61. 
  46. ^ Goncharova, E; Goncharov, D; Noonan, D; Krymskaya, VP (2004). "TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase". J Cell Biol 167 (6): 1171-1182. 
  47. ^ a b Goncharova, EA; Goncharov, DA; Lim, PN; Noonan, D; Krymskaya, VP (2006). "Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis". Am J Respir Cell Mol Biol 34 (4): 473-480. 
  48. ^ Goncharova, EA; Goncharova, DA; Li, H; Pimtong, W; Lu, S; Khavin, I; Krymskaya, VP (2011). "mTORC2 is required for proliferation and survival of TSC2-null cells". Mol Cell Biol 31 (12): 2484-2498. 
  49. ^ El-Hashemite, N; Kwiatkowski, DJ (2005). "Interferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target". Am J Respir Cell Mol Biol 33 (3): 227-230. 
  50. ^ El-Hashemite, N; Zhang, H; Walker, V; Hoffmeister, KM; Kwiatkowski, DJ (2004). "Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment". Cancer Res 64 (10): 3436-3443. 
  51. ^ Goncharova, EA; Goncharova, DA; Chisolm, A; Spaits, MS; Lim, PN; Cesarone, G; Khavin, I; Tliba, O; Amrani, Y; Panettieri, RA Jr; Krymskaya, VP (2008). "Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation". Mol Pharmacol 73 (3): 778-788. 
  52. ^ Goncharova, EA; Goncharova, DA; Damera, G; Tliba, O; Amrani, Y; Panettieri, RA Jr; Krymskaya, VP (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 (4): 766-777. 
  53. ^ Parkhitko, A; Myachina, F; Morrison, TA; Hindi, KM; Auricchio, N; Karbowniczek, M; Wu, JJ; Finkel, T; Kwiatkowski, DJ; Yu, JJ; Henske, EP (2011). "Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent". Proc Natl Acad Sci U S A 108 (30): 12455-12460. 
  54. ^ Henske, EP (2003). "Metastasis of benign tumor cells in tuberous sclerosis complex". Genes Chromosomes Cancer 38 (4): 376-381. 
  55. ^ a b c Henske, EP; McCormack, FX (2012). "Lymphangioleiomyomatosis - a wolf in sheep's clothing". J Clin Invest 122 (11): 3807-3816. 
  56. ^ Zhe, X; Yang, Y; Jakkaraju, S; Schuger, L (2003). "Tissue inhibitor of metalloproteinase-3 downregulation in lymphangioleiomyomatosis: potential consequence of abnormal serum response factor expression". Am J Respir Cell Mol Biol 28 (4): 504-511. 
  57. ^ Chang, WY; Clements, D; Johnson, SR (2010). "Effect of doxycycline on proliferation, MMP production, and adhesion in LAM-related cells". Am J Physiol Lung Cell Mol Physiol 299 (3): L393-400. 
  58. ^ Glassberg, MK; Elliot, SJ; Fritz, J; Catanuto, P; Potier, M; Donahue, R; Stetler-Stevenson, W; Karl, M (2008). "Activation of the estrogen receptor contributes to the progression of pulmonary lymphangioleiomyomatosis via matrix metalloproteinase-induced cell invasiveness". J Clin Endocrinol Metab 93 (5): 1625-1633. 
  59. ^ Lee, PS; Tsang, SW; Moses, MA; Trayes-Gibson, Z; Hsiao, LL; Jensen, R; Squillace, R; Kwiatkowski, DJ (2010). "Rapamycin-insensitive up-regulation of MMP2 and other genes in tuberous sclerosis complex 2-deficient lymphangioleiomyomatosis-like cells". Am J Respir Cell Mol Biol 42 (2): 227-234. 
  60. ^ Moir, LM; Ng, HY; Poniris, MH; Santa, T; Burgess, JK; Oliver, BG; Krymskaya, VP; Black, JL (2011). "Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells". Br J Pharmacol 164 (1): 83-92. 
  61. ^ Kumasaka, T; Seyama, K; Mitani, K; Souma, S; Kashiwagi, S; Hebisawa, A; Sato, T; Kubo, H; Gomi, K; Shibuya, K; Fukuchi, Y; Suda, K (2005). "Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis". Am J Surg Pathol 29 (10): 1356-1366. 
  62. ^ Seyama, K; Mitani, K; Kumasaka, T; Gupta, SK; Oommen, S; Liu, G; Ryu, JH; Vlahakis, NE (2010). "Lymphangioleiomyoma cells and lymphatic endothelial cells: expression of VEGFR-3 in lymphangioleiomyoma cell clusters". Am J Pathol 176 (4): 2051-2052. 
