Resolution in PET hypoxia imaging: Voxel size matters

INTRODUCTION: Tumor hypoxia adversely affects treatment outcome, especially in squamous cell carcinomas (SCCs). Image guided radiotherapy (IGRT) based on PET-generated tumor hypoxia maps allows dose boosting to hypoxic sub-volumes and has received considerable interest. However, the combination of slow oxygenation-dependent tracer retention, slow clearance of unbound tracer from non-hypoxic tissue and the necessity to average signal over large non-homogenous tissue areas due to the low PET resolution remains problematic. MATERIALS AND METHODS: To assess pitfalls inherent to low-resolution imaging we have analyzed the fine-scale distribution of a PET hypoxia tracer (autoradiograms) and tissue architecture (immunofluorescence microscopy) in sectioned experimental SCCs, and compared the results to those obtained when applying macroscopic averaging mimicking the resolution in clinical PET scanners. RESULTS AND DISCUSSION: We show that tumor areas that would be classified as non-hypoxic based on simple PET threshold identification, often contains foci of hypoxic cells, in particular in tumors where necrosis and severely hypoxic cells are intermixed. In contrast, in a non-necrotic tumor model we found that the risk of missing hypoxic cells was greatly reduced, however, its patchy hypoxic pattern made a clear delineation of a target to boost unfeasible. We discuss the implications of these and other complicating factors in PET hypoxia-imaging and outline future strategies to overcome or circumvent them.