Angiogenesis Biomarkers May Be Useful in the Management of Patients With Indeterminate Pulmonary Nodules

Ann Thorac Surg. 2015 Aug;100(2):429-36. doi: 10.1016/j.athoracsur.2015.04.018. Epub 2015 Jun 30.


Background: Low-dose computed tomography (CT) lung cancer screening is known to have a high false positive rate. This study aims to survey biomarkers of angiogenesis for those capable of assigning clinical significance to indeterminate pulmonary nodules detected through CT imaging studies.

Methods: An institutional database and specimen repository was used to identify 193 patients with stage I non-small cell lung cancer (T1N0M0) and 110 patients with benign solitary pulmonary nodules detected by CT imaging studies. All specimens were evaluated in a blinded manner for 17 biomarkers of angiogenesis using multiplex immunoassays. Biomarker performance was calculated through the Mann-Whitney rank sum U test and a receiver operator characteristic analysis. These data were used to refine our previously reported multi-analyte classification panel, which was then externally validated against an independent patient cohort (n = 80).

Results: A total of 303 patients were screened for 17 biomarkers of angiogenesis. Median nodule size was 1.2 cm for benign cases and 1.8 cm for non-small cell lung cancer, whereas median smoking histories were 25 and 40 pack-years, respectively. Differences in serum concentrations of heparin-binding epidermal growth factor (HB-EGF), epidermal growth factor (EGF), vascular (V)EGF-A, VEGF-C, and VEGF-D were strongly significant (p ≤ 0.001) while follistatin, placental growth factor (PLGF), and bone morphogenic protein (BMP)-9 were significant (p ≤ 0.05) between patients with benign and malignant nodules. Our previously reported multi-analyte classification panel was refined to include interleukin (IL)-6, IL-10, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF)-α, insulin-like growth factor binding protein (IGFBP)-5, IGFBP-4, IGF-2, stromal cell-derived factor (SDF)-1(α+β), HB-EGF, and HGF resulting in improved accuracy and a validated negative predictive value of 96.4%.

Conclusions: Angiogenesis biomarkers may be useful in discriminating stage I NSCLC from benign pulmonary nodules.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / blood*
  • Carcinoma, Non-Small-Cell Lung / blood*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Diagnosis, Differential
  • Female
  • Humans
  • Lung Neoplasms / blood*
  • Lung Neoplasms / pathology*
  • Male
  • Middle Aged
  • Neovascularization, Pathologic
  • Retrospective Studies
  • Solitary Pulmonary Nodule / blood*
  • Solitary Pulmonary Nodule / pathology*
  • Tomography, X-Ray Computed


  • Biomarkers, Tumor