title: Hypoxia, blood flow and metabolism in squamous-cell carcinoma of the head and neck: correlations between multiple immunohistochemical parameters and PET.
abstract: BACKGROUND
  The relationship between the uptake of [18F]fluoroerythronitroimidazole ([18F]FETNIM), blood flow ([15O]H2O) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC).
  
  
  METHODS
  [18F]FETNIM and [18F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [18F]FETNIM was coupled with measurement of tumor blood flow using [15O]H2O. Uptake of [18F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [18F]FDG as standardized uptake value (SUV) and the metabolically active tumor volume (TV). Tumor biopsies were cut and stained for GLUT-1, Ki-67, p53, CD68, HIF-1α, VEGFsc-152, CD31 and apoptosis. The expression of biomarkers was correlated to PET findings and patient outcome.
  
  
  RESULTS
  None of the PET parameters depicting hypoxia and metabolism correlated with the expression of the biomarkers on a continuous scale. When PET parameters were divided into two groups according to median values, a significant association was detected between [18F]FDG SUV and p53 expression (p =0.029) using median SUV as the cut-off. There was a significant association between tumor volume and the amount of apoptotic cells (p =0.029). The intensity of VEGF stained cells was associated with [18F]FDG SUV (p =0.036). Patient outcome was associated with tumor macrophage content (p =0.050), but not with the other biomarkers. HIF-1α correlated with GLUT-1 (rs =0.553, p =0.040) and Ki-67 with HIF-1α (rs =506, p =0.065). p53 correlated inversely with GLUT-1 (rs = -618, p =0.019) and apoptosis with Ki-67 (rs = -638, p =0.014).
  
  
  CONCLUSIONS
  A high uptake of [18F]FDG expressed as SUV is linked to an aggressive HNSCC phenotype: the rate of apoptosis is low and the expressions of p53 and VEGF are high. None of the studied biomarkers correlated with perfusion and hypoxia as evaluated with [15O]H2O-PET and [18F]FETNIM-PET. Increased tumor metabolism evaluated with PET may thus signify an aggressive phenotype, which should be taken into account in the management of HNSCC.
authors.affiliation: Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6 A, FI-20520 Turku, Finland. tove.gronroos@utu.fi.
authors.forename: Tove J
authors.initials: TJ
authors.lastname: Grönroos
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehtiö
authors.forename: Karl-Ove
authors.initials: KO
authors.lastname: Söderström
authors.forename: Pauliina
authors.initials: P
authors.lastname: Kronqvist
authors.forename: Jukka
authors.initials: J
authors.lastname: Laine
authors.forename: Olli
authors.initials: O
authors.lastname: Eskola
authors.forename: Tapio
authors.initials: T
authors.lastname: Viljanen
authors.forename: Reidar
authors.initials: R
authors.lastname: Grénman
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.forename: Heikki
authors.initials: H
authors.lastname: Minn
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D019788:Fluorodeoxyglucose F18; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007150:Immunohistochemistry; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D015415:Biomarkers; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18