Chest
Volume 135, Issue 5, May 2009, Pages 1293-1300
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Original Research
Lymphangioleiomyomatosis
Serum Vascular Endothelial Growth Factor-D Levels in Patients With Lymphangioleiomyomatosis Reflect Lymphatic Involvement

https://doi.org/10.1378/chest.08-1160Get rights and content

Background

Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder affecting primarily women of child-bearing age, and characterized by cystic lung destruction, tumors of the kidney (angiomyolipomas [AMLs]), and involvement of the axial lymphatics (lymphangioleiomyomas). Patients with LAM experience loss of pulmonary function attributed to the proliferation of abnormal-appearing smooth muscle-like cells (LAM cells). It is possible to group the LAM population by the presence or absence of extrapulmonary involvement (eg, AMLs, lymphangioleiomyomas, chylous effusions). Serum vascular endothelial growth factor (VEGF)-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM patients.

Methods

Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers.

Results

Serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (p < 0.001). However, when patient samples were grouped based on the extent of lymphatic extrapulmonary involvement (eg, lymphangioleiomyomas and adenopathy), the statistical difference was maintained only for patients with LAM with lymphatic involvement (p < 0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker for lymphatic involvement (area under the curve [AUC], 0.845; p < 0.0001), and a fair predictor for LAM disease (AUC, 0.751; p < 0.0001). Serum levels correlated to CT scan grade (p = 0.033).

Conclusions

Serum VEGF-D concentration is a measure of lymphatic involvement in patients with LAM.

Section snippets

Participants

The research was approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute (protocols 95-H-0186 and 96-H-0100); all participants gave written informed consent. The diagnosis of LAM was made by tissue biopsy and/or clinical and roentgenographic data. The presence or absence of lymphangioleiomyoma and adenopathy in 111 patients with LAM was determined by screening CT scan (model 9800 and Lightspeed scanners; General Electric; Milwaukee, WI) and/or sonography

Results

The study group was composed of 111 patients with sporadic LAM (all women; mean age, 51.4 years) and 40 healthy volunteers (all women; mean age, 49.6 years) [Table 1]. The diagnosis of LAM was confirmed by biopsy or by roentgenographic evidence of characteristic cystic lung lesions and extrapulmonary manifestations (eg, AMLs lymphangioleiomyomas). Subjects presenting with pulmonary involvement alone can be considered as possible false-positive findings. Of the 111 patients in the LAM cohort,

Discussion

A patient with cystic lung disease is likely to have LAM if presenting with extrapulmonary manifestations (eg, AML lymphangioleiomyoma). It is in patients whose disease is restricted to the lung that the diagnostic dilemma occurs. Similar thin-walled cysts may be seen in other diseases characterized by lung involvement. In these cases, an open-lung biopsy is often recommended to confirm LAM. The discovery of a biomarker for diagnosis might obviate the need for an invasive biopsy procedure.

Acknowledgment

We thank Dr. Martha Vaughan, Dr. Wendy Steagall, Dr. Souheil El-Chemaly, and Dr. Gustavo Pacheco-Rodriguez (Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health) for helpful discussions and critical review of the manuscript.

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      The lymphangiogenic factor VEGF-D is produced by normal mesothelial cells, and VEGF-D expression is sensitive to inhibition by rapamycin in these cells [46]. VEGF-D is elevated in the serum of women with LAM, is of value as a diagnostic biomarker of LAM [47–50] and is strongly associated with lymphatic involvement in LAM [48,51–53]. This is consistent with expansion of a VEGF-D-expressing hyperplastic mesothelial cell population and with elevation of VEGF-D expression in these cells consequent to mTORC activation.

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    This research was funded by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute.

    The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

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