Lymphangioleiomyomatosis and Tuberous Sclerosis Complex

Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease of women of child-bearing age and affects mainly the lungs, promoting cystic destruction of lung parenchyma or leading to abdominal tumor formation (e.g., angiomyolipomas, lymphangioleiomyomas). LAM can arise sporadically or in association with tuberous sclerosis complex (TSC), an autosomal inherited syndrome characterized by hamartoma-like tumor growth and pathologic features that are distinct from manifestations of pulmonary LAM. A substantial body of evidence has now been gathered suggesting that the two diseases share a common genetic origin. TSC is caused by mutations in two genes, TSC1 on chromosome 9q34 and TSC2 on 16p13. Both of these genes are tumor suppressor genes encoding hamartin (TSC1) and tuberin (TSC2). Sporadic LAM is correlated with a mutation in the TSC2 gene and tuberin appears to play a central role in the pathogenesis of the disease. A TSC2 loss or mutation leads to disruption of the tuberin-hamartin heteromer and dysregulation of S6K1 activation leading to aberrant cell proliferation seen in LAM disease. The extremely diverse clinical and radiologic features of the disease and the complex therapeutic approach are reviewed in detail. Although new therapeutic agents have been tested, to date no effective treatment has been proposed and the prognosis of patients with LAM remains poor. As long as newer therapeutic agents do not change this picture, lung transplantation remains the last hope for patients with respiratory failure at the advanced stage of the disease.     

Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex. Renal angiomyolipomas, which are found in most tuberous sclerosis patients, also occur in 60% of sporadic LAM patients. We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis. In this study, we report the identification of somatic TSC2 mutations in five of seven angiomyolipomas from sporadic LAM patients. In all four patients from whom lung tissue was available, the same mutation found in the angiomyolipoma was present in the abnormal pulmonary smooth muscle cells. In no case was the mutation present in normal kidney, morphologically normal lung, or lymphoblastoid cells. Our data demonstrate that somatic mutations in the TSC2 gene occur in the angiomyolipomas and pulmonary LAM cells of women with sporadic LAM, strongly supporting a direct role of TSC2 in the pathogenesis of this disease.     

Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism

Lymphangiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells and cystic degeneration of the lung. LAM affects almost exclusively young women. Although lung transplantation provides effective therapy for end-stage LAM, there are reports of LAM recurrence after lung transplantation. Whether these recurrent LAM cells arise from the patient or the lung transplant donor is an area of controversy. We used microsatellite marker fingerprinting and TSC2 gene mutational analysis to study a patient with recurrent LAM after single-lung transplantation. The DNA microsatellite marker pattern indicated the presence of patient-derived LAM cells in the allograft. A somatic one base pair deletion in exon 18 of the TSC2 gene was identified in pulmonary and lymph node LAM cells before transplantation. The same mutation was in the recurrent LAM, demonstrating that the recurrent LAM was derived from the patient. Fluorescence in situ hybridization revealed that cells immunoreactive with the monoclonal antibody HMB-45 did not contain a Y chromosome. These data indicate that histologically benign LAM cells can migrate or metastasize in vivo to the transplanted lung. In addition, the patient had no evidence of a renal angiomyolipoma at autopsy and therefore demonstrated for the first time that somatic TSC2 mutations cause LAM in patients without angiomyolipomas.     

