Addressing the challenges of lymphangioleiomyomatosis assessment in the clinic

ABSTRACT

Introduction: Lymphangioleiomyomatosis (LAM) is a disease primarily 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 of the tuberous sclerosis complex (TSC) TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins that regulate the mechanistic Target of Rapamycin (mTOR) signaling pathway. LAM occurs sporadically or in association with tuberous sclerosis complex. LAM presents with dyspnea or recurrent pneumothoraces. The severity and progression of disease may be assessed by pulmonary function and exercise testing, and computer tomography scans of the chest. Pulmonary function tests show reduced flow rates and lung diffusion capacity. Exercise testing may reveal hypoxemia and ventilatory limitation. mTOR inhibitors, e.g., sirolimus, everolimus, are effective in stabilizing lung function, and reducing the size of chylous effusions, lymphangioleiomyomas, angiomyolipomas, and sub-ependymal giant cell astrocytomas.

Expert opinion: LAM presents in middle-aged women with symptoms of dyspnea and recurrent pneumothoraces but a definite diagnosis is frequently delayed for years. Different clinical phenotypes lead to variable rates of disease progression and no one test can predict the course of disease at the time of diagnosis. Close follow-up of LAM patients is recommended to avoid delays in starting therapy. mTOR inhibitor therapy is recommended for patients with lymphatic disease, FEV₁ ≤ 70% predicted, rapidly declining function and angiomyolipomas.

KEYWORDS:

• Lymphangioleiomyomatosis
• tuberous sclerosis complex (TSC)
• TSC 1 and TSC2 mutations
• mechanistic target of Rapamycin (mTOR)
• mTOR inhibitors
• sirolimus
• everolimus

Article highlights

• LAM is a disease characterized by cystic lung lesions, abdominal angiomyolipomas, and lymphatic involvement, which may present sporadically or in association with the Tuberous Sclerosis Complex (TSC).

• In either case, LAM is caused by mutations of the TSC1 or TSC2 genes. These genes encode hamartin and tuberin respectively, which are two major regulators of the mTOR signalling pathway. Absence or loss of activity of hamartin or tuberin causes proliferation and growth of abnormal smooth muscle-like LAM cells.

• LAM patients are predominantly pre-menopausal women who frequently present with pneumothorax or dyspnea. Less frequently, they may present with cough, respiratory infections. hemoptysis chylous effusions, and hemorrhage from renal angiomyolipomas,

• LAM is frequently misdiagnosed, because symptoms are attributed to other more frequent conditions, e.g., pneumothoraces are attributed to spontaneous causes. Dyspnea, and recurrent pneumothorax in a young pre-menopausal woman should prompt pulmonary function testing/imaging studies including computed tomography scan of the lungs and abdomen and measurement of serum vascular endothelial growth factor-D (VEGF-D) levels.

• A definite diagnosis of LAM can be established by the presence of characteristic round thin-walled cysts scattered throughout the lungs, along with extrapulmonary LAM, the presence of TSC, or a serum VEGF-D level equal or greater than 800 pg/ml. Lung biopsy should be considered when those criteria are not met. Transbronchial lung biopsy may be considered before a surgical biopsy.

• The clinical course of LAM is highly variable but it tends to progress more rapidly in younger, pre-menopausal patients. No single test can predict the prognosis of LAM.

• Accordingly, LAM patients must receive close medical follow-up, consisting of pulmonary function tests, exercise testing and imaging studies when appropriate, to monitor disease progression.

• Treatment with the mTOR inhibitors sirolimus or everolimus has been shown to stabilize or improve lung function, and reduce the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas. In patients with TSC, everolimus is also effective in reducing the volume of sub-ependymal giant cell astrocytomas .

• The main indications for mTOR inhibitor therapy are chylous effusions and symptomatic lymphangioleiomyomas, FEV1≤70% predicted, rapid progression of lung disease as assessed by measurement of FEV₁ and DL_CO, and renal angiomyolipomas greater than 3 cm in diameter that may be at risk for bleeding, and sub-ependymal giant cell astrocytomas.

• Patents with LAM should be under the care of an experienced pulmonary specialist, who should evaluate the patient and do pulmonary function testing at least once every six months, based on clinical status. Patients should receive yearly influenza vaccine as well as other vaccines, as recommended. Avoidance of smoking and estrogens is recommended. Otherwise, patients should be advised to carry on a normal life style within the limitations imposed by their disease, such as exercise-induced hypoxemia. Fatigue and deconditioning are major factors causing limitations to normal activities of daily living. Based on disease status, enrollment into a pulmonary rehabilitation program may be helpful.

• Recurrent pneumothorax should be treated by mechanical pleural abrasion, talc poudrage, or pleurectomy. Chylothorax should be treated with mTOR inhibitors. Hemorrhage caused by angiomyolipomas should be evaluated by a renal expert with experience in TSC.

• Current research into other factors involved in the pathogenesis of LAM, e.g., estrogens, lymphangiogenic growth factors, chemokines, metalloproteinases, may generate targets for novel therapies.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The investigators were supported by the Intramural Research Program, NIH, NHLBI.