Abstract
BackgroundLymphangioleiomyomatosis (LAM) is a low-grade neoplasm characterized by the pulmonary infiltration of smooth muscle-like cells (LAM cells) and cystic destruction. Patients usually present with airway obstruction in pulmonary function tests (PFTs). Previous studies have shown correlations among histological parameters, lung function abnormalities and prognosis in LAM. We investigated the lung tissue expression of proteins related to the mTOR pathway, angiogenesis and enzymatic activity and its correlation with functional parameters in LAM patients.MethodsWe analyzed morphological and functional parameters of thirty-three patients. Two groups of disease severity were identified according to FEV1 values. Lung tissue from open biopsies or lung transplants was immunostained for SMA, HMB-45, mTOR, VEGF-D, MMP-9 and D2-40. Density of cysts, density of nodules and protein expression were measured by image analysis and correlated with PFT parameters.ResultsThere was no difference in the expression of D2-40 between the more severe and the less severe groups. All other immunohistological parameters showed significantly higher values in the more severe group (p ≤ 0.002). The expression of VEGF-D, MMP-9 and mTOR in LAM cells was associated with the density of both cysts and nodules. The density of cysts and nodules as well as the expression of MMP-9 and VEGF-D were associated with the impairment of PFT parameters.ConclusionsSevere LAM represents an active phase of the disease with high expression of VEGF-D, mTOR, and MMP-9, as well as LAM cell infiltration. Our findings suggest that the tissue expression levels of VEGF-D and MMP-9 are important parameters associated with the loss of pulmonary function and could be considered as potential severity markers in open lung biopsies of LAM patients.
Highlights
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm characterized by the pulmonary infiltration of smooth muscle-like cells (LAM cells) and cystic destruction
To investigate the association of immunohistological features with impairment in Pulmonary function tests (PFT), we evaluated morphological parameters related to tissue destruction, LAM cell infiltration, and the expression of proteins related to the Mammalian target of rapamycin (mTOR) pathway, angiogenesis and enzymatic activity in LAM patients with different functional severities
Our results showed that 1) the more severe, advanced phase of disease presents with increased mTOR, Vascular endothelial growth factor (VEGF)-D and MMP-9 expression, as well as greater extent of cystic areas and LAM cell nodules; and 2) the main immunohistochemical and histological parameters associated with loss of pulmonary function were MMP-9, VEGF-D, the density of cysts and the density of nodules
Summary
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm characterized by the pulmonary infiltration of smooth muscle-like cells (LAM cells) and cystic destruction. We investigated the lung tissue expression of proteins related to the mTOR pathway, angiogenesis and enzymatic activity and its correlation with functional parameters in LAM patients. Lymphangioleiomyomatosis (LAM) is a rare low-grade neoplasm that affects women of reproductive age, characterized by the proliferation of immature smooth musclelike cells (LAM cells), mainly in the lungs [1,2,3]. The pathologic changes in pulmonary LAM (LAM lesions) are characterized by two distinct components: the cystic and the cellular components [7] The former consists of multiple cysts distributed diffusely throughout the lungs and the latter is composed by two cellular subpopulations (LAM cells): spindle myofibroblast-like cells and polygonal cells with epithelioid morphology. The dysregulation and hyperactivation of the mTOR kinase pathway leads to increased protein translation and to inappropriate cellular proliferation, migration and invasion [11, 12]
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