title: Differential role of angiogenesis and tumour cell proliferation in brain metastases according to primary tumour type: analysis of 639 cases.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center CNS Tumors Unit, Medical University of Vienna, Vienna, Austria; Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Berghoff
authors.forename: Aysegül
authors.initials: A
authors.lastname: Ilhan-Mutlu
authors.forename: Carina
authors.initials: C
authors.lastname: Dinhof
authors.forename: Manuel
authors.initials: M
authors.lastname: Magerle
authors.forename: Monika
authors.initials: M
authors.lastname: Hackl
authors.forename: Georg
authors.initials: G
authors.lastname: Widhalm
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Hainfellner
authors.forename: Karin
authors.initials: K
authors.lastname: Dieckmann
authors.forename: Josef
authors.initials: J
authors.lastname: Pichler
authors.forename: Markus
authors.initials: M
authors.lastname: Hutterer
authors.forename: Thomas
authors.initials: T
authors.lastname: Melchardt
authors.forename: Rupert
authors.initials: R
authors.lastname: Bartsch
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000098:blood supply / Q000401:mortality* / Q000556:secondary*; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000096:biosynthesis; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000401:mortality* / Q000473:pathology*; D016016:Proportional Hazards Models
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen
keywords: HIF-1 alpha index; brain metastases; ki67 proliferation index; microvascular density