Proliferation Of Lymphangioleiomyomatosis Cells Research Articles

Unexpected sirolimus-stimulated airway hyperreactivity in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a multisystem disease affecting primarily women, characterised in the lung by proliferation of LAM cells, abnormal smooth muscle-like cells with dysfunctional tuberous sclerosis complex genes. This dysfunction results in activation of mechanistic target of rapamycin (mTOR), leading to LAM cell proliferation. Sirolimus (rapamycin) is the only United States Food and Drug Administration-approved treatment for pulmonary LAM, resulting in decreased LAM cell growth/size and stabilised lung function [1].

A pulmonary lymphangioleiomyomatosis with multi-site angiomyolipoma: a case report

BackgroundLymphangioleiomyomatosis (LAM) is a rare low-grade malignant tumor featured with diffuse cystic changes due to the destructive proliferation of LAM cells, closely related to angiomyolipoma (AML). Here, we reported a rare case of pulmonary LAM coexisting with AMLs in multiple sites of the lung, liver, kidney, and retroperitoneum. We aimed to contribute to the body of knowledge regarding the diagnosis, identification and treatment of such cases.Case DescriptionA 48-year-old female with no symptoms underwent a chest computed tomography (CT) scan that showed diffuse thin-walled cysts and multiple solid nodules in the lungs. She received a right nephrectomy due to right kidney AML 30 years previously. The pathological manifestations of the right lower lung mass removed by thoracoscopic surgery was a multifocal AML with mutations in the tuberous sclerosis complex gene. Abdominal magnetic resonance imaging (MRI) reveals a vast area of fat signal shadow behind the peritoneum and multiple scattered fatty signal nodules in the liver parenchyma. No other treatment was given due to personal factors of the patient, and there was no significant change at the 1-year follow-up.ConclusionsLAM and AML are two different but substantively related rare neoplastic diseases. When typical LAM imaging features are found on chest CT or in pathological specimens collected from patients diagnosed with AML, multisystem screening should be performed for the early detection and diagnosis of LAM.

Circulating Lymphangioleiomyomatosis Tumor Cells With Loss of Heterozygosity in the TSC2 Gene Show Increased Aldehyde Dehydrogenase Activity

Lymphangioleiomyomatosis (LAM) is a destructive metastasizing neoplasm of the lung characterized by proliferation of LAM cells in specialized lung nodules. LAM cells are characterized by expression of the prometastatic and cancer-initiating hyaluronan receptor CD44v6, and loss of heterozygosity (LOH) of TSC1 and TSC2. The circulating neoplastic LAM cells are thought to be involved in metastasis. Because LAM cells display properties of neoplastic, metastatic, and stem cell-like cancer cells, we hypothesized that elevated aldehyde dehydrogenase (ALDH) activity, characteristic of cancer and stem cells, is a property of LAM cells. We performed an insilico search of ALDH genes in microdissected LAM lung nodules. To identify circulating LAM cells, we osmotically removed red blood cells from whole blood to obtain peripheral blood mononuclear cells, which were then sorted by fluorescence-activated cell sorting based on their level of ALDH activity. Microdissected LAM lung nodules possess a distinctive ALDH gene profile. The cell subpopulation with high ALDH activity, isolated from circulating cells, possessed TSC2 LOH in 8 of 14 patients with LAM. Approximately 60%of the circulating cells with high ALDH activity expressed CD44v6. Cells with TSC2 LOH from patients with LAM and LAM/TSC exhibited different properties in different body locations, but all cell types showed high ALDH activity. This new procedure allows for isolation of circulating LAM cells from cultured cells, blood, and chylous effusions and shows that circulating LAM cells are heterogeneous with neoplastic, metastatic, and cancer-stem cell-like properties.

