Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis

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, lymphangioleiomyo-mas, 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: TSC1 and TSC2 mutations; lymphangioleiomyomatosis; mammalian target of rapamycin signaling pathway; tuberous sclerosis.

Figure 1

Skin manifestations of tuberous sclerosis complex in adult women. Notes: (A) Two hypomelanotic macules located on the back. (B) Facial angiofibromas involving the nose and adjacent cheek. (C) Shagreen patch involving the lower back. (D) Periungual fibroma.

Figure 2

Simplified scheme of the mTOR signaling pathways showing potential sites of action of some agents tested or in use in LAM. Notes: 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. mTORC1 is also a major regulator of autophagy. Blockade of mTORC1 by sirolimus augments autophagy, which may lead to increased cell survival. In vitro, this effect can be inhibited by chloroquine. mTORC2 regulates the actin cytoskeleton through Rho GTPases, which affect cell migration, morphogenesis, and apoptosis. Simvastatin reduces Rheb and Rho activities and promotes apoptosis. Combined therapy with sirolimus, chloroquine, or simvastatin may act synergically to inhibit LAM cell growth. Absence of TSC1/2, eg, hamartin and 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, mammalian target of rapamycin; LAM, lymphangiolei-omyomatosis; TSC, tuberous sclerosis complex; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; Rheb, Ras homologue enriched in brain; 4EBP1, factor 4E-binding protein 1; S6K, S6 kinase 1; ULK2, Unc-51-like kinase 2.

Figure 3

Computed tomography scans showing pulmonary and extrapulmonary images of patients with LAM. Notes: (A) Multiple large (white asterisk) thin-walled cysts scattered throughout the lungs. Between the cystic areas there is normal-appearing lung parenchyma. (B) Numerous small thin-walled cysts have completely replaced the normal lung parenchyma. (C) Small posterior mediastinal lymphangioleiomyoma surrounding the descending aorta (white asterisk). (D) Right renal (white asterisk) and liver (white asterisk) angiomyolipomas in a patient with TSC-LAM. The fatty, low-density component is clearly visualized. Abbreviations: LAM, lymphangioleiomyomatosis; TSC, tuberous sclerosis complex.