Lymphangioleiomyomatosis (
LAM), a rare multisystem disease, occurs primarily in women, with cystic destruction of the lungs, abdominal
tumors, and involvement of the axial lymphatics in the thorax and abdomen. To understand the pathogenesis of
LAM, we initiated a longitudinal study of patients with
LAM; over 500 patients have been enrolled.
LAM results from the proliferation of a neoplastic cell (
LAM cell), which has mutations in the
tuberous sclerosis complex (
TSC) genes, TSC1 or TSC2. Consistent with their metastatic behavior,
LAM cells were isolated from blood, urine, and chylous effusions.
Surface proteins on
LAM cells include those found on metastatic cells and those involved in cell migration. In the lung,
LAM cells are found clustered in nodules, which appear in the walls of the
cysts, and in the interstitium.
LAM lung nodules are traversed by slit-like vascular structures, with lining cells showing reactivity with
antibodies against components of lymphatic endothelial cells. The axial lymphatics appear to be infiltrated by
LAM cells, which may result in obstruction and formation of chyle-filled
lymphangioleiomyomas.
LAM cell clusters have been isolated from chylous
pleural effusions, and it is hypothesized that these clusters may be responsible for metastatic spread of
LAM cells via lymphatic vessels. Consistent with a lymphangiogenic process, levels of
VEGF-D, a lymphangiogenic factor, were higher in sera of patients with
LAM and lymphatic involvement (i.e.,
lymphangioleiomyoma,
adenopathy) than in healthy volunteers or
LAM patients with cystic disease limited to the lung. These findings are consistent with an important function for lymphangiogenesis in
LAM.