Immune Checkpoint Ligand PD-L1 Is Upregulated in Pulmonary Lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis (LAM) is a slow-progressing metastatic disease that is driven by mutations in the tumor suppressor tuberous sclerosis complex 1/2 (TSC1/2). Rapamycin inhibits LAM cell proliferation and is the only approved treatment, but it cannot cause the regression of existing lesions and can only stabilize the disease. However, in other cancers, immunotherapies such as checkpoint blockade against PD-1 and its ligand PD-L1 have shown promise in causing tumor regression and even curing some patients. Thus, we asked whether PD-L1 has a role in LAM progression. In vitro, PD-L1 expression in murine Tsc2-null cells is unaffected by mTOR inhibition with torin but can be upregulated by IFN-γ. Using immunohistochemistry and single-cell flow cytometry, we found increased PD-L1 expression both in human lung tissue from patients with LAM and in Tsc2-null lesions in a murine model of LAM. In this model, PD-L1 is highly expressed in the lung by antigen-presenting and stromal cells, and activated T cells expressing PD-1 infiltrate the affected lung. In vivo treatment with anti-PD-1 antibody significantly prolongs mouse survival in the model of LAM. Together, these data demonstrate that PD-1/PD-L1-mediated immunosuppression may occur in LAM, and suggest new opportunities for therapeutic targeting that may provide benefits beyond those of rapamycin.

Minireview: Lymphangioleiomyomatosis (LAM): The "Other" Steroid-Sensitive Cancer.

Lymphangioleiomyomatosis (LAM) is a devastating rare lung disease affecting primarily childbearing age women in which tumors consisting of abnormal smooth-muscle-like cells grow within the lungs and progressively lead to loss of pulmonary function. LAM cells metastasize to the lungs, predominantly through the lymphatics; however, the source of the LAM cell is still unknown. LAM cells contain inactivating mutations in genes encoding tuberous sclerosis 1 or 2, proteins that normally limit cell growth through suppression of mammalian target of rapamycin complex 1. As of today, sirolimus (an mammalian target of rapamycin complex 1 inhibitor) is the only treatment, available for LAM patients that is approved by the Food and Drug Administration; however, this drug and others in its class provide stabilization but not remission of LAM. One of the biggest problems in treating LAM is that both the origin of the LAM cells and the mechanism of the sexual dimorphism in LAM are still not understood. LAM cells express estrogen and progesterone receptors, and lung function declines during periods of high circulating estrogen levels. Moreover, numerous basic research studies find that estrogen is a key driving force in LAM cell proliferation, migration, and metastasis. In this review, we highlight recent insights regarding the role of steroid hormones in LAM and discuss possible explanations for the profound female sexual dimorphism of LAM.

Lymphangioleiomyomatosis: New Treatment Perspectives.

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease, occurs in women, usually premenopausal, caused by the proliferation of neoplastic smooth muscle-derived cells. Mutations in the tuberous sclerosis complex genes, lead to the activation of mammalian target of rapamycin kinase (mTOR), results in proliferation of LAM cells, its increasing motility, and survival. Polycystic lung destruction, extensive involvement of lymphatic channels, chylothorax, chyloperitoneum, and renal angiomyolipomas can develop in LAM patients. The new, promising treatment strategies have been recently introduced due to discovery of the genetic and molecular mechanisms of LAM. Comprehension of the disease pathogenesis has resulted in the implementation of other therapeutic agents such as mTOR inhibitors, VEGF-D inhibitors, statins, interferon, chloroquine analogs, cyclin-dependent kinase inhibitors, matrix metalloproteinase inhibitors, aromatase inhibitors, and their combinations. The mTOR inhibitors appear to be the most important, and the efficacy of sirolimus in LAM treatment has been proved. The article discussed the new control studies with mTOR inhibitors, doxycycline, simvastatin, and combination of them in LAM patients.

LAM cells biology and lymphangioleiomyomatosis

Progressive lung tissue destruction in lymphangioleiomyomatosis (LAM) occurs as a result of excessive proliferation of LAM cells caused by a mutation in one of the tuberous sclerosis complex suppressor genes, TSC1 or TSC2. These cells show constitutive activation of the mammalian target of rapamycin (mTOR) pathway and many of the mTOR-related kinases such as Akt, Erk, S6K1 and S6. Phenotype of LAM cells differs considerably depending on their microenvironment. LAM cells show differences in morphology, size and expression of various factors depending on their location in the tumor or body fluids. The presence of LAM cells in blood, urine, bronchoalveolar lavage fluid (BALF), and chyle proves their ability to metastasis. Antigens of smooth muscle cells are expressed in most LAM cells. Some of these cells are immunoreactive with HMB-45 antibody, which is used for the immunohistochemical diagnosis of LAM. Receptors for estrogen and progesterone may also be expressed in these cells, which probably is associated with the fact that LAM occurs almost exclusively in women of childbearing age. LAM cells via increased production of metalloproteinases are involved in the destruction of the extracellular matrix, as well as the remodeling and damage of lung tissue. Sporadic LAM occurs extremely rarely. Therefore a good experimental model of this disease is necessary. To date, several animal and human cell lines, which both genetically and phenotypically resemble LAM cells, have been obtained. These cell lines, derived from LAM nodule or an angiomyolipoma, are usually characterized by a mutation of the TSC2 gene, expression of smooth muscle cell antigens such as a-smooth muscle actin (aSMA) or S6K1 and S6 protein hyperphosphorylation. Presently, there is no commercially available cell line representing a good model of LAM. A better understanding of LAM cell biology is necessary for creating a useful model in vitro for further exploration of both LAM pathomechanisms and more general mechanisms of carcinogenesis.

Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis

The primary function of the lymphatic system is absorbing and transporting macromolecules and immune cells to the general circulation, thereby regulating fluid, nutrient absorption and immune cell trafficking. Lymphangiogenesis plays an important role in tissue inflammation and tumour cell dissemination. Lymphatic involvement is seen in lymphangioleiomyomatosis (LAM) and idiopathic pulmonary fibrosis (IPF). LAM, a disease primarily affecting females, involves the lung (cystic destruction), kidney (angiomyolipoma) and axial lymphatics (adenopathy and lymphangioleiomyoma). LAM occurs sporadically or in association with tuberous sclerosis complex (TSC). Cystic lung destruction results from proliferation of LAM cells, which are abnormal smooth muscle-like cells with mutations in the TSC1 or TSC2 gene. Lymphatic abnormalities arise from infiltration of LAM cells into the lymphatic wall, leading to damage or obstruction of lymphatic vessels. Benign appearing LAM cells possess metastatic properties and are found in the blood and other body fluids. IPF is a progressive lung disease resulting from fibroblast proliferation and collagen deposition. Lymphangiogenesis is associated with pulmonary destruction and disease severity. A macrophage subset isolated from IPF bronchoalveolar lavage fluid (BALF) express lymphatic endothelial cell markers in vitro, in contrast to the same macrophage subset from normal BALF. Herein, we review lymphatic involvement in LAM and IPF.

TSC2 modulates cell adhesion and migration via integrin-α1β1

Recent evidence suggests that the rare and progressive lung disease lymphangioleiomyomatosis (LAM) is metastatic in nature. Dysfunction of the tumor suppressor genes tuberous sclerosis complex (TSC), in particular mutational inactivation of TSC2, enhances both cell proliferation and migration. Although substantial progress has been made in understanding the role of TSC2 in abnormal LAM cell proliferation and its pharmacological targeting, the mechanisms underlying the enhanced migratory capacity in LAM are not well understood. In this study, we examined the role of TSC2 in cell attachment, spreading, and migration, processes that contribute to the metastatic phenotype. Here we show that loss of TSC2 increased both the attachment and spreading of mouse embryonic fibroblasts to the extracellular matrix proteins collagen type I and fibronectin and that reexpression of TSC2 reduced these effects. Integrin-α1β1 modulated cell migration with the β1-subunit involved in cell attachment and spreading as shown by using functional blocking antibodies. Loss of TSC2 increased integrin-α1 expression, and inhibition of this integrin subunit reduced cell migration. The enhanced attachment and spreading were independent of the intracellular signaling pathways mammalian target of rapamycin complex 1 and Rho-associated kinase, as pharmacological inhibition with rapamycin or Y27632, respectively, was without effect. Together, these data demonstrate that TSC2 controls cell migration, attachment, and spreading through the α1β1-integrin receptor and thus suggest a potential therapeutic target for the treatment of increased cell invasiveness in LAM.

Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells

Lymphangioleiomyomatosis (LAM) is characterized by the abnormal growth of smooth muscle-like cells (LAM cells) and cystic destruction of the lung parenchyma. LAM cell-derived matrix metalloproteinases (MMPs) are thought to play a prominent role in the tissue destruction. The aim of this study was to determine whether doxycycline, a known MMP inhibitor, can inhibit LAM cell proliferation or mitochondrial function and/or modulate MMPs and their tissue inhibitors (TIMPs). Wild-type and tuberous sclerosis complex-2 (TSC2)-null mouse embryonic fibroblasts (MEFs) were cultured in DMEM containing 10% fetal bovine serum (FBS). Human LAM cells were derived from the lungs of LAM patients and airway smooth muscle cells from control subjects. Cells were stimulated with FBS with or without doxycycline for up to 9 days. Proliferation was assessed by manual cell counts and MTT assay, MMP production by zymography and ELISA, and TIMP production using elisa. Doxycycline did not change FBS-induced proliferation in MEFs or human cells. However, doxycycline did reduce metabolic activity of both wild-type and TSC2-null MEFs and LAM cells, but had no effect on control cells. Furthermore, doxycycline reduced MMP-2 from MEFs and decreased active-MMP-2 from LAM cells but had no effect on TIMP-1 and TIMP-2 from human LAM cells. Doxycycline decreased MMP levels and cell metabolic activity, which raises the possibility of therapeutic efficacy in LAM.

Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor gene TSC2.

Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction, resulting from proliferation of smooth-muscle-like cells, which have mutations in the tumor suppressor genes TSC1 or TSC2. Among 277 LAM patients, severe disease was associated with hypoxia and elevated red blood cell indexes that accompanied reduced pulmonary function. Because high red cell indexes could result from hypoxemia-induced erythropoietin (EPO) production, and EPO is a smooth muscle cell mitogen, we investigated effects of EPO in human cells with genetic loss of tuberin function, and we found that EPO increased proliferation of human TSC2-/-, but not of TSC2+/-, cells. A discrete population of cells grown from explanted lungs was characterized by the presence of EPO receptor and loss of heterozygosity for TSC2, consistent with EPO involvement. In LAM cells from lung nodules, EPO was localized to the extracellular matrix, supporting evidence for activation of an EPO-driven signaling pathway. Although the high red cell mass of LAM patients could be related to advanced disease, we propose that EPO, synthesized in response to episodic hypoxia, may increase disease progression by enhancing the proliferation of LAM cells.

Phenotypic characterization of disseminated cells with TSC2 loss of heterozygosity in patients with lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM), occurring sporadically (S-LAM) or in patients with tuberous sclerosis complex (TSC), results from abnormal proliferation of LAM cells exhibiting mutations or loss of heterozygosity (LOH) of the TSC genes, TSC1 or TSC2. To identify molecular markers useful for isolating LAM cells from body fluids and determine the frequency of TSC1 or TSC2 LOH. Candidate cell surface markers were identified using gene microarray analysis of human TSC2⁻(/)⁻ cells. Cells from bronchoalveolar lavage fluid (BALF), urine, chylous effusions, and blood were sorted based on reactivity with antibodies against these proteins (e.g., CD9, CD44v6) and analyzed for LOH using TSC1- and TSC2-related microsatellite markers and single nucleotide polymorphisms in the TSC2 gene. CD44v6(+)CD9(+) cells from BALF, urine, and chyle showed TSC2 LOH in 80%, 69%, and 50% of patient samples, respectively. LAM cells with TSC2 LOH were detected in more than 90% of blood samples. LAM cells from different body fluids of the same patients showed, in most cases, identical LOH patterns, that is, loss of alleles at the same microsatellite loci. In a few patients with S-LAM, LAM cells from different body fluids differed in LOH patterns. No patients with S-LAM with TSC1 LOH were identified, suggesting that TSC2 abnormalities are responsible for the vast majority of S-LAM cases and that TSC1-disease may be subclinical. Our data support a common genetic origin of LAM cells in most patients with S-LAM, consistent with a metastatic model. In some cases, however, there was evidence for genetic heterogeneity between LAM cells in different sites or within a site.

Effects of prolactin on TSC2-null Eker rat cells and in pulmonary lymphangioleiomyomatosis.

Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in lymphangioleiomyomatosis cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues. To determine the role of prolactin in signaling and proliferation in lymphangioleiomyomatosis. Prolactin levels in the sera of patients with lymphangioleiomyomatosis were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro. Higher prolactin levels in the sera of patients with lymphangioleiomyomatosis were associated with a faster rate of decline in FEV(1) and an increased history of pneumothorax (P < 0.01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of signal transducer and activator of transcription-1 (STAT1), STAT3, p44/42, and p38 mitogen-activated protein kinase. Tsc2(-/-) Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2(+/+) cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo. Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis.