Lymphangioleiomyomatosis and tuberous sclerosis

Tuberous sclerosis (TSC) is an inherited disorder best known for its association with severe learning difficulties, epilepsy, behavioural problems, skin and renal pathology Lymphangioleiomyomatosis (LAM), characterized by alveolar smooth muscle proliferation and cystic destruction of parenchyma, occurs as an infrequent symptomatic pulmonary complication in TSC and as a very rare sporadic disease in those without signs of TSC. Considered a generalized and progressive cystic lung disease that is difficult to treat with a poor prognosis, it has been reported almost exclusively in women, most commonly presenting with dyspnoea and pneumothorax in those of childbearing age.We investigated the clinical features and prognosis of LAM in patients with TSC including the effects of treatment, stratified by the method of diagnosis of LAM (i.e. histological or radiological).We found histological proof of diagnosis in 10 of 21 patients with TSC and symptomatic lung disease, onset in childhood in four, three males with LAM, individuals with apparently focal disease, great variation in clinical course and no clear treatment benefit. In those with TSC, symptomatic LAM is infrequent but causes a significant morbidity and mortality It was not possible to detect predisposing factors, other than being female. Males with apparent LAM should be rigorously investigated.     

Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex

The true prevalence of pulmonary lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex (TSC) is unknown. The prevalence of LAM, radiological features, and lung function in patients with TSC was measured. The presence of LAM, as defined by the presence of cysts by high-resolution chest computed tomography (HRCT) scan, was determined in patients with TSC without prior pulmonary disease (Group 1). To determine the significance of early detection, severity of disease in screened patients (Group 1) was compared with that in patients with TSC with a prior diagnosis of LAM (Group 2). Forty-eight patients with TSC and no prior history of LAM were screened. Of the 38 females, 13 (34%) had LAM; LAM was absent in males. Lung function was preserved in patients with TSC who were found to have LAM by screening. In patients previously known to have LAM, FEV(1) and DL(CO) correlated inversely with severity of disease as assessed by CT scan. The prevalence of LAM in women with TSC was 34%, approximately 10-fold that previously reported, consistent with a large hitherto unrecognized subclinical population of patients at risk for pulmonary complications.     

The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis

Lymphangiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex (TSC). Because only a minority of women with TSC develops symptomatic LAM, we hypothesized that a relationship might exist between the type of germline TSC1 or TSC2 gene mutation and the risk of developing LAM. We examined all 41 exons of the TSC2 gene and 21 coding exons of the TSC1 gene for mutations in a group of 14 women with both TSC and LAM using single-strand conformation polymorphism analysis. Seven mutations were found in TSC2 and one in TSC1. Of the seven patients with TSC2 mutations, two had the same in-frame exon 40 deletion and one had an exon 41 missense change. We conclude that germline mutations in the extreme carboxy-terminus of tuberin can result in LAM. Further studies will be required to determine whether mutations in exons 40 and 41 are associated with an increased incidence and/or severity of LAM in women with TSC.     

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a multisystem disorder of women, characterized by cystic degeneration of the lungs, renal angiomyolipomas (AML), and lymphatic abnormalities. LAM lesions result from the proliferation of benign-appearing, smooth muscle-like LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the tuberous sclerosis complex (TSC) genes. LAM cells are believed to migrate among the involved organs. Because of the apparently metastatic behavior of LAM, we tried to isolate LAM cells from body fluids. A cell fraction separated by density gradient centrifugation from blood had TSC2 LOH in 33 of 60 (55%) LAM patients. Cells with TSC2 LOH were also found in urine from 11 of 14 (79%) patients with AML and in chylous fluid from 1 of 3 (33%) patients. Identification of LAM cells with TSC2 LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases.     

Release of somatomedin-like activity by cultured WI-38 human fibroblasts

Confluent cultures of normal diploid WI-38 human embryonic lung fibroblasts released somatomedin (SM)-like activity into their incubation medium during culture in serum-free medium. This postculture medium (conditioned medium) stimulated cell division in these same cultured WI-38 fibroblasts and 35SO4 uptake by hypophysectomized rat cartilage in vitro. The conditioned medium also contained immunoreactive SM (IRSM) activity which yielded parallel dose-response curves to human serum in a RIA for SM. The IRSM activity measured in conditioned medium was not the artifactual result of effects of possible SM-binding proteins or proteolytic enzymes in conditioned medium. These studies suggest that cultured WI-38 fibroblasts produce and release SM-like activity which has SM-like biological activity and is immunoreactive with a basic SM purified from human plasma Cohn fraction and having similarity with SM-C and insulin-like growth factor-I. Human GH appears to stimulate production and release of IRSM activity by these cells.     

Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis

Basic fibroblast growth factor (bFGF) is a potent mitogenic factor for smooth muscle cells, myofibroblasts, and fibroblasts, proliferation of which is a hallmark of idiopathic pulmonary fibrosis (IPF) and lymphangioleiomyomatosis (LAM). Mast cells produce bFGF and have been associated with pulmonary fibrosis. We hypothesize that smooth muscle cell/myofibroblast-like cells will be spatially associated with bFGF-containing mast cells and that bFGF receptors will be expressed on the effector cells in IPF and LAM. We performed quantitative immunohistochemistry for bFGF, mast cell tryptase, smooth muscle actin for smooth muscle cell/myofibroblast-like cells, and fibroblast growth factor receptors (Flg, Bek) and measured collagen and elastic fiber in lung sections from IPF (n = 14), LAM (n = 9), and control lung (n = 10). IPF and LAM lung contained more smooth muscle cell/myofibroblast-like cells than did control lung. bFGF-containing mast cells were abundant both in IPF and LAM and were associated with collagen, elastic fibers, and smooth muscle cell/myofibroblast-like cells in IPF. Flg was expressed on epithelial cells, endothelial cells, smooth muscle cell/myofibroblast-like cells, and macrophages in IPF. In LAM, Flg was expressed on epithelial cells adjacent to smooth muscle cell/myofibroblast-like cell aggregates. Bek was expressed dominantly on smooth muscle cell/myofibroblast-like cells in LAM and on smooth muscle cell/myofibroblast-like cells as well as neutrophils in IPF. These data suggest that mast cell-derived bFGF might exert fibrogenic, proliferative effects on smooth muscle cell/myofibroblast-like cells through its receptors.     

Tumor suppressor TSC1 is critical for T-cell anergy

T-cell anergy is a state of T cells that is hyporesponsive to stimulation via the T-cell receptor and costimulatory molecules and is thought to be important for self-tolerance. How T-cell anergy is regulated is still poorly understood. We report here that tuberous sclerosis (TSC)1 is critical for T-cell anergy. Deficiency of TSC1 resulted in enhanced T-cell proliferation and cytokine production in the absence of cluster of differentiation (CD)28-mediated costimulation, accompanied by enhanced T-cell metabolism. Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.     

Lymphangioleiomyomatosis: a review of the literature

Lymphangioleiomyomatosis (LAM), characterized by alveolar smooth muscle proliferation and cystic destruction of lung parenchyma, can occur as a rare sporadic disease or as a complication of tuberous sclerosis (TSC). It is a cystic lung disease, usually generalized and progressive, may be extremely difficult to treat and has been considered to have a poor prognosis. It has almost exclusively been reported to present in women of childbearing age, most commonly with dyspnoea and pneumothorax. We reviewed the English literature from 1939 to 1997 for cases of LAM both with and without TSC, in order to document the prevalence, clinical features, investigations, treatment and outcome within and between these two groups. No study has yet determined the prevalence of LAM symptomatically within the general population, but it probably affects 1-3% of the TSC population. Patients with TSC often present with an insidious onset of dyspnoea whilst non-TSC patients present more commonly with acute breathlessness secondary to pneumothorax. Patients with TSC are also less likely to suffer from chylothorax. The age of onset of symptoms and of diagnosis are similar. LAM is rare in children and even less common in males in both groups. The natural course of LAM remains unclear and effect of treatment variable. Although symptomatic LAM is uncommon it causes a significant amount of morbidity and mortality both in the TSC and general population, but asymptomatic LAM is not uncommon in TSC. Further research is required to determine the natural history of this condition and to evaluate current treatment regimes.     