  63. ^ Taveira-DaSilva, AM; Hathaway, O; Stylianou, M; Moss, J (2011). "Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus". Ann Intern Med 154 (12): 797-805. 
  64. ^ Glasgow, CG; El-Chemaly, S; Moss, J (2012). "Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis". Eur Respir Rev 21 (125): 196-206. 
  65. ^ Glasgow, CG; Taveira-DaSilva, A; Pacheco-Rodriguez, G; Steagall, WK; Tsukada, K; Cai, X; El-Chemaly, S; Moss, J (2009). "Involvement of lymphatics in lymphangioleiomyomatosis". Lymphat Res Biol 7 (4): 221-228. 
  66. ^ Glasgow, CG; Taveira-Dasilva, AM; Darling, TN; Moss, J (2008). "Lymphatic involvement in lymphangioleiomyomatosis". Ann N Y Acad Sci 1131: 206-214. 
  67. ^ Seyama, K; Kumasaka, T; Souma, S; Sato, T; Kurihara, M; Mitani, K; Tominaga, S; Fukuchi, Y (2006). "Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis". Lymphat Res Biol 4 (3): 143-152. 
  68. ^ a b Young, LR; Vandyke R, Gulleman, PM; Inoue, Y; Brown, KK; Schmidt, LS; Linehan, WM; Hajjar, F; Kinder, BW; Trapnell, BC; Bissler, JJ; Franz, DN; McCormack, FX (2010). "Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases". Chest 138: 674-681. 
  69. ^ a b Young, LR; Lee, HS; Moss, J; Singer, LG; Strange, C; Nakata, K; Baker, AF; Chapman, JT; Brantly, ML; Stocks, JM; Brown, KK; Lynch III, JP; Goldberg, HJ; Downey, GP; Swigris, JJ; Taveira-DaSilva, A; Krischer, JP; Trapnell, BC; McCormack, FX (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 Resp Med 1: 445-452. 
  70. ^ Achen, MG; Jeltsch, M; Kukk, E; Mäkinen, T; Vitali, A; Wilks, AF; Alitalo, K; Stacker, SA (1998). "Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)". Proc Natl Acad Sci U S A 95 (2): 548-553. 
  71. ^ Karnezis, T; Shayan, R; Caesar, C; Roufail, S; Harris, NC; Ardipradja, K; Zhang, YF; Williams, SP; Farnsworth, RH; Chai, MG; Rupasinghe, TW; Tull, DL; Baldwin, ME; Sloan, EK; Fox, SB; Achen, MG; Stacker, SA (2012). "VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium". Cancer Cell 21 (2): 181-195. 
  72. ^ Stacker, SA; Williams, SP; Karnezis, T; Shayan, R; Fox, SB; Achen, MG (2014). "Lymphangiogenesis and lymphatic vessel remodelling in cancer". Nat Rev Cancer 14 (3): 159-172. 
  73. ^ Achen, MG; Williams, RA; Baldwin, ME; Lai, P; Roufail, S; Alitalo, K; Stacker, SA (2002). "The angiogenic and lymphangiogenic factor vascular endothelial growth factor-D exhibits a paracrine mode of action in cancer". Growth Factors 20 (2): 99-107. 
  74. ^ Kumasaka, T; Seyama, K; Mitani, K; Souma, S; Kashiwagi, S; Hebisawa, A; Sato, T; Kubo, H; Gomi, K; Shibuya, K; Fukuchi, Y; Suda, K (2005). "Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis". Am J Surg Pathol 29 (10): 1356-1366. 
  75. ^ Davis, JM; Hyjek, E; Husain, AN; Shen, L; Jones, J; Schuger, LA (2013). "Lymphatic endothelial differentiation in pulmonary lymphangioleiomyomatosis cells". J Histochem Cytochem 61 (8): 580-590. 
  76. ^ Stacker, SA; Williams, SP; Karnezis, T; Shayan, R; Fox, SB; Achen, MG (2014). "Lymphangiogenesis and lymphatic vessel remodelling in cancer". Nat Rev Cancer 14 (3): 159-172. 
  77. ^ Baldwin, ME; Catimel, B; Nice, EC; Roufail, S; Hall, NE; Stenvers, KL; Karkkainen, MJ; Alitalo, K; Stacker, SA; Achen, MG (2001). "The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man". J Biol Chem 276 (22): 19166-19171. 
