lymphangioleiomyomatosis lymphangioleiomyomatosis lymphangioleiomyomatosis (lam) is a rare, progressive and systemic disease that typically results in cystic lung destruction. it predominantly affects women, especially during childbearing years. the term sporadic lam is used for patients with lam not associated with tuberous sclerosis complex (tsc), while tsc-lam refers to lam that is associated with tsc. lymphangioleiomyomatosis (lam)other nameslymphangiomyomatosis, lamfigure 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.specialtypulmonology signs and symptoms the average age of onset is the early-to-mid-30s. exertional dyspnea (shortness of breath) and spontaneous pneumothorax (lung collapse) have been reported as the initial presentation of the disease in 49% and 46% of patients, respectively. diagnosis is typically delayed 5 to 6 years. the condition is often misdiagnosed as asthma or chronic obstructive pulmonary disease. the first pneumothorax, or lung collapse, precedes the diagnosis of lam in 82% of patients. the consensus clinical definition of lam includes multiple symptoms: fatigue cough coughing up blood (rarely massive) chest pain chylous complications arising from lymphatic obstruction, including chylothorax chylous ascites chylopericardium chyloptysis chyluria chyle in vaginal discharge chyle in stool angiomyolipomas (fatty kidney tumors) are present in about 30% of patients with sporadic lam and up to 90% of patients with tsc-lam. angiomyolipomas can sometimes spontaneously bleed, causing pain or low blood pressure. cystic lymphangiomas or lymph nodes with hypodense centers, which mimic necrotizing lymphomas, ovarian or renal cancers, or other malignancies can occur in the retroperitoneum, pelvis or mediastinum. lung destruction in lam is a consequence of diffuse infiltration by neoplastic smooth muscle-like cells that invade all lung structures including the lymphatics, airway walls, blood vessels and interstitial spaces. the consequences of vessel and airway obstruction include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. the typical disease course displays progressive dyspnea on exertion, spaced by recurrent pneumothoraces and in some patients, chylous pleural effusions or ascites. most people have dyspnea on exertion with daily activities by 10 years after symptom onset. many patients require supplemental oxygen over that interval. genetics 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). 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. the tsc1 gene is located on the long arm of chromosome 9 (9q34) and the tsc2 gene is located on the short arm of chromosome 16 (16p13). tsc-lam occurs in women who have germline mutations in either the tsc1 or the tsc2 gene. sporadic lam is primarily associated with somatic tsc2 gene mutations. 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. 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. 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. loh can be detected in microdissected lam cells, in angiomyolipomas and lymph nodes from women with lam, and in circulating lam cells (cells in blood and urine). angiomyolipomas and pulmonary lam cells from women with the sporadic form of lam carry identical mutations in tsc2. this, together with the fact that recurrent lam after lung transplantation carries the same tsc2 mutations as the original lam, has led to the "benign metastasis" hypothesis that lam cells can migrate or metastasize from one site to another. pathophysiology a variable percentage of cells within the lam lesion contain mutational inactivation of the tuberous sclerosis complex (tsc1 or tsc2) tumor suppressor genes. tsc1 mutations cause a less severe clinical phenotype than tsc2 mutations. the discovery of tsc1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mtorc1) led to successful use of rapamycin analog sirolimus in clinical trials and fda approval of sirolimus for treatment of lam. tsc1 and tsc2 form a tumor suppressor complex that regulates 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 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. mtorc1 consists of five proteins including raptor that positively regulate mtor activity. mtorc2 consists of six proteins including mtor and rictor, which defines the activation level of mtorc2 and modulates the assembly of the actin cytoskeleton through rho gtpases, and rac1 is required for mtor activation. in tsc2-null and human lam cells, rho gtpase activity is required for cell adhesion, motility, proliferation and survival. loss of tsc1/tsc2 in lam induces uncontrolled lam cell growth and increases lam cell viability. upregulation of stat1 and stat3 and autophagy are known mediators of lam cell viability and survival. lam cells behave, in many ways, like metastatic tumor cells. lam cells appear to arise from an extrapulmonary source and migrate to the lung. increased lam cell migration and invasiveness is rescued by tsc2 re-expression. 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 metalloproteinases (mmps) and their endogenous inhibitors timps. the invasive cell phenotype in lam is associated with timp-3 downregulation and tsc2-dependent upregulation of mmps. clinical and histopathological evidence demonstrate the lymphatic involvement in lam. 