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 [F-18]fluoroerythronitroimidazole ([F-18]FETNIM), blood flow ([O-15]H2O) and 2-[F-18]fluoro-2-deoxyglucose ([F-18]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC). Methods: [F-18]FETNIM and [F-18]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [F-18]FETNIM was coupled with measurement of tumor blood flow using [O-15]H2O. Uptake of [F-18]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [F-18] 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-1 alpha, 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 [F-18]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 [F-18]FDG SUV (p = 0.036). Patient outcome was associated with tumor macrophage content (p = 0.050), but not with the other biomarkers. HIF-1 alpha correlated with GLUT-1 (r(s) = 0.553, p = 0.040) and Ki-67 with HIF-1 alpha (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 [F-18]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 [O-15]H2O-PET and [F-18]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.