Lymphangioleiomyomatosis

The cause of lymphangioleiomyomatosis is thought to be due to loss-of-function genetic mutations of the tuberous sclerosis proteins, tuberin and hamartin. Unregulated expression of growth factors have been implicated in the pathogenesis. The hypothesis that female sex hormones play a role in pathogenesis remains unproven.

The disease usually arises spontaneously, but LAM bears many similarities to the pulmonary findings of tuberous sclerosis; LAM occurs in some patients with tuberous sclerosis and is thought by some to be a forme fruste of tuberous sclerosis. Mutations in the tuberous sclerosis complex-2 gene (TSC-2) have been described in LAM cells and angiomyolipomas (benign renal hamartomas made of smooth muscle, blood vessels, and adipose). Angiomyolipomas occur in up to 50% of patients with LAM. These observations suggest 1 of 2 possibilities:

• Somatic mosaicism for TSC-2 mutations within the lungs and kidneys results in foci of disease superimposed against a background of normal cells within these tissues (although multiple discrete sites of disease might be expected). These mutations lead to an unregulated overexpression of growth factors (eg, vascular endothelial growth factor [VEGF], insulin-like growth factor [IGF], platelet-derived growth factor [PDGF], fibroblast growth factor [FGF])which are also thought to contribute to disease progression. Matrix metalloproteinases and cathepsins may be responsible for cell migrations and differentiation, contributing to tissue remodeling.

• Lymphangioleiomyomatosis represents a low-grade, destructive, metastasizing neoplasm, perhaps of uterine origin, that spreads through the lymphatic system.

Initial symptoms of lymphangioleiomyomatosis are fatigue and dyspnea (especially during exertion). These symptoms can be misconstrued as presenting symptoms of asthma or chronic obstructive pulmonary disease (COPD). Less commonly, cough, chest pain, and hemoptysis may occur. There are few signs of disease, but some women have crackles and rhonchi. Rarely, pulmonary hypertension occurs.

Many patients present with spontaneous pneumothorax as well as pleural effusions. They may also present with manifestations of axial lymphadenopathy, often causing lymphatic obstruction, including chylothorax, chylous ascites, and chyluria. Symptoms are thought to worsen during pregnancy.

Renal angiomyolipomas, although usually asymptomatic, can cause bleeding if they grow large (eg, > 4 cm), usually manifesting as hematuria or flank pain.

• Chest radiograph and high-resolution CT (HRCT)

• Pulmonary function testing

• VEGF-D testing

• Lung biopsy if HRCT and VEGF-D testing are nondiagnostic

Diagnosis of lymphangioleiomyomatosis is suspected in young women with dyspnea plus interstitial changes with normal or increased lung volumes on chest radiograph, spontaneous pneumothorax, or chylous effusion (1). Lymphangioleiomyomatosis is often misdiagnosed as another form of interstitial lung disease.

HRCT is recommended in all patients suspected of having the disorder; findings of multiple, small, diffusely distributed, thin-walled cysts are generally pathognomonic for LAM. Pneumothorax,pleural effusions, and chylous effusions (in the thorax or abdomen) may be seen on imaging.

Lymphangioleiomyomatosis

Image

Image courtesy of Joyce Lee, MD, MAS.

Serum VEGF-D (vascular endothelial growth factor D) testing is recommended. Serum VEGF-D levels are elevated in the majority of women with LAM and are normal in women with other forms of cystic lung disease. An elevated VEGF-D level can confirm LAM, but a normal level does not exclude the diagnosis (2).

Biopsy (surgical) is indicated only when HRCT findings and VEGF-D testing are nondiagnostic. Findings of an abnormal proliferation of smooth muscle cells (LAM cells) associated with cystic changes on histologic examination confirm disease.

Pulmonary function tests support the diagnosis and are especially useful for monitoring. Typical findings are of an obstructive or mixed obstructive and restrictive pattern. The lungs are usually hyperinflated with an increase in the total lung capacity (TLC) and thoracic gas volume. Gas trapping (an increase in residual volume [RV] and RV/TLC ratio) is commonly present. The partial pressure of arterial oxygen (PaO2) and diffusing capacity of the lung for carbon monoxide (DLCO) are commonly reduced. Exercise performance is decreased in most patients.

• Sirolimus Sirolimus

• Lung transplantation

Sirolimus (an mTOR inhibitor) may help stabilize or slow the decline in pulmonary function among patients with moderate lung impairment (forced expiratory volume in 1 second [FEV1] < 70% predicted). Treatment withSirolimus (an mTOR inhibitor) may help stabilize or slow the decline in pulmonary function among patients with moderate lung impairment (forced expiratory volume in 1 second [FEV1] < 70% predicted). Treatment withsirolimus is recommended for patients with abnormal or declining lung function (1). Alternative treatments, such as hormonal manipulation with progestins, tamoxifen, oophorectomy, or anti-inflammatory tetracycline therapy are largely ineffective and not recommended. ). Alternative treatments, such as hormonal manipulation with progestins, tamoxifen, oophorectomy, or anti-inflammatory tetracycline therapy are largely ineffective and not recommended.

Pneumothorax may be difficult to manage because it often recurs, is bilateral, and is less responsive to standard measures. Recurrent pneumothorax requires pleural abrasion, talc or chemical pleurodesis, or pleurectomy. Embolization to prevent bleeding should be considered for angiomyolipomas Pneumothorax may be difficult to manage because it often recurs, is bilateral, and is less responsive to standard measures. Recurrent pneumothorax requires pleural abrasion, talc or chemical pleurodesis, or pleurectomy. Embolization to prevent bleeding should be considered for angiomyolipomas> 4 cm.

Standard treatment of lymphangioleiomyomatosis is lung transplantation, but the disorder can recur in transplanted lungs.

Air travel is well-tolerated by most patients (2).

The prognosis for patients with lymphangioleiomyomatosis is unclear because the disorder is so rare and because the clinical course of patients with LAM is variable. In general, the disease is slowly progressive, leading eventually to respiratory failure and death. The estimated 10-year survival rates are variable, but exceed 90% and are more favorable than previously believed (1). Women should be advised that progression may accelerate during pregnancy.

The following English-language resource may be useful. Please note that The Manual is not responsible for the content of this resource.

1. LAM Foundation