Lymphangioleiomyomatosis

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Lymphangioleiomyomatosis
Lymphangioleiomyomatosis.jpg
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]

Pathophysiology[edit]

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.

Genetics[edit]

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]

Diagnosis[edit]

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.

Treatment[edit]

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.

Prognosis[edit]

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.

Epidemiology[edit]

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]

References[edit]

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