Hypoxia, blood flow and metabolism in squamous-cell carcinoma of the head and neck: correlations between multiple immunohistochemical parameters and PET

BACKGROUND: The relationship between the uptake of [(18)F]fluoroerythronitroimidazole ([(18)F]FETNIM), blood flow ([(15)O]H(2)O) and 2-[(18)F]fluoro-2-deoxyglucose ([(18)F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC). METHODS: [(18)F]FETNIM and [(18)F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [(18)F]FETNIM was coupled with measurement of tumor blood flow using [(15)O]H(2)O. Uptake of [(18)F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [(18)F]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, VEGF(sc-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 [(18)F]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 [(18)F]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 (r(s) =0.553, p =0.040) and Ki-67 with HIF-1α (r(s) =506, p =0.065). p53 correlated inversely with GLUT-1 (r(s) = −618, p =0.019) and apoptosis with Ki-67 (r(s) = −638, p =0.014). CONCLUSIONS: A high uptake of [(18)F]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 [(15)O]H(2)O-PET and [(18)F]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.