Lymphangioleiomyomatosis (LAM) is a multisystem disorder characterized by cystic lung disease and abdominal tumors (e.g., lymphangioleiomyomas, angiomyolipomas). The disease, which often presents in middle-aged women, is characterized by the proliferation of abnormal-appearing smooth muscle-like cells, LAM cells, which contain mutations in one of two tuberous sclerosis complex genes (TSC), TSC1 or TSC2. LAM occurs more frequently in women with TSC, an autosomal dominant disorder. A clinical protocol has enabled the Branch to assemble a large cohort of patients with LAM and to document the natural history of the disease, the histopathological findings, the radiographic appearance, characteristic pulmonary function abnormalities, and the association with tuberous sclerosis complex. ? ? Patients with LAM frequently develop pneumothoraces, which may be treated by pleuredesis.? We examined the spectrum and frequency of pleural abnormalities on high resolution computed tomography (CT) in patients with lymphangioleiomyomatosis (LAM) and the pleural findings associated with different types of pleurodesis (talc, mechanical, and chemical) performed to treat the complications of pleural disease in these patients. Two hundred fifty-eight patients with LAM underwent CT of the chest. Pleural abnormalities assessed included pleural thickening, presence of a pleural mass, areas of high attenuation, effusion, and pneumothorax. In patients who had had pleurodesis, the CT findings were correlated with the type of procedure performed. One hundred thirty-three (52%) of 258 patients had pleurodesis (unilateral, 68/133; bilateral, 65/133). Pleural abnormalities were more common in patients who had pleurodesis (101/133, 76%) than in those who had not had the procedure (47/125, 38%); further, the abnormalities were more prevalent on the operated side than on the unoperated side of those 68 patients who had unilateral pleurodesis. The frequencies of findings for the group without pleurodesis versus the group with pleurodesis were pleural thickening (26% vs 65%), effusion (10% vs 13%), loculated effusion (2.4% vs 11%), pneumothorax (1.6% vs 10%), areas of high attenuation (1.6% vs 23%), and mass (0.8% vs 14%), respectively. Areas of high attenuation in the pleura were present in all types of pleurodesis (mechanical, 8%; chemical, 13%; talc, 40%) and in two patients who had had repeated thoracentesis or pleurectomy. Pleural masses were present in patients who had had all types of pleurodesis (mechanical, 10%; chemical, 9%; talc, 24%) and in one patient who had had thoracentesis and thoracostomy; of importance in the differential diagnosis, the masses commonly enhanced and did not change in size over time. From this study, we conclude that abnormalities are common in patients with LAM as complications of the disease itself and as sequelae of pleurodesis and other pleura manipulations. Pneumothorax and pleural effusion result from the underlying pathophysiology of LAM, whereas areas of high attenuation and masses develop after all types of pleurodesis and other manipulations of the pleura (i.e., thoracentesis, thoracostomy).? ? The P-CCMB continued to support the NHLBI lymphangioleiomyomatosis Registry; we were responsible for ~84-86% of the sporadic LAM and LAM/TSC patients enrolled in the study. An objective of the LAM Registry was to provide a patient database for this rare disease. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients. The initial report, published this year, described the baseline clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis-related forms. From 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded from thhe current analysis. All 230 of the remaining subjects were women, aged 18 to 76 yr (mean +/- SE, 44.5 +/- 0.65 yr). The average age at onset of symptoms was 38.9 +/- 0.73 yr and at diagnosis was 41.0 +/- 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Recruitment of LAM patients with TSC was based on referral for symptoms to the lung or referral for high resolution CT to determine whether cysts characteristic of LAM were present, given a prior diagnosis of TSC. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis-related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form. The analysis of the TSC cohort with LAM was affected by the ascertainment bias in patient recruitment. Based on these data, we conclude that the age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry.? ? The cystic lung destruction in LAM is believed to result from the proliferation of LAM cells in the lung parenchyma. 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 LAM 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.
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