  78. ^ Baldwin, ME; Halford, MM; Roufail, S; Williams, RA; Hibbs, ML; Grail, D; Kubo, H; Stacker, SA; Achen, MG (2005). "Vascular endothelial growth factor D is dispensable for development of the lymphatic system". Mol Cell Biol 25 (6): 2441-2449. 
  79. ^ Karnezis, T; Shayan, R; Caesar, C; Roufail, S; Harris, NC; Ardipradja, K; Zhang, YF; Williams, SP; Farnsworth, RH; Chai, MG; Rupasinghe, TW; Tull, DL; Baldwin, ME; Sloan, EK; Fox, SB; Achen, MG; Stacker, SA (2012). "VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium". Cancer Cell 21 (2): 181-195. 
  80. ^ Stacker, SA; Williams, SP; Karnezis, T; Shayan, R; Fox, SB; Achen, MG (2014). "Lymphangiogenesis and lymphatic vessel remodelling in cancer". Nat Rev Cancer 14 (3): 159-172. 
  81. ^ a b Crino, PB; Nathanson, KL; Henske, EP (2006). "The tuberous sclerosis complex". N Engl J Med 355 (13): 1345-1356. 
  82. ^ a b McCormack, FX; Travis, WD; Colby, TV; Henske, EP; Moss, J (2012). "Lymphangioleiomyomatosis: calling it what it is: a low-grade, destructive, metastasizing neoplasm". Am J Respir Crit Care Med 186 (12): 1210-1212. 
  83. ^ van Slegtenhorst, M; de Hoogt, R; Hermans, C; Nellist, M; Janssen, B; Verhoef, S; Lindhout, D; van den Ouweland, A; Halley, D; Young, J; Burley, M; Jeremiah, S; Woodward, K; Nahmias, J; Fox, M; Ekong, R; Osborne, J; Wolfe, J; Povey, S; Snell, RG; Cheadle, JP; Jones, AC; Tachataki, M; Ravine, D; Sampson, JR; Reeve, MP; Richardson, P; Wilmer, F; Munro, C; Hawkins, TL; Sepp, T; Ali, JB; Ward, S; Green, AJ; Yates, JR; Kwiatkowska, J; Henske, EP; Short, MP; Haines, JH; Jozwiak, S; Kwiatkowski, DJ (1997). "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34". Science 277: 805-808. 
  84. ^ a b Strizheva, GD; Carsillo, T; Kruger, WD; Sullivan, EJ; Ryu, JH; Henske, EP (2001). "The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis". Am J Respir Crit Care Med 163: 253-258. 
  85. ^ a b Badri, KR; Gao, L; Hyjek, E; Schuger, N; Schuger, L; Qin, W; Chekaluk, Y; Kwiatkowski, DJ; Zhe, X (2013). "Exonic mutations of TSC2/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis". Am J Respir Crit Care Med 187: 663-665. 
  86. ^ Knudson, AG, Jr (1971). "Mutation and cancer: statistical study of retinoblastoma". Proc Natl Acad Sci U S A 68: 820-823. 
  87. ^ Knudson, AG (2001). "Two genetic hits (more or less) to cancer". Nat Rev Cancer 1: 157-162. 
  88. ^ Henske, EP; Scheithauer, BW; Short, MP; Wollmann, R; Nahmias, J; Hornigold, N; van Slegtenhorst, M; Welsh, CT; Kwiatkowski, DJ (1996). "Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions". Am J Hum Genet 59: 400-406. 
  89. ^ Yu, J; Astrinidis, A; Henske, EP (2001). "Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis". Am J Respir Crit Care Med 164: 1537-1540. 
  90. ^ Crooks, DM; Pacheco-Rodriguez, G; DeCastro, RM; McCoy, JP; Wang, JA; Kumaki, F; Darling, T; Moss, J (2004). "Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis". Proc Natl Acad Sci U S A 101: 17462-17467. 
  91. ^ Cai, X; Pacheco-Rodriguez, G; Fan, QY; Haughey, M; Samsel, L; El-Chemaly, S; Wu, HP; McCoy, JP; Steagall, WK; Lin, JP; Darling, TN; Moss, J (2010). "Phenotypic characterization of disseminated cells with TSC2 loss of heterozygosity in patients with lymphangioleiomyomatosis". Am J Respir Crit Care Med 182: 1410-1418. 
