Differential role of angiogenesis and tumour cell proliferation in brain metastases according to primary tumour type: analysis of 639 cases

Neuropathol Appl Neurobiol. 2015 Feb;41(2):e41-55. doi: 10.1111/nan.12185.


Aim: We aimed to characterize angiogenesis and proliferation and their correlation with clinical characteristics in a large brain metastasis (BM) series.

Methods: Ki67 proliferation index, microvascular density (MVD) and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry in BM and primary tumour specimens.

Results: Six hundred thirty-nine BM specimens of 639 patients with lung cancer (344/639; 53.8%), breast cancer (105/639; 16.4%), melanoma (67/639; 10.5%), renal cell carcinoma (RCC; 52/639; 8.1%) or colorectal cancer (CRC; 71/639; 11.1%) were available. Specimens of the corresponding primary tumour were available in 113/639 (17.7%) cases. Median Ki67 index was highest in CRC BM and lowest in RCC BM (P < 0.001). MVD and HIF-1 alpha index were both highest in RCC BM and lowest in melanoma BM (P < 0.001). Significantly higher Ki67 indices, MVD and HIF-1 alpha indices in the BM than in matched primary tumours were observed for breast cancer, non-small cell lung cancer (NSCLC) and CRC. Correlation of tissue-based parameters with overall survival in individual tumour types showed a favourable and independent prognostic impact of low Ki67 index [hazard ratio (HR) 1.015; P < 0.001] in NSCLC BM and of low Ki67 index (HR 1.027; P = 0.008) and high angiogenic activity (HR 1.877; P = 0.002) in RCC.

Conclusion: Our data argue for differential pathobiological and clinical relevance of Ki67 index, HIF1-alpha index and MVD between primary tumour types in BM patients. An independent prognostic impact of tissue-based characteristics was observed in patients with BM from NSCLC and RCC, supporting the incorporation of these tissue-based parameters into diagnosis-specific prognostic scores.

Keywords: HIF-1 alpha index; brain metastases; ki67 proliferation index; microvascular density.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / mortality*
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Carcinoma, Renal Cell / mortality
  • Carcinoma, Renal Cell / pathology
  • Cell Proliferation
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / analysis
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Ki-67 Antigen / analysis
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Melanoma / mortality
  • Melanoma / pathology
  • Middle Aged
  • Neovascularization, Pathologic / mortality*
  • Neovascularization, Pathologic / pathology*
  • Proportional Hazards Models


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ki-67 Antigen