Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is the result of disorderly smooth muscle proliferation throughout the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax) and lymphatics (leading to chylous pleural effusion). LAM occurs in a sporadic form, which only affects females, who are usually of childbearing age. LAM also occurs in patients who have tuberous sclerosis.

Cause

Sporadic LAM only affects women.

The proliferating smooth muscle that occurs in the type of LAM seen in patients with tuberous sclerosis (TSC-LAM) has been shown to represent clones of the smooth muscle in those patients' renal angiomyolipomas. Thus it is believed to represent metastases of this "benign" tumor. There is a female preponderance to TSC-LAM.

Radiography

With LAM, there is diffuse replacement of the pulmonary parenchyma by thin-walled cysts measuring 2-20 mm in diameter, with equal involvement of upper and lower lung zones. On chest X-rays, superimposition of the cysts gives a reticulonodular pattern of interstitial lung disease. High-resolution CT of the chest is both more specific for the diagnosis, as well as better able to assess the degree of pulmonary involvement.

(The CXRs demonstrate pulmonary hyperexpansion and fine linear, cystic or nodular opacities)

Prognosis

Exact data on survival rates are difficult to collect because LAM is often misdiagnosed as asthma or other more common diseases, and may not be correctly identified until it is in an advanced condition. A comprehensive study of all known British LAM patients found that out of 21 patients that had been observed for 15 years or more since diagnosis, 18 were still alive; and 11 of 12 patients that had been observed for 20 years or more were alive.

Complications

• Worsening pulmonary insufficiency
• Pneumothorax, secondary to rupture of a cyst into the pleural space
• Chylous pleural effusions

Treatment

The association of LAM with women of childbearing age suggests that hormonal stimulation plays a role in the disease process, and several approaches to treatment involve diminishing the effect of estrogen. At one time or another, therapeutic approaches have included

• progesterone
  
• oophorectomy
• tamoxifen
• 
  
• gonadotropin-releasing hormone (GnRH) agonists
• androgen therapy

No therapy is clearly efficacious, and all have undesirable side-effects. There is some evidence which shows that tamoxifen may actually cause worsening of LAM in some patients.

When pulmonary function deteriorates to the point where oxygenation is inadequate, lung transplantation is usually performed. Following lung transplant (usually unilateral), LAM patients have Kaplan-Meier estimators (survival curves) similar to other lung transplant patients.

A single case report of an apparent response to Doxycycline has recently been reported.

Sirolimus is being tested for the treatment of LAM. The MILES Trial (Multicenter International LAM Efficacy of Sirolimus Trial) is now underway. The first site, the University of Cincinnati, is open for enrollment. The National Institutes of Health will open enrollment soon. The MILES Trial is randomized, double-blinded, and placebo-controlled. The objective of the Trial is to determine if sirolimus has a beneficial effect on lung function in LAM patients.