Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis

Clinical Epidemiology Dovepress open access to scientific and medical research Review Open Access Full Text Article Clinical Epidemiology downloaded from https://www.dovepress.com/ by 95.246.15.150 on 10-Jul-2020 For personal use only. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis This article was published in the following Dove Press journal: Clinical Epidemiology 7 April 2015 Number of times this article has been viewed Angelo M Taveira-DaSilva Joel Moss Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA Abstract: Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, characterized by proliferation of abnormal smooth muscle-like LAM cells, leading to the formation of lung cysts, fluid-filled cystic structures in the axial lymphatics (eg, lymphangioleiomyomas), and renal angiomyolipomas. LAM is caused by mutations of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins with a major role in control of the mammalian target of rapamycin (mTOR) signaling pathway. LAM occurs sporadically or in association with tuberous sclerosis complex, an autosomal-dominant syndrome characterized by widespread hamartomatous lesions. LAM may present with progressive dyspnea, recurrent pneumothorax, or chylothorax. Pulmonary function tests show reduced flow rates (forced expiratory volume in the first second) and diffusion capacity. Exercise testing may reveal gas exchange abnormalities, ventilatory limitation, and hypoxemia. The severity and progression of disease may be assessed by lung histology scores, quantification of computed tomography, pulmonary function testing, 6-minute walk tests, cardiopulmonary exercise testing, and measurement of serum vascular endothelial growth factor D levels. Sirolimus and everolimus, two mTOR inhibitors, are effective in stabilizing lung function and reducing the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas. However, inhibition of mTOR complex 1 increases autophagy, possibly enhancing LAM cell survival. Inhibition of autophagy with hydroxychloroquine, in combination with sirolimus, has been proposed as a possible treatment for LAM. Deficiency of tuberin results in increased RhoA GTPase activity and cell survival, an effect that is mediated through mTOR complex 2 signaling. Because sirolimus and everolimus only affect the activity of mTOR complex 1, therapies targeting RhoA GTPases with simvastatin, which inhibits Rho GTPases and promotes apoptosis, are being investigated. As in the case of cancer, LAM may be best treated with multiple drugs targeting signaling pathways considered important in the pathogenesis of disease. Keywords: lymphangioleiomyomatosis, tuberous sclerosis, TSC1 and TSC2 mutations, mammalian target of rapamycin signaling pathway Introduction Correspondence: Angelo M TaveiraDaSilva Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D03, MSC 1590, Bethesda, MD 20892-1590, USA Tel +1 301 451 4950 Fax +1 301 496 2363 Email 249 submit your manuscript | www.dovepress.com Clinical Epidemiology 2015:7 249–257 Dovepress © 2015 Taveira-DaSilva and Moss. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/CLEP.S50780 Powered by TCPDF (www.tcpdf.org) Lymphangioleiomyomatosis (LAM), a multisystem disorder affecting predominantly women, is characterized by cystic lung destruction and extrapulmonary disease consisting of angiomyolipomas (AMLs), lymphatic tumors, eg, lymphangioleiomyomas, and chylous effusions.1–6 The pathologic features of LAM result from the proliferation of neoplastic cells (LAM cells), which have characteristics of both smooth muscle cells and melanocytes.2,4–6 LAM occurs with increased frequency in patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes, and characterized by mental retardation, autism, seizures, Dovepress Taveira-DaSilva and Moss and hamartomatous lesions in the brain, heart, skin, kidney, eyes, lungs, and liver.7–10 A noninherited form of LAM called sporadic LAM is caused by somatic mutations of the TSC2 gene8–10 and is estimated to have a prevalence of approximately 3.3–7.7 per 1,000,000 women.11 Clinical Epidemiology downloaded from https://www.dovepress.com/ by 95.246.15.150 on 10-Jul-2020 For personal use only. Epidemiology LAM was once considered to be a fatal disease of women of childbearing age for which there was no effective treatment except for lung transplantation.12–14 Thanks to intensive study in the past 2 decades,1,3,15 LAM is now considered to be a chronic disease that can affect both pre- and postmenopausal women, with a median transplant-free survival of approximately 29 years from the onset of symptoms and a 10-year transplant-free survival of 86%.1,15,16 TSC is a multisystem, autosomal-dominant disorder that occurs in 1 in 12,000–14,000 children aged ,10 years or 1 in 6,000 live births.7 TSC is characterized by facial angiofibroma, periungual fibromas, Shagreen patches, cortical tubers, cardiac rhabdomyomas, giant cell astrocytomas, mental retardation, and seizures, in addition to clinical features found in sporadic LAM.7 The prevalence of LAM in TSC was once thought to be 1%–4%,17–20 but subsequent studies showed that the occurrence of cystic lung disease in women with TSC ranges from 26% to 38%.21–23 In a recent study, it was estimated that as many as 80% of women with TSC will develop lung cysts.24 Lung cysts occur in only about 13% of men with TSC,25 who show much less clinically significant disease than women. Pathology Histologically, lung lesions consist of LAM cells in the walls of cysts and along blood vessels, lymphatics, and bronchioles, leading to narrowing of the airways, thickening of the vascular walls, lymphatic disruption, and venous occlusion.5,6 Noncystic lesions consist of nodular infiltrates of LAM cells. The center of the nodules contains a preponderance of small, spindle-shaped cells, whereas epithelioid cells with large cytoplasm predominate in the periphery.5,6 Both types of cells react with antibodies against smooth muscle antigens, eg, α-actin, vimentin, and desmin. Epithelioid cells react with human melanin black antibody (HMB-45), a monoclonal antibody that recognizes gp100, a (...truncated)