Vascular Endothelial Growth Factors C and D Induces Proliferation of Lymphangioleiomyomatosis Cells through Autocrine Crosstalk with Endothelium

Lymphangioleiomyomatosis (LAM) is a potentially fatal lung disease characterized by nodules of proliferative smooth muscle-like cells. The exact nature of these LAM cells and their proliferative stimuli are poorly characterized. Herein we report the novel findings that the lymphangiogenic vascular endothelial growth factors (VEGF) C and D induce LAM cell proliferation through activation of their cognate receptor VEGF-R3 and activation of the signaling intermediates Akt/mTOR/S6. Furthermore, we identify expression of the proteoglycan NG2, a marker of immature smooth muscle cells, as a characteristic of LAM cells both in vitro and in human lung tissue. VEGF-C-induced LAM cell proliferation was in part a result of autocrine stimulation that resulted from cross talk with lymphatic endothelial cells. Ultimately, these findings identify the lymphangiogenic VEGF proteins as pathogenic growth factors in LAM disease and at the same time provide a novel pharmacotherapeutic target for a lung disease that to date has no known effective treatment.

Silence of the LAM

To the Editors: We read with interest the article by Warth et al. 1 on mediastinal angiomyolipoma and tuberous sclerosis. Apart from mediastinal angiomyolipoma, lymphangioleiomyomatosis (LAM) can occur as part of the genetic condition tuberous sclerosis 2. Since the first report by Cornog and Eterline 3, LAM has been increasingly studied for the pathological processes involved in atypical smooth muscle LAM cell proliferation. However, it has been difficult to gain complete understanding of the natural history of LAM due to its rarity. LAM tends to progress slowly and …

Tissue-Specific Renin–Angiotensin System in Pulmonary Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM), a multisystem disease found in middle-aged women, is characterized by cystic lung destruction and abdominal tumors (e.g., angiomyolipomas, lymphangioleimyomas), resulting from proliferation of abnormal-appearing, smooth muscle-like cells (LAM cells). The LAM cells, in combination with other cells, form nodular structures within the lung interstitium and in the walls of the cysts. LAM cells contain mutations in the tuberous sclerosis complex TSC1 and/or TSC2 genes, which lead to dysregulation of the mammalian target of rapamycin, affecting cell growth and proliferation. Proliferation and migration of vascular smooth muscle cells and production of angiogenic factors are regulated, in part, by angiotensin II. To determine whether a LAM-specific renin-angiotensin system might play a role in the pathogenesis of LAM, we investigated the expression of genes and gene products of this system in LAM nodules. mRNA for angiotensinogen was present in RNA isolated by laser-captured microdissection from LAM nodules. Angiotensin I-converting enzyme and chymase-producing mast cells were present within the LAM nodules. We detected renin in LAM cells, as determined by the presence of mRNA and immunohistochemistry. Angiotensin II type 1 and type II receptors were identified in LAM cells by immunohistochemistry and immunoblotting of microdissected LAM nodules. Angiotensin II is localized in cells containing alpha-smooth muscle actin (LAM cells). A LAM-specific renin-angiotensin system appears to function within the LAM nodule as an autocrine system that could promote LAM cell proliferation and migration, and could represent a pharmacologic target.

In vitrostudies of lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is associated with abnormal airway smooth muscle that leads to the characteristic pathology of lung nodule formation and destruction of lung tissue. The current authors have previously identified abnormal behaviour of airway smooth muscle cells from patients with asthma. In this study, cells and tissue sections derived from patients with LAM (n=7), asthma (n=8), and nonasthmatic controls (n=9) were compared. The presence of the antigen human melanosome (HM)B-45 was investigated, along with the proliferation and release of extracellular matrix proteins, release of endogenous prostaglandin E2 (PGE2), vascular endothelial growth factor and connective tissue growth factor, and the expression of integrins. Positive HMB-45 staining was found in all LAM patients and no controls. Proliferation of LAM cells was not different from control cells nor was its inhibition by beta-agonists, corticosteroids, rapamycin or PGE2. However, endogenous PGE2 levels were markedly decreased in LAM cells, and this was associated with decreased expression of the inducible form of cyclooxygenase (COX-2). The increased levels of connective tissue growth factor seen in asthma cells were not observed in LAM. Elastin mRNA in response to transforming growth factor-beta stimulation was markedly lower in LAM cells than either asthma or control cells. In conclusion, lymphangioleiomyomatosis cells exhibit abnormal properties in vitro that may contribute to pathophysiology and symptomatology in patients with lymphangioleiomyomatosis.

