Involvement of lymphatics in lymphangioleiomyomatosis

Abstract

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.

FIG. 1.

Computer tomography scans of four patients with LAM. (A) shows numerous, relatively large, thin-walled cysts replacing the normal lungs. Arrow points to the wall of a cyst. (B) shows innumerous small thin-walled cysts distributed throughout the lungs replacing the normal lung parenchyma. (C) shows a large abdominal lymphangioleiomyoma (marked by the asterisk) surrounding the iliac vessels. (D) shows the same tumor surrounding the aorta (A) and inferior vena cava (IVC). (E) shows that lymphangioleiomyomas may appear as fluid-filled cystic structures (box and arrow). (F) shows large angiomyolipomas involving the right (inside box) and left kidneys. The normal kidney anatomy is distorted, making the kidney parenchyma almost completely unrecognizable.

FIG. 2.

Lymphatics involvement in lymphangioleimyomatosis. (A) shows a hematoxylin and eosin (H & E) staining of LAM nodule that is characterized by proliferating smooth muscle-like cells (asterix, LAM cells) surrounded by type II pneumocytes (arrow). (B) shows close view of a LAM nodule; the arrowhead indicates the lymphatic-like structures. (C) shows reactivity of lymphatic nodules with anti D2-40 antibody, which recognizes an epitope of podoplanin (arrow) (Pacheco–Rodriguez et al. 2007).

FIG. 3.

Serum Levels of VEGF-D in lymphangioleiomyomatosis. In (A), serum VEGF-D levels in all patients with sporadic lymphangioleiomyomatosis (LAM) (n = 111) were compared to those of healthy volunteers (n = 40). (B) shows patient samples further grouped and compared on the basis of thoracic or abdominal lymphatic involvement (presence (n = 77) or absence (n = 34) of lymphangioleiomyomas and/or adenopathy), and the presence (n = 40) or absence (n = 71) of renal angiomyolipomas (AMLs). All groups were compared to healthy volunteers (n = 40). (+) = presence of, (−) = absence of. Each ♦ represents serum measurement of VEGF-D from one patient or healthy volunteer. Lines represent mean values. (From Reference 69).