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. vegf-d serum levels are increased in lam compared to other cystic lung diseases, including pulmonary langerhans cell histiocytosis, emphysema, sjögren's syndrome, or birt–hogg–dubé syndrome. vegf-d levels correlate with the severity of lam, evaluated as a measure of ct grade (the abundance of chylous effusions and lymphatic involvement). vegf-d is a secreted homodimeric glycoprotein and a member of the vegf family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis. proteolytic processing of vegf-d affects cognate binding to vegfr3. histopathologically, lam lesions are surrounded by cells that stain for vegfr3, the lymphatic vessel endothelial hyaluronan receptor 1 (lyve-1) and podoplanin. vegf-d binds to the receptor protein tyrosine kinases vegfr-2 and vegfr-349 in humans, and to vegfr3 in mice. surprisingly, knock-out of vegf-d in mice has little effect on lymphatic system development. nevertheless, during tumorigenesis vegf-d promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells. however, little is known about a role of abnormal lymphatics and vegf-d in lam pathogenesis. diagnosis micrograph of lymphangioleiomyomatosis. h&e stain ct scan of the lungs in a patient with lymphangioleiomyomatosis showing numerous thin walled cysts within the lungs lam can come to medical attention in several ways, most of which trigger a chest 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. hrcts of tsc patients reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40. lam is sometimes revealed by chest ct 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 a chest ct. a review of the ct by an expert familiar with lam may increase diagnostic accuracy. chylothorax can also bring lam to attention. in some cases, a lam diagnosis 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. 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 technique, but transbronchial biopsy has a yield of over 50% and can also be effective. 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 be diagnostic. diagram 1 outlines a proposed algorithm for the diagnosis of lam.diagram 1. outlines a proposed algorithm for the diagnosis of lam. ct: computed tomography; tsc: tuberous sclerosis complex; aml: angiomyolipoma; vegf-d: vascular endothelial growth factor d; tbbx: transbronchial biopsy; vats: video-assisted thoracoscopic surgery chest radiograph the chest radiograph may appear relatively normal, even late in the disease, or may suggest hyperinflation only. as the disease progresses, the chest radiograph often demonstrates diffuse, bilateral and symmetric reticulonodular opacities, cysts, bullae or a "honeycomb" (i.e., pseudo fibrotic) appearance. pleural effusion and pneumothorax may be apparent. preservation of lung volumes in the presence of increased interstitial markings is a radiographic hallmark of lam that helps distinguish it from most other interstitial lung diseases, in which alveolar septal and interstitial expansion tend to increase the lung's elastic recoil properties and decreased lung volumes. computed tomography the high-resolution computed tomography (hrct) chest scan is better than the chest radiograph to detect cystic parenchymal disease and is almost always abnormal at the time of diagnosis, even when the chest radiograph and pulmonary function assessments are normal. the typical ct shows diffuse round, bilateral, thin-walled cysts of varying sizes ranging from 1 to 45 mm in diameter. the numbers of cysts varies in lam from a few to almost complete replacement of normal lung tissue. the profusion of cysts tends to be milder in patients with tsc-lam than s-lam, perhaps explained in part because tsc-lam patients typically receive earlier screening. pleural effusions are seen on ct in 12% of patients with s-lam and 6% of patients with tsc-lam. other ct features include linear densities (29%), hilar or mediastinal lymphadenopathy (9%), pneumothorax, lymphangiomyoma, and thoracic duct dilation. ground-glass opacities (12%) suggest the presence of interstitial edema due to lymphatic congestion. in patients with tsc, nodular densities on hrct may represent multifocal micronodular pneumocyte hyperplasia (mmph) made up of clusters of hyperplastic type ii pneumocytes. mmph may be present in males or females with tsc in the presence or absence of lam, but not in patients with s-lam. mmph is not typically associated with physiologic or prognostic consequences, but one case of respiratory failure due to mmph has been reported. ventilation-perfusion scans in one study ventilation-perfusion scans were abnormal in 34 of 35 lam patients. the most common abnormality was nonspecific diffuse heterogeneity, usually grossly matched. these authors also described an “unusual,” “speckling pattern” on the perfusion images in 74% of patients, consisting of “small, often peripheral collections of radioisotope.” positron emission tomography lam and aml lesions do not typically exhibit increased uptake of 18f-fluorodeoxyglucose on positron emission tomography (pet) scanning. other neoplasms (or sources of inflammation) should therefore be considered in known or suspected lam cases in which fdg-pet results are positive. abdominal imaging abnormalities on abdominal imaging, such as renal aml and enlarged lymphatic structures, are also common in lam. fat density within a renal mass is pathognomonic of amls. amls are more prevalent and more frequently bilateral and large in patients with tsc-lam than in patients with s-lam. aml size correlates with the prevalence of pulmonary cysts in patients with tsc. one study ct imaged 256 patients with s-lam and 67 with tsc-lam. renal amls were present in 32% of patients with s-lam and 93% of patients with tsc-lam. hepatic amls were present in