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Original Research: LYMPHANGIOLEIOMYOMATOSIS |

Serum Vascular Endothelial Growth Factor-D Prospectively Distinguishes Lymphangioleiomyomatosis From Other Diseases

Lisa R. Young, MD; Rhonda VanDyke, PhD; Peter M. Gulleman, BS; Yoshikazu Inoue, MD, PhD; Kevin K. Brown, MD, FCCP; Laura S. Schmidt, PhD; W. Marston Linehan, MD; Fuad Hajjar, MD; Brent W. Kinder, MD, FCCP; Bruce C. Trapnell, MD; John J. Bissler, MD, PhD; David N. Franz, MD; Francis X. McCormack, MD, FCCP
Author and Funding Information

From the Division of Pulmonary Medicine (Drs Young and VanDyke, and Mr Gulleman), the Division of Biostatistics (Dr VanDyke), the Division of Pulmonary Biology (Dr Trapnell), the Division of Nephrology (Dr Bissler), and the Division of Neurology (Dr Franz), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; the National Hospital Organization Kinki-Chuo Chest Medical Center (Dr Inoue), Osaka, Japan; the Department of Medicine (Dr Brown), National Jewish Health, Denver, CO; the Basic Research Program (Dr Schmidt), SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, and the Urologic Oncology Branch (Drs Linehan and Schmidt) National Cancer Institute, National Institutes of Health, Bethesda, MD; and the Division of Pulmonary, Critical Care, and Sleep Medicine (Drs Young, Hajjar, Kinder, and McCormack), University of Cincinnati College of Medicine, Cincinnati, OH.

Correspondence to: Francis X. McCormack, MD, FCCP, Division of Pulmonary, Critical Care, and Sleep Medicine, The University of Cincinnati College of Medicine, 231 Albert Sabin Way, Medical Sciences Building Room 6114, MLC 0564, Cincinnati, OH 45267; e-mail: Frank.McCormack@uc.edu


Funding/Support: This study was funded in part by a pilot project grant from The LAM Foundation, The Tante Mela Foundation, and NIH/NHLBI RR19498. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E (to L. S. S.).

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


© 2010 American College of Chest Physicians


Chest. 2010;138(3):674-681. doi:10.1378/chest.10-0573
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Objectives:  The majority of women with lymphangioleiomyomatosis (LAM) present with cystic lung disease, and most require lung biopsy for definitive diagnosis. The purpose of this study was to determine the prospective diagnostic usefulness of a serologic test for vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor.

Methods:  We prospectively measured serum VEGF-D levels by enzyme-linked immunoassay in 48 women presenting with cystic lung disease. Diagnostic test performance was determined from a cohort of 195 women, with tuberous sclerosis complex (TSC), TSC-LAM, sporadic LAM (S-LAM), and other cystic lung diseases in the differential diagnosis, including biopsy-proven or genetically proven pulmonary Langerhans cell histiocytosis, emphysema, Sjögren syndrome, or Birt-Hogg-Dubé syndrome.

Results:  Serum VEGF-D levels were significantly greater in S-LAM (median 1,175 [interquartile range (IQR): 780-2,013] pg/mL; n = 56) than in other cystic lung diseases (median 281 [IQR 203-351] pg/mL; n = 44, P < .001). In the cohort evaluated prospectively, 12 of the 15 individuals ultimately diagnosed with LAM by biopsy had VEGF-D levels of > 800 pg/mL, whereas levels were < 600 pg/mL in all 18 subjects later diagnosed with other causes of cystic lung disease. Receiver operating characteristic curves demonstrated that VEGF-D effectively identified LAM, with an area under the curve of 0.961(95% CI, 0.923-0.992). A VEGF-D level of > 600 pg/mL was highly associated with a diagnosis of LAM (specificity 97.6%, likelihood ratio 35.2) and values > 800 pg/mL were diagnostically specific. Serum VEGF-D levels were significantly elevated in women with TSC-LAM (median 3,465 [IQR 1,970-7,195] pg/mL) compared with women with TSC only (median 370 [IQR 291-520] pg/mL), P < .001).

Conclusions:  A serum VEGF-D level of > 800 pg/mL in a woman with typical cystic changes on high-resolution CT (HRCT) scan is diagnostically specific for S-LAM and identifies LAM in women with TSC. A negative VEGF-D result does not exclude the diagnosis of LAM. The usefulness of serum VEGF-D testing in men or in women who do not have cystic lung disease on HRCT scan is unknown.

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