title: Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.forename: Rhonda
authors.initials: R
authors.lastname: Vandyke
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gulleman
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Inoue
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Fuad
authors.initials: F
authors.lastname: Hajjar
authors.forename: Brent W
authors.initials: BW
authors.lastname: Kinder
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
authors.forename: David N
authors.initials: DN
authors.lastname: Franz
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000097:blood* / Q000473:pathology*; D018192:Lymphangioleiomyomatosis / Q000097:blood* / Q000175:diagnosis*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D015203:Reproducibility of Results; D042643:Vascular Endothelial Growth Factor D / Q000097:blood*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D042643:Vascular Endothelial Growth Factor D
references.citation: Chest. 2009 May;135(5):1293-1300
references.pmid: 19420197
references.citation: Chest. 2008 Feb;133(2):507-16
references.pmid: 18252917
references.citation: Nat Med. 2001 Feb;7(2):186-91
references.pmid: 11175849
references.citation: Am J Respir Cell Mol Biol. 2007 Apr;36(4):398-408
references.pmid: 17099139
references.citation: N Engl J Med. 2008 Jan 10;358(2):199-200
references.pmid: 18184970
references.citation: J Child Neurol. 1998 Dec;13(12):624-8
references.pmid: 9881533
references.citation: Am J Pathol. 2009 Oct;175(4):1410-20
references.pmid: 19717640
references.citation: Am J Surg Pathol. 2005 Oct;29(10):1356-66
references.pmid: 16160479
references.citation: Radiographics. 1991 May;11(3):457-72
references.pmid: 1852937
references.citation: Acta Cytol. 2009 Jul-Aug;53(4):402-9
references.pmid: 19697724
references.citation: Am J Hum Genet. 2001 Oct;69(4):876-82
references.pmid: 11533913
references.citation: AJR Am J Roentgenol. 2003 Mar;180(3):827-35
references.pmid: 12591705
references.citation: Arch Neurol. 2000 May;57(5):662-5
references.pmid: 10815131
references.citation: Am J Respir Crit Care Med. 2001 Aug 15;164(4):661-8
references.pmid: 11520734
references.citation: Am J Respir Crit Care Med. 2006 Jan 1;173(1):105-11
references.pmid: 16210669
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):548-53
references.pmid: 9435229
references.citation: N Engl J Med. 2006 Sep 28;355(13):1345-56
references.pmid: 17005952
references.citation: Am J Respir Crit Care Med. 2001 Aug 15;164(4):669-71
references.pmid: 11520735
references.citation: Lymphat Res Biol. 2006;4(3):143-52
references.pmid: 17034294
references.citation: Am J Surg Pathol. 2004 Aug;28(8):1007-16
references.pmid: 15252306
references.citation: Eur Respir J. 2006 May;27(5):1056-65
references.pmid: 16707400