Current aspects of lymphangioleiomyomatosis

Lymphoangioleiomyomatosis (LAM) is a characteristic diffuse proliferation of abnormal smooth muscle fibers predominantly developing in the lung and leading to cystic destruction. An almost totally specific marker, HMB45, is available. This monoclonal antibody labels cells of the melanocyte line, LAM cells and renal angiomyolipoma cells. The antigen carried by all these cell lines is probably gp-100 involved in melanogenesis. Two gene loci are formally implicated in the pathogenesis of Bourneville tuberous sclerosis (BTS): TSC1 (9q 34.3) and TSC2 (16p 13.3). The TSC2 locus could be implicated in the pathogenesis of pulmonary LAM. LAM and BTS have similar clinical and histological features and could be two different phenotypic forms, distinguished strictly on a nosological basis, of the same disease. The hormone-dependence theory is suggested on the basis of purely clinical arguments, particularly the almost exclusive female predominance, generally during the period of genital activity. Certain counter arguments have also been put forward and consequently, since no in vitro cell culture model or animal model of LAM is available, it is not really possible to verify the hypothesis. Epidemiological data have been recently acquired in France with the constitution of the GERM"O"P registry of LAM cases in France. Recent technological progress in imaging techniques has also been helpful for earlier, more precise diagnosis. HMB45 immunolabeling improves diagnostic sensitivity on small tissue fragments obtained with transbronchial biopsies. The course of LAM appears to be different in certain patient subgroups. Certain patients develop rapidly fatal disease in months or years while in the majority of patients the disease is much less aggressive for years. A minority of patients also have very slowly evolving disease sometimes diagnosed after menopause. Lung transplantation remains the ultimate treatment in case of life-threatening prognosis.     

Regulation of mast cell survival and function by tuberous sclerosis complex 1

Mast cells play critical roles in allergic disorders and asthma. The importance of tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown. Here, we report that TSC1 is a critical regulator for mTOR signaling in mast cells downstream of FcεRI and c-Kit, and differentially controls mast cell degranulation and cytokine production. TSC1-deficiency results in impaired mast cell degranulation, but enhanced cytokine production in vitro and in vivo after FcεRI engagement. Furthermore, TSC1 is critical for mast cell survival through multiple pathways of apoptosis including the down-regulation of p53, miR-34a, reactive oxygen species, and the up-regulation of Bcl-2. Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast cell-mediated diseases.     

Transforming growth factor-beta 1 and extracellular matrix-associated fibronectin expression in pulmonary lymphangioleiomyomatosis

STUDY OBJECTIVES: Lymphangioleiomyomatosis (LAM) is a rare disorder of unknown etiology, affecting almost exclusively women of childbearing age, that is associated with the proliferation of spindle cells and cystic changes in the affected lung. The underlying processes that contribute to this disease are poorly understood. Transforming growth factor (TGF)-beta(1) is a potent cytokine that promotes mesenchymal cell proliferation and regulates the synthesis of extracellular matrix (ECM) components, particularly fibronectins. Herein, we evaluate the expression of TGF beta(1) and matrix-associated fibronectin in lung specimens demonstrating LAM. DESIGN: Lung biopsy specimens that were confirmed to contain pathologic LAM cells were obtained from 13 patients. The specimens were submitted to immunohistochemical evaluation for TGF beta(1) and fibronectin, as well as the typical markers of LAM cells. Healthy lung parenchyma surrounding resected neoplasms was studied in a parallel fashion as control tissues. MEASUREMENTS AND RESULTS: In all 13 LAM cases and in healthy lung parenchyma, we demonstrated that TGF beta(1) localized consistently to airway epithelial cells. However, in LAM tissues, matrix-associated TGF beta(1) was also consistently found in regions containing pathologic LAM cells. Notably, more abundant TGF beta(1) was observed in highly cellular areas compared to the walls of chronic cystic regions in LAM tissues. Fibronectin, a matrix component that is strongly expressed in response to active TGF beta(1) was found to consistently colocalize with this protein in these highly cellular regions, supporting TGF beta(1) activity in these regions. The markers of proliferating LAM cells, including proliferating cell nuclear antigen, were also markedly present in these highly cellular LAM regions. CONCLUSION: These studies suggest that the proliferation of aberrant LAM cells may be associated with altered regional expression of TGF beta(1) and related ECM proteins.     

