Lymphangioleiomyomatosis (LAM) is a multisystem disorder characterized by cystic lung disease and abdominal tumors (lymphangiomyomas and angiomyolipomas). The disease, which presents in middle-aged women, is characterized by the proliferation of abnormal smooth muscle containing premelanosomal structures similar to those found in melanoma cells. 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 an inherited disorder, tuberous sclerosis complex. Gene expression and cell regulatory pathways have been examined in tissue samples. There are recent advances in several areas: 1. Lymphangioleiomyomas: Patients with LAM were found to have thoracic and abdominal involvement of the axial lymphatic system, resulting from infiltration by the abnormal smooth muscle cells (LAM cells) pathognomonic of the disease. When evaluated by CT and ultrasound, the lymphangiomas appear cystic and are probably filled with chylous fluid. On histologic examination, the LAM cells appear to penetrate the lymph node capsule and migrate into the surrounding adipose tissue. The abdominal lesions have been misdiagnosed as sarcomas and ovarian tumors. Even on histological examination, LAM smooth muscle lesions have been mistaken for sarcoma. We have observed that, unlike other lesions in the differential diagnosis, lymphangioleiomyomas can change in size during the day. Increase in size may result from the pooling of chylous fluid within these structures during daily activities. Symptoms are relieved in some patients by elevation of the legs at midday. To assist in evaluation, ultrasound or CT is being used to estimate the size of lesions over the course of a day. 2. Tuberous Sclerosis Complex (TSC): TSC is characterized by widespread hamartomatous lesions, seizure disorders, and mental retardation. TSC is believed to occur in 1:5800 live births. It had been reported that the frequency of LAM (<4%) was greater in women with TSC than in those without. To determine the true prevalence of pulmonary LAM in patients with TSC, a prospective study was initiated to screen for the presence of cystic lung lesions characteristic of LAM. Patients with TSC, with or without pulmonary symptoms, were recruited through the screening protocol with the assistance of the LAM Foundation and the National Tuberous Sclerosis Association/Tuberosis Sclerosis Alliance. Of 38 women without pulmonary symptoms, 13 (34%) had cystic lung lesions characteristic of LAM. No pulmonary LAM lesions were found in 10 men with TSC. Lung function was preserved in patients with TSC who were found to have LAM by screening. In patients already known to have LAM, FEV1.0 and DLCO correlated inversely with severity of disease as assessed by CT scan. These data suggest that LAM is underdiagnosed, and is more common among individuals with TSC that had been generally believed. 3. Progression of Lung Disease: a) Histologic analysis: Prognostic significance of pulmonary LAM histologic score was evaluated in 105 women with LAM, with actuarial survival from the time of biopsy to time of transplantation or death of 85.1% and 71%, after 5 and 10 years, respectively. The LAM histologic severity score (LHS) was based on the semiquantative estimation of the percentage of tissue involvement by the cystic lesions and abnormal smooth muscle cells, with LHS-1, LHS-2 and LHS-3 defined respectively, as <25%, 25-50%, and >50% involvement. Kaplan-Meier analysis revealed differences in survival between each of the three classes. The 5- and 10-year survivals were 100% and 100% for LHS-1, 81.2% and 74.4% for LHS-2 and 62.8% and 52.4% for LHS-3. Greater accumulation of hemosiderin in macrophages was associated with higher LHS scores and a worse prognosis. b) Pulmonary function, LHS and Prognosis: Lung function in 143 patients with LAM was reviewed. Open lung biopsies from 74 of these patients were independently reviewed for evidence of airway disease and histologic scoring of disease severity. A positive response to bronchodilators was observed in 23% of 418 tests and was associated with more severe airway obstruction, greater proliferation of the smooth muscle cells (LAM cells) in lung biopsy specimens, and a more rapid decline in expiratory flow. Airway inflammation, present in 61% of lung specimens, was not associated with reversible airway obstruction and did not correlate with the severity of airflow obstruction. The diffusion capacity for carbon monoxide (DLCO) post-bronchodilator correlated best with the LAM histology score (LHS), which was, as noted above, a predictor of disease outcome and time to transplantation. DLCO appears to correlate with disease severity. However, in patients with severe disease, DLCO alone does not give an accurate assessment of disease severity. To address this point, cardiopulmonary exercise studies, which evaluate both diffusion and ventilation, are now being used to assess the status of disease. 4. LAM cells: LAM cells in the characteristic lung nodules that penetrate the lung cysts are heterogeneous. Both spindle-shaped and epitheloid cells are present, with the latter found at the periphery of the lesion. Immunoreactivity with antibodies against smooth muscle antigens (e.g., smooth muscle actin) is found in both cell types. The spindle- shaped cells reacted with antibodies against PCNA (proliferating cell nuclear antigen), whereas the epitheloid cells had progesterone and estrogen receptors and reacted with HMB-45, a monoclonal antibody that recognizes gp100, a melanoma antigen. HMB-45 reactivity was not present in all LAM cells. Epitheloid LAM cells are thought to be more differentiated than the spindle-shaped cells. Using laser-capture microscopy, we are examining gene expression in LAM nodules, lymphangioleiomyomas, and angiomyolipomas, and comparing the levels of expression to those in melanoma cells (both grown in culture and from tissue sections), smooth muscle cells (both cultured and from tissue sections [aortic, pulmonary]), epithelial cells, lung carcinomas, and fibroblasts. 5. Progesterone Therapy: A number of therapeutic interventions have been tried for the treatment of patients with LAM, based primarily on hormonal manipulation (e.g., oophorectomy, progesterone, tamoxifen). At the time of initiation of our LAM protocols, progesterone appeared to be the most commonly used; oophorectomy and tamoxifen had fallen out of favor. Of primary concern with tamoxifen were its pro- estrogenic effects. Some patients chose to take progesterone, either IM or oral, and others declined progesterone primarily due to its side effects. A retrospective review of our data supports the conclusion that progesterone did not significantly affect the decline in lung function. The data are now being analyzed to determine whether there are differences in decline in lung function among different patient subgroups.6. Meningiomas: Slightly greater than 4% of patients with LAM were found to have meningiomas. The frequency is far in excess of that expected for the general population. Patients with meningiomas included those who were treated with progesterone and had tuberous sclerosis. However, some of the patients neither had tuberous sclerosis nor were treated with progesterone, consistent with the conclusion that LAM may be in part responsible for the tumors.
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