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Lymphangioleiomyomatosis

By

Joyce Lee

, MD, MAS, University of Colorado Denver

Last full review/revision Sep 2019| Content last modified Sep 2019
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Lymphangioleiomyomatosis (LAM) is an indolent, progressive growth of smooth muscle cells throughout the lungs, pulmonary blood vessels, lymphatics, and pleurae. It is rare and occurs exclusively in young women. Symptoms are dyspnea, cough, chest pain, and hemoptysis; spontaneous pneumothorax is common. Diagnosis is suspected on the basis of symptoms and chest x-ray findings and is confirmed by high-resolution CT. Prognosis is uncertain, but the disorder is slowly progressive and over years often leads to respiratory failure and death. Treatment is with sirolimus or lung transplantation.

Lymphangioleiomyomatosis (LAM) is a rare disease exclusive to women, typically affecting those between 20 and 40 years. Whites are at greatest risk. LAM affects < 1 in 1 million people. It is characterized by proliferation of atypical smooth muscle cells throughout the chest, including lung parenchyma, vasculature, lymphatics, and pleurae, leading to distortion of lung architecture, cystic emphysema, and progressive deterioration of lung function.

Etiology

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

Symptoms and Signs

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.

Diagnosis

  • 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.

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 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.

Diagnosis reference

  • 1. McCormack FX, Gupta N, Finlay GR, et al: Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med 194 (6):748–761, 2016.

Prognosis

Prognosis of 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, but the time to death varies widely among reports. Median survival is likely > 8 years from diagnosis. Lung function declines 2 to 3 times faster than it does in healthy people. Women should be advised that progression may accelerate during pregnancy.

Treatment

  • Sirolimus

  • Lung transplantation

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

Recent data suggest that sirolimus (an mTOR inhibitor) can 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.

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.

In the US, patients can receive education and psychologic support from the LAM Foundation.

Key Points

  • Lymphangioleiomyomatosis (LAM) can mimic interstitial lung disease but is actually a rare, slowly progressive growth of smooth muscle cells in various organs.

  • Consider the diagnosis in young women with unexplained dyspnea plus interstitial changes with normal or increased lung volumes on chest x-ray, spontaneous pneumothorax, or chylous effusion.

  • Do high-resolution CT and, if results are inconclusive, biopsy.

  • Consider sirolimus treatment for LAM with abnormal or progressively decreasing pulmonary function.

Drugs Mentioned In This Article

Drug Name Select Trade
RAPAMUNE
NOLVADEX
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