Chest
Volume 138, Issue 3, September 2010, Pages 674-681
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Original Research
Lymphangioleiomyomatosis
Serum Vascular Endothelial Growth Factor-D Prospectively Distinguishes Lymphangioleiomyomatosis From Other Diseases

https://doi.org/10.1378/chest.10-0573Get rights and content

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.

Section snippets

Study Population

Prospective VEGF-D testing was performed in 48 women presenting for clinical evaluation who did not meet criteria for definite LAM diagnosis at the time of initial evaluation. In comparison, results of retrospectively performed VEGF-D testing were analyzed from 122 women with known diagnoses. Subjects were recruited from pulmonary clinics and LAM and TSC clinics at the University of Cincinnati and Cincinnati Children's Hospital Medical Center, and via referral from other physicians and several

Study Subjects

Serum samples were evaluated from 195 female subjects with definite S-LAM or other proven causes of cystic lung disease that may mimic LAM (emphysema, PLCH, BHD, and Sjögren), TSC-LAM, TSC only, lymphangiomatosis, and healthy volunteers. The clinical characteristics of the study population are shown in Table 1. The presentations and disease severity of subjects with LAM and those with other cystic lung diseases were similar. There was no significant difference in the age of subjects with LAM

Discussion

The objective of this study was to prospectively evaluate the test characteristics and diagnostic usefulness of serum VEGF-D for LAM. We found that VEGF-D effectively discriminated LAM and lone elevated serum LAM from other cystic lung diseases that are commonly considered in the differential diagnosis, and was associated with the presence of cystic lung disease in women with TSC. We conclude that serum VEGF-D is a useful diagnostic test for S-LAM and a promising screening tool for LAM in women

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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).

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