Lymphangioleiomyomatosis

The cause of lymphangioleiomyomatosis is unknown. The tempting hypothesis that female sex hormones play a role in pathogenesis remains unproved.

The disease usually arises spontaneously, but LAM bears many similarities to the pulmonary findings of tuberous sclerosis (TS); LAM occurs in some patients with TS and is thought by some to be a forme fruste of TS. 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).

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

Initial symptoms of lymphangioleiomyomatosis are dyspnea and, less commonly, cough, chest pain, and hemoptysis. There are few signs of disease, but some women have crackles and rhonchi. Many patients present with spontaneous pneumothorax. They may also present with manifestations of 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 x-ray and high-resolution CT (HRCT)

• 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 x-ray, spontaneous pneumothorax, or chylous effusion. Lymphangioleiomyomatosis is often misdiagnosed as interstitial lung disease.

HRCT is done in all patients suspected of having the disorder; findings of multiple, small, diffusely distributed cysts are generally pathognomonic for LAM.

Lymphangioleiomyomatosis

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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 (1).

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 PaO2 and diffusing capacity for carbon monoxide (DLCO) are commonly reduced. Exercise performance is decreased in most patients.

• Sirolimus Sirolimus

• Lung transplantation

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

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 with sirolimus is recommended for patients with abnormal or declining lung function. Alternative treatments, such as hormonal manipulation with progestins, tamoxifen, and oophorectomy, are largely ineffective and not recommended. 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] sirolimus is recommended for patients with abnormal or declining lung function. Alternative treatments, such as hormonal manipulation with progestins, tamoxifen, and oophorectomy, 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.

Air travel is well-tolerated by most patients.

Prognosis for 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 favourable 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: Provides education and support for patients and has resources for clinicians and researchers