Tumour microenvironment heterogeneity affects the perceived spatial concordance between the intratumoural patterns of cell proliferation and 18F-fluorothymidine uptake

Abstract

Background and purpose PET imaging with 18F-fluorothymidine (18F-FLT) can potentially be used to identify tumour subvolumes for selective dose escalation in radiation therapy. The purpose of this study is to analyse the co-localization of intratumoural patterns of cell proliferation with 18F-FLT tracer uptake. Materials and methods Mice bearing FaDu or SQ20B xenograft tumours were injected with 18F-FLT, and bromodeoxyuridine (proliferation marker). Ex vivo images of the spatial pattern of intratumoural 18F-FLT uptake and that of bromodeoxyuridine DNA incorporation were obtained from thin tumour tissue sections. These images were segmented by thresholding and relative operating characteristic (ROC) curves and Dice similarity indices were evaluated. Results The thresholds at which maximum overlap occurred between FLT-segmented areas and areas of active cell proliferation were significantly different for the two xenograft tumour models, whereas the median Dice values were not. However, ROC analysis indicated that segmented FLT images were more specific at detecting the proliferation pattern in FaDu tumours than in SQ20B tumours. Conclusion Highly dispersed patterns of cell proliferation observed in certain tumours can affect the perceived spatial concordance between the spatial pattern of 18F-FLT uptake and that of cell proliferation even when a high-resolution ex vivo autoradiography imaging is used for 18F-FLT imaging.

Proliferation PET Image to Characterize Pathological Spatial Features in Patients With Non-Small Cell Lung Cancer: A Pilot Study

“…We can only got a highly consistent distribution in less than half of the patients. However, Esther found a weak correlation between 18 F-FLT uptake and Ki-67 staining intensity in oral cavity tumors [18], and Marian Axente demonstrated that higher 18 F-FLT uptake was co-localized with the areas of active proliferation in FaDu tumor models [20]. Besides, many previous studies have demonstrated that 18 F-FLTstandard uptake value had a signification correlation with the tumor cell proliferation.…”

An alternative approach to histopathological validation of PET imaging for radiation therapy image-guidance: A proof of concept

“…3A), was analysed utilising overlap analysis described in a previous work [8]. In summary, for each unique activity value found inside the volume defined by the whole tumour mask, the sPET image was thresholded obtaining a distinct segmentation 3D volume.…”

“…However, the chaotic morphology of cancer tissue results in spatial variations of microenvironment and relevant biological characteristics on a much smaller scale (<250–300 μm) as indicated by histopathology studies [3–7]. When PET imaging is used to guide the delivery of radiotherapy, inherent averaging effects can significantly alter the resulting images [8–10], making it necessary to demonstrate the spatial coincidence between the pattern of tracer uptake as seen in PET images and the pattern of the underlying biological parameter of interest. Therefore, for any PET tracer or segmentation method, validation of PET imaging for image guidance in radiotherapy requires an approach that allows one to test spatial colocalisation of the regions of high tracer uptake, as segmented from PET images, with the spatial distribution of the biological/ morphological features of interest.…”

A method for comparing intra-tumoural radioactivity uptake heterogeneity in preclinical positron emission tomography studies

“…Although the fact that heterogeneity has an impact on quantifications performed has been recognised in many studies (e.g. [ 14 , 15 , 33 ]), methods for estimating specifically the intra-tumoural uniformity in preclinical tumours are not yet, to our knowledge, available.…”