In vivo imaging of cell proliferation in meningioma using 3'-deoxy-3'-[18F]fluorothymidine PET/MRI

Abstract

Purpose: Positron emission tomography (PET) with 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT) provides a noninvasive assessment of tumour proliferation in vivo and could be a valuable imaging modality for assessing malignancy in meningiomas. We investigated a range of static and dynamic [¹⁸F]FLT metrics by correlating the findings with cellular biomarkers of proliferation and angiogenesis.

Methods: Seventeen prospectively recruited adult patients with intracranial meningiomas underwent a 60-min dynamic [¹⁸F]FLT PET following surgery. Maximum and mean standardized uptake values (SUV_max, SUV_mean) with and without normalization to healthy brain tissue and blood radioactivity obtained from 40 to 60 min summed dynamic images (PET_40-60) and ~ 60-min blood samples were calculated. Kinetic modelling using a two-tissue reversible compartmental model with a fractioned blood volume (V_B) was performed to determine the total distribution volume (V_T). Expressions of proliferation and angiogenesis with key parameters including Ki-67 index, phosphohistone-H3 (phh3), MKI67, thymidine kinase 1 (TK1), proliferating cell nuclear antigen (PCNA), Kirsten RAt Sarcoma viral oncogene homolog (KRAS), TIMP metallopeptidase inhibitor 3 (TIMP3), and vascular endothelial growth factor A (VEGFA) were determined by immunohistochemistry and/or quantitative polymerase chain reaction.

Results: Immunohistochemistry revealed 13 World Health Organization (WHO) grade I and four WHO grade II meningiomas. SUV_max and SUV_mean normalized to blood radioactivity from PET_40-60 and blood sampling, and V_T were able to significantly differentiate between WHO grades with the best results for maximum and mean tumour-to-whole-blood ratios (sensitivity 100%, specificity 94-95%, accuracy 99%; P = 0.003). Static [¹⁸F]FLT metrics were significantly correlated with proliferative biomarkers, especially Ki-67 index, phh3, and TK1, while no correlations were found with VEGFA or V_B. Using Ki-67 index with a threshold > 4%, the majority of [¹⁸F]FLT metrics showed a high ability to identify aggressive meningiomas with SUV_mean demonstrating the best performance (sensitivity 80%, specificity 81%, accuracy 80%; P = 0.024).

Conclusion: [¹⁸F]FLT PET could be a useful imaging modality for assessing cellular proliferation in meningiomas.

Keywords: Ki-67 index; Meningioma; Thymidine kinase 1; [18F]FLT.