Correlation of [18F]FMISO autoradiography and pimonodazole immunohistochemistry in human head and neck carcinoma xenografts
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Tumour cell hypoxia is a common feature in solid tumours adversely affecting radiosensitivity and chemosensitivity in head and neck squamous cell carcinomas. Positron emission tomography (PET) using the tracer [18F]fluoromisonidazole ([18F]FMISO) is most frequently used for non-invasive evaluation of hypoxia in human tumours. A series of ten human head and neck xenograft tumour lines was used to validate [18F]FMISO as hypoxia marker at the microregional level.
Autoradiography after injection of [18F]FMISO was compared with immunohistochemical staining for the hypoxic cell marker pimonidazole in the same tumour sections of ten different human head and neck xenograft tumour lines. The methods were compared: first, qualitatively considering the microarchitecture; second, by obtaining a pixel-by-pixel correlation of both markers at the microregional level; third, by measuring the signal intensity of both images; and fourth, by calculating the hypoxic fractions by pimonidazole labelling.
The pattern of [18F]FMISO signal was dependent on the distribution of hypoxia at the microregional level. The comparison of [18F]FMISO autoradiography and pimonidazole immunohistochemistry by pixel-by-pixel analysis revealed moderate correlations. In five tumour lines, a significant correlation between the mean [18F]FMISO and pimonidazole signal intensity was found (range, r 2 = 0.91 to r 2 = 0.99). Comparison of the tumour lines with respect to the microregional distribution pattern of hypoxia revealed that the correlation between the mean signal intensities strongly depended on the microarchitecture. Overall, a weak but significant correlation between hypoxic fractions based on pimonidazole labeling and the mean [18F]FMISO signal intensity was observed (r 2 = 0.18, p = 0.02). For the three tumour models with a ribbon-like microregional distribution pattern of hypoxia, the correlation between the hypoxic fraction and the mean [18F]FMISO signal intensity was much stronger and more significant (r 2 = 0.73, p < 0.001) than for the tumours with a more homogenous, patchy, microregional distribution pattern of hypoxia.
Different patterns of [18F]FMISO accumulation dependent on the underlying microregional distribution of hypoxia were found in ten head and neck xenograft tumours. A weak albeit significant correlation was found between the mean [18F]FMISO signal intensity and the hypoxic fraction of the tumours. In larger clinical tumours, [18F]FMISO–PET provides information on the tumour oxygenation status on a global level, facilitating dose painting in radiation treatment planning. However, caution must be taken when studying small tumour subvolumes as accumulation of the tracer depends on the presence of hypoxia and on the tumour microarchitecture.
Keywords[18F]Fluoromisonidazole Pimonidazole Digital autoradiography Immunohistochemistry Hypoxia
This research was supported by EC FP6 funding (Biocare contract no. LSHC-CT-2004-505785) and by Junior Investigator Grant 2006-38 of the Radboud University Nijmegen Medical Centre, The Netherlands. We thank Dr. J. A. Raleigh for the gift of anti-pimonidazole MAb and Dr. H. J. J. M. Rennen for his kind support with the [18F]FMISO synthesis.
Conflict of interest statement
The authors have no conflict of interest.
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