Lymphangiogenesis-Mediated Shedding of LAM Cell Clusters as a Mechanism for Dissemination in Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) affects exclusively women of reproductive age, involves the lungs and axial lymphatic system, and is frequently complicated with renal angiomyolipomas. LAM lesions are generated by the proliferation of LAM cells with mutations of one of the tuberous sclerosis complex (TSC) genes. Recent studies indicate that LAM cells can migrate or metastasize to form new lesions in multiple organs, although they show a morphologically benign appearance. In the previous study, we reported LAM-associated lymphangiogenesis and implicated its role in the progression of LAM. In this study, we further focused on the lymphatic abnormalities in LAM: LAM-associated chylous fluid (5 pleural effusion and 2 ascites), surgically resected diaphragm (1 patient), and axial lymphatic system including the thoracic duct, lymph nodes at various regions, and diaphragmatic lymphatic system (5 autopsy cases). We demonstrated that LAM cell clusters enveloped by lymphatic endothelial cells (LCC) in all chylous fluid examined. We identified LAM lesion in the diaphragm (2 of 5 autopy cases and one surgical specimen), thoracic duct (5 of 5), and lymph nodes (retroperitoneal (5 of 5), mediastinal (4 of 5), left venous angle (5 of 5) with total positive rate of 68% to 88% at each region of the lymph node, but less frequent or none at remote lymph nodes located away from the axial lymph trunk (cervical [1 of 5] and axillary [0 of 5]). LCCs were identified in intra-LAM lesional lymphatic channels where LAM cells proliferate along lymphatic system. In in vitro culture system, LCC can fragment into each proliferating LAM cell. These findings suggest that LAM-associated lymphangiogenesis demarcates LAM lesion into bundle- or fascicle-like structure and eventually shed LCC into the lymphatic circulation and that LCCs play a central role in the dissemination of LAM lesion.

Lymphangioleiomyomatosis: Radiologic-Pathologic Correlation

Lymphangioleiomyomatosis (LAM) is an uncommon interstitial lung disease that exclusively affects women, usually during their reproductive years. LAM is characterized pathologically by abnormal proliferation of LAM cells in the lungs and in thoracic and retroperitoneal lymphatics. Thirty-three cases of LAM were reviewed retrospectively for clinical and radiologic findings. Twenty-eight (85%) of 33 women (aged 21-62 years; mean, 37.5 years) were symptomatic. Radiographs (n = 32) demonstrated reticular opacities in 21 (66%) patients, large lung volumes in 17 (53%), pleural effusion in 14 (44%), and pneumothorax in 13 (41%). High-resolution CT (n = 15) and conventional CT (n = 3) showed 2-5-mm bilateral thin-walled cysts in all patients and cysts that were 6-12 mm or larger in patients with severe lung involvement. CT depicted diffuse lung involvement by cysts in nine (50%) patients, relative sparing of lung apices in seven (39%), and relative sparing of lung bases in two (11%). Pleural effusion and pneumothorax were seen at CT in four (22%) and three (17%) patients, respectively. Four cases of tuberous sclerosis complex-associated LAM (TSC-LAM) (women aged 27-50 years; mean, 35.7 years) were similarly reviewed. Three (75%) were symptomatic. Radiographs (n = 4) demonstrated reticular opacities in three (75%) and large lung volumes in two (50%). All high-resolution CT (n = 3) and conventional CT (n = 1) studies showed 2-5-mm bilateral thin-walled cysts and cysts that were 6-12 mm or larger in two patients with severe lung involvement. Pleural effusion and pneumothorax were demonstrated at CT in three (75%) and two (50%) patients, respectively. LAM and TSC-LAM affect symptomatic women who often exhibit reticular opacities and large lung volumes at radiography and bilateral uniform small thin-walled cysts at CT. Large (>12 mm) cysts occur in patients with severe cystic lung involvement. Pneumothorax and pleural effusion are common associated findings.

Distribution and mRNA Expression of Insulin-Like Growth Factor System in Pulmonary Lymphangioleiomyomatosis

BackgroundInsulin-like growth factors (IGF-1 and IGF-2), the IGF-1 receptor (IGF-1R), and IGF-binding proteins (IGFBPs) are involved in normal pulmonary development and in the pathogenesis of smooth muscle cell tumors.MethodsTo evaluate...