Correlation of (18)F-fluoroethyl tyrosine positron-emission tomography uptake values and histomorphological findings by stereotactic serial biopsy in newly diagnosed brain tumors using a refined software tool

Abstract

Background: Magnetic resonance imaging (MRI) is the standard neuroimaging method to diagnose neoplastic brain lesions, as well as to perform stereotactic biopsy surgical planning. MRI has the advantage of providing structural anatomical details with high sensitivity, though histological specificity is limited. Although combining MRI with other imaging modalities, such as positron-emission tomography (PET), has proven to increment specificity, exact correlation between PET threshold uptake ratios (URs) and histological diagnosis and grading has not yet been described.

Objectives: The aim of this study was to correlate exactly the histopathological criteria of the biopsy site to its PET uptake value with high spatial resolution (mm(3)), and to analyze the diagnostic value of PET using the amino acid O-(2-[(18)F]fluoroethyl)-l-tyrosine ((18)F-FET) PET in patients with newly diagnosed brain lesions in comparison to histological findings obtained from stereotactic serial biopsy.

Patients and methods: A total of 23 adult patients with newly diagnosed brain tumors on MRI were enrolled in this study. Subsequently to diagnoses, all patients underwent a (18)F-FET PET-guided stereotactic biopsy, using an original newly developed software module, which is presented here. Conventional MRI, stereotactic computed tomography series, and (18)F-FET PET images were semiautomatically fused, and hot-spot detection was performed for target planning. UR was determined using the uptake value from the biopsy sites in relation to the contralateral frontal white matter. UR values ≥1.6 were considered positive for glioma. High-grade glioma (HGG) was suspected with URs ≥3.0, while low-grade glioma (LGG) was suspected with URs between 1.6 and 3.0. Stereotactic serial biopsies along the trajectory at multiple sites were performed in millimeter steps, and the FET URs for each site were correlated exactly with a panel of 27 different histopathological markers. Comparisons between FET URs along the biopsy trajectories and the histological diagnoses were made with Pearson product-moment correlation coefficients. Analysis of variance was performed to test for significant differences in maximum UR between different tumor grades.

Results: A total of 363 biopsy specimens were taken from 23 patients by stereotactic serial biopsies. Histological examination revealed eight patients (35%) with an LGG: one with a World Health Organization (WHO)-I lesion and seven with a WHO-II lesion. Thirteen (57%) patients revealed an HGG (two with a WHO-III and three with a WHO-IV tumor), and two patients (9%) showed a process that was neither HGG nor LGG (group X or no-grade group). The correlation matrix between histological findings and the UR revealed five strong correlations. Low cell density in tissue samples was found to have a significant negative correlation with the measured cortical uptake rate (r=-0.43, P=0.02), as well as moderate cell density (r=-0.48, P=0.02). Pathological patterns of proliferation (r=0.37, P=0.04), GFAP (r=0.37, P=0.04), and Olig2 (r=0.36, P=0.05) showed a significant positive correlation with cortical URs. Analysis of variance tests showed a significant difference between the LGG and the HGG groups (F=8.27, P<0.002), but no significant differences when differentiating between the X group and the HGG (P=0.2)/LGG (P=0.8) groups, nor between the no-grade group and the WHO-I group.

Conclusion: (18)F-FET PET is a valuable tool, as it allows the differentiation of HGGs from LGGs. Its use is not limited to preoperative evaluation; it may also refine biopsy targeting and improve tumor delimitation for radiotherapy. Histology is still necessary, and remains the gold standard for definitive diagnosis of brain lesions.

Keywords: 18F-FET PET-guided stereotactic biopsy; biopsy target; diagnostic and treatment management of cerebral gliomas; newly developed software module; newly diagnosed brain lesions; stereotactic serial biopsy.

Figure 1

¹⁸F-FET PET-guided stereotactic serial biopsy of a frontal lesion. Notes: Automatic hot-spot detection (+) and biopsy-trajectory planning with regard to blood vessels and eloquent brain areas. Circles indicate sites of biopsies with the possibility to exactly calculate URs. Due to MRI and PET findings, biopsy of two sites was performed. The first targeted the small contrast-enhancement area, whereas the second was aimed at the area of highest metabolic activity, which coincided with the largest lesion seen on MRI. Histological analysis from the first target showed a tumor relapse (fibrillary astrocytoma, UR 1.8) while the second revealed upgrading into an anaplastic astrocytoma (UR 3.5). Abbreviations: FET, fluoroethyl tyrosine; PET, positron-emission tomography; MRI, magnetic resonance imaging; UR, uptake ratio.

