[18F]Fludarabine-PET as a promising tool for differentiating CNS lymphoma and glioblastoma: Comparative analysis with [18F]FDG in human xenograft models

Abstract

This paper investigated whether positron emission tomography (PET) imaging with [¹⁸F]fludarabine ([¹⁸F]FDB) can help to differentiate central nervous system lymphoma (CNSL) from glioblastoma (GBM), which is a crucial issue in the diagnosis and management of patients with these aggressive brain tumors. Multimodal analyses with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), magnetic resonance imaging (MRI) and histology have also been considered to address the specificity of [¹⁸F]FDB for CNSL. Methods: Nude rats were implanted with human MC116 lymphoma-cells (n = 9) or U87 glioma-cells (n = 4). Tumor growth was monitored by MRI, with T2-weighted sequence for anatomical features and T1-weighted with gadolinium (Gd) enhancement for blood brain barrier (BBB) permeability assessment. For PET investigation, [¹⁸F]FDB or [¹⁸F]FDG (~11 MBq) were injected via tail vein and dynamic PET images were acquired up to 90 min after radiotracer injection. Paired scans of the same rat with the two [¹⁸F]-labelled radiotracers were investigated. Initial volumes of interest were manually delineated on T2w images and set on co-registered PET images and tumor-to-background ratio (TBR) was calculated to semi-quantitatively assess the tracer accumulation in the tumor. A tile-based method for image analysis was developed in order to make comparative analysis between radiotracer uptake and values extracted from immunohistochemistry staining. Results: In the lymphoma model, PET time-activity curves (TACs) revealed a differential response of [¹⁸F]FDB between tumoral and healthy tissues with average TBR varying from 2.45 to 3.16 between 5 to 90 min post-injection. In contrast, [¹⁸F]FDG demonstrated similar uptake profiles for tumoral and normal regions with TBR varying from 0.84 to 1.06 between these two time points. In the glioblastoma (GBM) model, the average TBRs were from 2.14 to 1.01 for [¹⁸F]FDB and from 0.95 to 1.65 for [¹⁸F]FDG. Therefore, inter-model comparisons showed significantly divergent responses (p < 0.01) of [¹⁸F]FDB between lymphoma and GBM, while [¹⁸F]FDG demonstrated overlap (p = 0.04) between the groups. Tumor characterization with histology (based mainly on Hoechst and CD79), as well as with MRI was overall in better agreement with [¹⁸F]FDB-PET than [¹⁸F]FDG with regard to tumor selectivity. Conclusions: [¹⁸F]FDB-PET demonstrated considerably greater specificity for CNSL when compared to [¹⁸F]FDG. It also permitted a more precise definition of target volume compared to contrast-enhanced MRI. Therefore, the potential of [¹⁸F]FDB-PET to distinguish CNSL from GBM is quite evident and will be further investigated in humans.

Keywords: CNS lymphoma; [18F]FDG; [18F]fludarabine-PET; differential diagnosis; glioblastoma.

Figure 1

Experimental paradigm of imaging sessions. The tumor growth was assessed by MRI at (A) days 7, 13 and 20 for the CNSL and (B) day 13 for the GBM model (laboratory-based experience). In both models, the PET(/CT) sessions with [¹⁸F]FDB and [¹⁸F]FDG were performed on two consecutive days. D0: inoculation day; euth: euthanasia.

Figure 2

Quantitative PET data of inter- and intra-model analysis. Radiotracer uptake (average 40-60 min) expressed as tumor-to-background ratio (TBR) for (A) [¹⁸F]FDB (combined results from two examinations: days 14 and 21) and (B) [¹⁸F]FDG. Horizontal lines indicate the median. Mean ± SD of TBR is indicated for each group and per radiotracer. ** p < 0.01, * p < 0.05 Mann Whitney test. (C) Comparative inter-tracer analysis in the CNSL model; the paired samples are connected with lines. ** p < 0.01 paired t-test. See Method 1 in Supplementary Material for data quantification.

Figure 3

Illustrations of representative PET and MRI scans. From left to right, corresponding planes of [¹⁸F]FDB-, [¹⁸F]FDG-PET (acquisition time 40-60 min), T2w- and T1w(Gd)-MRI (subtracted image resulting from post- minus pre-contrast frame) scans for the (A) CNSL and (B) GBM models.

Figure 4

PET and histological data. (A) Correlation of static analysis of the PET radiotracer uptake (average 40-60 min) and the density of CD79 staining; *** p < 0.001 t-test. (B) Relationship (Pearson's correlation r) between [¹⁸F]FDB-avid surface (active tumor area, ATA), MRI measurements and CD79-stained surface. *** p < 0.001, ** p < 0.01, ns p > 0.05. See Method 2 for (A) and Method 3 for (B) in Supplementary Material for data quantification. (C) From left to right, CD79-density image and the corresponding planes of [¹⁸F]FDB, [¹⁸F]FDG (acquisition time 40-60 min).

Figure 5

Representative microscopic (x 100 magnification) and macroscopic illustrations of CNSL. (A) H&E staining and (B) ex-vivo [¹⁸F]FDB autoradiography of the same tumor section and (C) CD79b staining of an adjacent section. Red arrow: lymphoid cells; white arrow: necrotic area.