A patient with TSC1 germline mutation whose clinical phenotype was limited to lymphangioleiomyomatosis

BACKGROUND: Lymphangioleiomyomatosis (LAM) can occur as in isolated form (sporadic LAM) or as a pulmonary manifestation of tuberous sclerosis complex (TSC) (TSC-associated LAM). Recent studies, however, revealed that both forms of LAM are genetically related but that sporadic LAM is a distinct clinical entity caused by somatic mutations of TSC2 (not TSC1) rather than a forme fruste of TSC carrying either of the TSC1 or TSC2 germline mutations. METHOD: Case presentation and in-depth molecular and histopathological examinations. A 34-year-old Japanese woman was diagnosed as having pulmonary lymphangioleiomyomatosis (LAM) when bilateral pneumothoraces were surgically treated in 1992. Although slowly progressive renal disfunction was observed due to bilateral multiple renal cysts during the past 4 years, she had no other clinical features of TSC and was diagnosed as having sporadic LAM with multiple renal cysts of undetermined aetiology. Her subsequent clinical course was complicated by an endobrochial carcinoid tumour, which eventually resulted in her death in June 1999 due to massive haemoptysis. RESULTS: Postmortem examination revealed the presence of LAM lesions in the lungs, mediastinal lymph nodes, kidneys and uterus. Diffuse renal LAM lesions are presumed to generate multiple renal cysts by constricting the nephron rather than epithelial hyperplasia obstructing lumina, which is analysis of the TSC genes demonstrated that she did not have TSC2/PKD1 contiguous gene syndrome but had a TSC1 germline mutation (Sato T et al. J Hum Genet 2002; 47: 20-8) that had occured de novo. CONCLUSION: This patient therefore illustrates that clinical manifestations of TSC are sufficiently diverse as to allow a forme fruste of TSC that mimics sporadic LAM and that TSC1 mutation can cause multiple renal cysts resulting in renal failure.     

Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes.

AIM: The stability of an atherosclerotic plaque is a key-determining factor in the clinical outcome of cardiovascular disease. In this respect, smooth muscle (SM) alfa actin positive cells play an important role in maintaining plaque stability through formation of a fibrous cap. Recent evidence suggests that circulating progenitors may be a source of these cells. We hypothesized that they may be fibrocytes bone-marrow derived cells that acquire SM-like characteristics, including the expression of SM alfa actin. METHODS: We examined human carotid endarterectomy specimens for the presence of fibrocytes by immunohistochemistry staining for CD34/procollagen I and leukocyte specific protein-1/procollagen I) and examined fibrocyte differentiation in vitro. RESULTS: Fibrocytes were found in regions of plaque growth/healing. They possessed a SM-like spindle shape, produced collagen, and consistent with being fibrocytes they co-localized with transformation growth factor beta, but not serum amyloid P factors, known to promote and inhibit their formation, respectively. While fibrocytes were detected in regions of new growth in 35/40 specimens, only 1/3 of the specimens expressed the SM cell marker calponin, and smoothelin was absent, in these regions. CONCLUSION: Our results demonstrate that fibrocytes contribute to formation of the fibrous cap. With fibrocytes being a monocyte derived cell, we suggest that monocytes may play a more crucial role in the clinical outcome of atherosclerosis than previously realized as they not only contribute directly to plaque instability (through foam cell formation), but also promote plaque stability by transformation into a fibrocyte.     

mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization

The Tuberous Sclerosis Complex component, TSC1, functions as a tumor suppressor via its regulation of diverse cellular processes, particularly cell growth. TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, although the TSC1/TSC2 complex also shows mTORC1-independent outputs to other pathways. Here, we explored the role of TSC1 in various aspects of stem cell biology and dissected the extent to which TSC1 functions are executed via mTORC1-dependent versus mTORC1-independent pathways. Using hematopoietic stem cells (HSCs) as a model system, we demonstrate that somatic deletion of TSC1 produces striking stem cell and derivative effector cell phenotypes characterized by increased HSC cell cycling, mobilization, marked progressive depletion, defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. On the mechanistic level, we further establish that TSC1 regulation of HSC quiescence and long-term repopulating potential and hematopoietic lineage development is mediated through mTORC1 signaling. In contrast, TSC1 regulation of HSC mobilization is effected in an mTORC1-independent manner, and gene profiling and functional analyses reveals the actin-bundling protein FSCN1 as a key TSC1/TSC2 target in the regulation of HSC mobilization. Thus, TSC1 is a critical regulator of HSC self-renewal, mobilization, and multilineage development and executes these actions via both mTORC1-dependent and -independent pathways.     

Rare lung diseases I �C Lymphangioleiomyomatosis

The present article is the first in a series that will review selected rare lung diseases. The objective of this series is to promote a greater understanding and awareness of these unusual conditions among respirologists. Each article will begin with a case that serves as a focal point for a discussion of the pathophysiology and management of the particular condition. The first article is on lymphangioleiomyomatosis (LAM); subsequent articles will focus on pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency and primary ciliary dyskinesia.LAM is a rare, progressive and (without intervention) often fatal interstitial lung disease that predominantly affects women of childbearing age. LAM is characterized by progressive interstitial infiltration of the lung by smooth muscle cells, resulting in diffuse cystic changes of the lung parenchyma. The molecular basis of this disorder has been delineated over the past five years and LAM is now known to be a consequence of mutations in the tuberous sclerosis genes. This knowledge, combined with advances in our understanding of the signalling pathways regulated by these genes, has given rise to potential molecular therapies that hold great promise for treating this devastating disease.     

肺淋巴管平滑肌瘤病九例临床和病理分析

目的 探讨肺淋巴管平滑肌瘤病(pulmonary lymphangionleiomyomatosis,PLAM)的临床和病理特征,提高临床诊治水平.方法 对广州呼吸疾病研究所确诊的9例PLAM患者的临床特点、影像学表现、肺功能及病理学检查进行分析并结合文献复习.结果 9例PLAM患者均为育龄期妇女(20～50岁),临床症状表现为呼吸困难(8/9)、咳嗽(6/9)、咯痰(2/9)、咯血(2/9)、胸痛(3/9)、自发性气胸(6/9)、乳糜胸(3/9)、乳糜性腹腔积液(2/9).胸部X线检查4例表现为双肺弥漫性网状结节影,2例表现为液气胸,2例表现为胸腔积液,1例表现为多发肺小囊状透光区及肺大疱,1例无异常.高分辨率CT具有特征性变化,9例双肺均可见多发小囊状影,直径2～20 mm,壁较薄.2例腹部CT于腹主动脉前可见多个肿大的淋巴结.6例患者进行了肺功能检查,3例通气功能正常,1例呈中度阻塞性通气功能障碍,1例呈重度混合性通气功能障碍,1例呈极重度混合性通气功能障碍,其中1例支气管舒张试验阳性.4例肺弥散功能下降.4例(4/9)经纤维支气管镜肺活检,5例(5/9)经胸腔镜活检,全部经病理确诊.病理学检查显示不同成熟度平滑肌细胞在细支气管壁、肺泡壁、淋巴管壁和血管壁周围增生,肺实质呈囊性变.结论 PLAM表现不典型,易被漏诊、误诊,应提高对本病的认识.