Figure 2

Automated hot-spot detection on surgical planning of ¹⁸FET PET-guided stereotactic serial biopsy. Notes: (A) 18-F FET-PET guided stereotactic serial biopsy of an insular lesion. The red line indicates the biopsy trajectory until the target point inside the contrast enhancing area. (B) The software allows image fusion between CT-MRI and FET PET. Biopsy target was achieved by means of an automated hot-spot detection system. Abbreviations: FET, fluoroethyl tyrosine; PET, positron-emission tomography; CT, computed tomography; MRI, magnetic resonance imaging.

Figure 3

Box-and-whisker plots displaying distribution and quartiles. Notes: Post hoc comparisons using Tukey’s honest significant-difference test for the first (A) and second (B) analysis of variance test results, and their 95% family-wise confidence intervals (C and D, respectively). (A) Mean URs of group L (LGG; mean 1.4, SD 0.56) was significantly different from group H (HGG; mean 2.28, SD 0.44), but not from group X (no-grade lesion; mean 1.65, SD 0.64). (B) There were no significant differences between mean URs of group 1 (WHO tumor grade I; mean 1), group 2 (WHO tumor grade II; mean 1.46, SD 0.57), group 3 (WHO tumor grade III; mean 1.95, SD 0.35), group 4 (WHO tumor grade IV; mean 2.35, SD 0.44) and group X, represented as “0” (no tumor grade; mean 1.65, SD 0.64). The mean score of group 4 was significantly different from that of group 2. Abbreviations: UR, uptake ratio; LGG, low-grade glioma; HGG, high-grade glioma; SD, standard deviation; WHO, World Health Organization.

Figure 4

¹⁸F-FET PET-guided stereotactic serial biopsy of a left frontal lesion. Notes: (A) CT + PET fusion. The green line indicates the biopsy trajectory until the target point inside the contrast-enhancing area. The anterosuperior part of the lesion showed the highest metabolic activity, and was thus selected as the target area. (B) Defining the target point with the automatic hotspot detection tool. (C) Sagittal and (D) axial views of CT-PET fusion. Abbreviations: FET, fluoroethyl tyrosine; PET, positron-emission tomography; CT, computer tomography.

Figure 5

FET PET-guided stereotactic biopsy. Notes: FET UR was retrospectively determined using the uptake value from the biopsy sites in relation to the contralateral frontal white matter. UR ≥1.6 was considered positive for glioma. High-grade glioma was suspected with UR ≥3.0, and low-grade glioma suspected with UR between 1.6 and 3.0. FET PET findings were compared to histological examinations. Abbreviations: FET, fluoroethyl tyrosine; PET, positron-emission tomography; UR, uptake ratio; R, right; L, left.

Figure 6

¹⁸F-FET PET-guided stereotactic serial biopsy of an insular lesion. Notes: The red line indicates the biopsy trajectory until the target point inside the contrast-enhancing area (A), which coincided with the area of highest metabolic activity in FET PET (B). Due to increased UR and contrast enhancement a high-grade glioma was suspected. Histological analysis, however, revealed the presence of a nonspecific inflammatory process. Abbreviations: FET, fluoroethyl tyrosine; PET, positron-emission tomography; UR, uptake ratio.

Figure 7

¹⁸F-FET PET-guided stereotactic serial biopsy of a frontal lesion. Notes: Due to the discordance between MRI and PET findings, biopsy of two sites were performed. The first targeted the contrast-enhancing area (A), and the second was aimed at the area of highest metabolic activity (D). (B) PET scan showed metabolic activity in the target chosen by contrast enhancement, however it was not the highest. Interestingly the target chosen by PET intake was invisible in the MRI as evidenced in (C). Histological analysis revealed the presence of a low-grade glioma. Specimens obtained from the PET-targeted area revealed an oligodendroglial component of the tumor, which differed from the other target, which presented predominantly an astroglial component. Abbreviations: FET, fluoroethyl tyrosine; PET, positron-emission tomography; MRI, magnetic resonance imaging.