  92. ^ Karbowniczek, M; Astrinidis, A; Balsara, BR; Testa, JR; Lium, JH; Colby, TV; McCormack, FX; Henske, EP (2003). "Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism". Am J Respir Crit Care Med 167: 976-982. 
  93. ^ Johnson, SR; Cordier, JF; Lazor, R; Cottin, V; Costabel, U; Harari, S; Reynaud-Gaubert, M; Boehler, A; Brauner, M; Popper, H; Bonetti, F; Kingswood, C (2010). "European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis". Eur Respir J 35: 14-26. 
  94. ^ Ye, L; Jin, M; Bai, C (2010). "Clinical analysis of patients with pulmonary lymphangioleiomyomatosis (PLAM) in mainland China". Respir Med 104 (10): 1521-1526. 
  95. ^ Torre, O; Harari, S (2010). "The diagnosis of cystic lung diseases: a role for bronchoalveolar lavage and transbronchial biopsy?". Respir Med 104 (Suppl 1): S81-85. 
  96. ^ Kumasaka, T; Seyama, K; Mitani, K; Souma, S; Kashiwagi, S; Hebisawa, A; Sato, T; Kubo, H; Gomi, K; Shibuya, K; Fukuchi, Y; Suda, K (2005). "Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis". Am J Surg Pathol 29: 1356-1366. 
  97. ^ Mitani, K; Kumasaka, T; Takemura, H; Hayashi, T; Gunji, Y; Kunogi, M; Akiyoshi, T; Takahashi, K; Suda, K; Seyama, K (2009). "Cytologic, immunocytochemical and ultrastructural characterization of lymphangioleiomyomatosis cell clusters in chylous effusions of patients with lymphangioleiomyomatosis". Acta Cytol 53: 402-409. 
  98. ^ Ohara, T; Oto, T; Miyoshi, K; Tao, H; Yamane, M; Toyooka, S; Okazaki, M; Date, H; Sano, Y (2008). "Sirolimus ameliorated post lung transplant chylothorax in lymphangioleiomyomatosis". Ann Thorac Surg 86: e7-8. 
  99. ^ Yamauchi, M; Nakahara, H; Uyama, K; Tsujimoto, A; Tamai, M; Aozasa, K (2000). "Cytologic finding of chyloascites in lymphangioleiomyomatosis. A case report". Acta Cytol 44: 1081-1084. 
  100. ^ Chang, WY; Cane, JL; Kumaran, M; Lewis, S; Tattersfield, AE; Johnson, SR (2014). "A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis". Eur Respir J 43: 1114-1123. 
  101. ^ Taveira-DaSilva, AM; Hathaway, O; Stylianou, M; Moss, J (2011). "Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus". Ann Intern Med 154: 797-805. 
  102. ^ El-Hashemite, N; Walker, V; Zhang, H; Kwiatkowski, D (2003). "Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin". Cancer Res 63 (17): 5173-5177. 
  103. ^ de la Fuente, J; Páramo, C; Román, F; Pérez, R; Masa, C; de Letona, JM (1993). "Lymphangioleiomyomatosis: unsuccessful treatment with luteinizing-hormone-releasing hormone analogues". Eur J Med 2 (6): 377-378. 
  104. ^ Zhe, X; Yang, Y; Schuger, L (2005). "Imbalanced plasminogen system in lymphangioleiomyomatosis: potential role of serum response factor". Am J Respir Cell Mol Biol 32 (1): 28-34. 
  105. ^ Rossi, GA; Balbi, B; Oddera, S; Lantero, S; Ravazzoni, C (1991). "Response to treatment with an analog of the luteinizing-hormone-releasing hormone in a patient with pulmonary lymphangioleiomyomatosis.". Am Rev Respir Dis 143 (1): 174-176. 
  106. ^ Schiavina, M; Contini, P; Fabiani, A; Cinelli, D; Di Scioscio, V; Zompatori, M; Campidelli, C; Pileri, SA (2007). "Efficacy of hormonal manipulation in lymphangioleiomyomatosis. A 20-year-experience in 36 patients". Sarcoidosis Vasc Diffuse Lung Dis 24 (1): 39-50. 
  107. ^ Aubry, MC; Myers, JL; Ryu, JH; Henske, EP; Logginidou, H; Jalal, SM; Tazelaar, HD (August 2000). "Pulmonary lymphangioleiomyomatosis in a man.". American Journal of Respiratory and Critical Care Medicine 162 (2 Pt 1): 749–52. doi:10.1164/ajrccm.162.2.9911006. PMID 10934115. 

External links[edit]