EPIDEMIOLOGY, PATHOGENESIS and DIAGNOSIS of LYMPHANGIOLEIOMYOMATOSIS

Abstract

Introduction: Lymphangioleiomyomatosis (LAM) is a disease of women characterized by cystic lung destruction, lymphatic involvement, and renal angiomyolipomas.

Areas covered: LAM is caused by proliferation of abnormal smooth muscle-like LAM cells containing mutations and perhaps epigenetic modifications of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins controlling the mechanistic target of rapamycin (mTOR) signaling pathway. LAM occurs sporadically or in association with tuberous sclerosis complex. LAM may present with dyspnea, recurrent pneumothorax or chylothorax. Pulmonary function tests show reduced flow rates and lung diffusion capacity. Exercise testing may reveal hypoxemia and ventilatory limitation. The severity and progression of disease may be assessed by computer tomography, and pulmonary function and exercise testing. mTOR inhibitors, (e.g., sirolimus) are effective in stabilizing lung function, and reducing the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas.

Expert opinion: Different clinical phenotypes including variable rates of disease progression and variable responses to therapy are seen in LAM patients. No one test is available that predicts the course of disease at the time of diagnosis. Further research regarding the molecular biology of LAM clinical phenotypes is warranted. Recent advances in the characterization of the pathogenesis of LAM are leading to the development of new therapies.

Keywords: Lymphangioleiomyomatosis; TSC 1 and TSC2 mutations; Tuberous sclerosis complex (TSC); mTOR.

Figure 1

Pulmonary histopathological findings of LAM. Panel A: Lung LAM nodule showing the characteristic spindle and epithelioid LAM cells. The right side of the panel demonstrates HMB45 immunoreactivity (brown color) of LAM cells. Panel B: Histopathology of the lung showing cystic lesions and smooth muscle cell-like infiltrates (black arrows) on the walls of the cysts (black asterisks).

Figure 2

Simplified scheme of the mTOR signaling pathways. TSC1/2 integrates multiple signals, such as those from growth factors, energy state and hypoxia, to control cell size and proliferation. TSC1/2 regulates mTORC1 negatively through its actions on Rheb. Activation of mTORC1 leads to cell growth and proliferation. mTORC2 regulates the actin cytoskeleton through Rho GTPases, which affect cell migration, morphogenesis and survival. Absence of TSC1/2, e.g., hamartin, tuberin, results in loss of Rheb inhibition, leading to activation of mTORC1, enhanced 4EBP1/S6K signaling and increased cell size and proliferation. Sirolimus blocks mTORC1, decreasing cell size and proliferation. Abbreviations : mTOR: mechanistic target of rapamycin; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; Rheb GAP: Ras homolog enriched in brain GTPase-activating protein; S6K: S6 kinase 1; 4E-BP1: factor 4E-binding protein 1.

Figure 3

Computed tomography scans of women with LAM showing pulmonary and extrapulmonary radiologic features of LAM. Panels A : Lung CT scan shows numerous cysts scattered throughout the lungs. Panel B: Lung CT scan of a LAM patient with lymphatic involvement. Thickening of the interlobar fissures and interstitial infiltrates indicate the presence of chylous fluid in the pleural space and lung parenchyma. Panel C: A large pelvic lymphangioleiomyoma is seen adjacent to the right iliac artery. Panel D: Large left renal angiomyolipoma (white asterisks), intermixed with normal kidney tissue (black asterisk).

Figure 4

Computed tomography scans image showing a large right renal angiomyolipoma complicated by severe bleeding. Large renal and perirenal hematomas (white asterisks) are seen surrounding the kidney parenchyma (black asterisk).