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

Figures & data

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.

Table 1 Correlation matrix between histopathological findings and FET uptake values

Sample	Findings	Correlation (r)	P-value (one-sided)
1	Coagulated blood	−0.08	0.37
2	Diapedesis/bleeding	0.23	0.30
3	Acute hemorrhage	−0.13	0.28
4	Exudate	0.09	0.35
5	Only edema	0.13	0.28
6	Gliosis	−0.23	0.15
7	Tissue-infiltration zone	0.17	0.22
8	Low cell density	−0.43	0.02*
9	Moderate cell density	−0.48	0.02*
10	Strong cell density	0.10	0.33
11	Pathological pattern of proliferation	0.37	0.04*
12	Prominent blood vessels	0.17	0.22
13	Mitosis	0.22	0.16
14	Necrosis	0.30	0.08
15	GFAP	0.37	0.04*
16	NogoA	−0.02	0.47
17	MAP2	−0.23	0.15
18	Olig2	0.36	0.05*
19	p53	−0.33	0.06
20	Tibor PAP silver impregnation for reticulin	−0.20	0.17
21	Vimentin	0.01	0.48
22	Strong gliosis	0.13	0.28
23	CNS with cell proliferation	0.04	0.43
24	Macrophages	0.04	0.42
25	LFP- or PAS-positive myelin	0.04	0.43
26	Reactive changes	−0.02	0.46
27	Lymphocyte infiltrates (TILs)	0.01	0.48

Note:

* P<0.05.

Abbreviations: PAP, peroxidase–antiperoxidase; CNS, central nervous system; LFP, lateral fluid percussion; PAS, periodic acid–Schiff; TILs, tumor-infiltrating lymphocytes; FET, fluoroethyl tyrosine; GFAP, glial fibrillary acidic protein; MAP2, microtubule-associated protein 2; p53, Proteina tumorale 53.

Table 2 The first one-way analysis of variance test²³ was used to evaluate differences in cortical uptake rate among three different grades of brain lesions (low-grade glioma, high-grade glioma, and no grade)

ANOVA 1	df	Sum of squares	Mean square	F*	P-value
Treatment	2	4.037	2.019	8.27	0.002
Residuals	20	4.882	0.244

Note:

* Snedecor distribution.

Table 3 Tukey’s honest significant difference comparisons for analysis of variance 1

	Mean difference	Lower bound	Upper bound	P-value
LGG vs group X	−0.25	−1.238	0.738	0.8
HGG vs group X	0.635	−0.315	1.584	0.233
HGG vs LGG	0.885	0.323	1.446	0.002

Notes: Mean score of LGG group (1.4, SD 0.56) significantly different from HGG group mean (2.28, SD 0.44); mean score of group X (no-grade lesion; 1.65, SD 0.64) not significantly different from HGG group or LGG group.

Abbreviations: LGG, low-grade glioma; HGG, high-grade glioma; SD, standard deviation.

Table 4 The second one-way analysis of variance test²³ was used to evaluate differences in cortical uptake rate among five different grades of brain lesions (WHO-I, -II, -III, -IV, and no-grade group)

	df	Sum of squares	Mean square	F*	P-value
Treatment	4	4.485	1.121	4.551	0.01
Residuals	18	4.434	0.246

Note:

* Snedecor distribution.

Abbreviation: WHO, World Health Organization.

Table 5 Tukey’s honest significant difference comparisons for analysis of variance 2

Groups	Mean difference	Lower bound	Upper bound	P-value
1–X	−0.65	−2.488	1.188	0.82
2–X	−0.193	−1.396	1.01	0.988
3–X	0.3	−1.201	1.801	0.973
4–X	0.695	−0.458	1.849	0.392
2–1	0.457	−1.147	2.062	0.907
3–1	0.95	−0.888	2.788	0.538
4–1	1.345	−0.222	2.913	0.113
3–2	0.493	−0.71	1.696	0.73
4–2	0.888	0.163	1.614	0.012
4–3	0.395	−0.758	1.549	0.835

Notes: Mean score of group 1 (WHO-I; 1) not significantly different from group 2 (WHO-II; 1.46, SD 0.57), group 3 (WHO-III; 1.95, SD 0.35), group 4 (WHO-IV; 2.35, SD 0.44), or group X (1.65, SD 0.64).

Abbreviations: WHO, World Health Organization; SD, standard deviation.

Table S1 Histopathological findings, classified and clustered

No	Findings	samples	Total samples	Samples/total (%)	UR average	UR SD	WHO-I	WHO-II	WHO-III	WHO-IV	Other	LGG	HGG	Patients	All Patients	Patients/all patients (%)
1	Coagulated blood	12	363	3	1.4	0.5	0	0	Yes	Yes	0	0	Yes	4	23	17
2	Diapedesis bleeding	49	363	13	1.8	0.6	0	Yes	Yes	Yes	Yes	Yes	Yes	12	23	52
3	Acute hemorrhage	27	363	7	1.4	0.6	0	Yes	Yes	Yes	Yes	Yes	Yes	8	23	35
4	Exudate	3	363	1	1.4	0.4	0	0	0	Yes	0	0	Yes	1	23	4
5	Only edema	2	363	1	1.9	0.1	0	0	0	Yes	0	0	Yes	1	23	4
6	Gliosis	3	363	1	0.8	0	0	0	0	0	Yes	0	0	1	23	4
7	Tissue-infiltration zone	25	363	7	1.6	0.6	Yes	Yes	Yes	Yes	Yes	Yes	Yes	10	23	43
8	Small cell presence	69	363	19	1.1	0.6	Yes	Yes	Yes	Yes	0	Yes	Yes	10	23	43
9	Moderate cell presence	77	363	21	1.2	0.6	Yes	Yes	Yes	Yes	0	Yes	Yes	14	23	61
10	Strong cell presence	74	363	20	1.7	0.6	Yes	Yes	Yes	Yes	0	Yes	Yes	12	23	52
11	Pathologic pattern of proliferation	45	363	12	1.9	0.6	0	0	0	Yes	0	0	Yes	9	23	39
12	Prominent blood vessels	3	363	1	2.3	0.5	0	0	Yes	Yes	0	0	Yes	2	23	9
13	Mitosis	24	363	7	1.9	0.5	0	0	Yes	Yes	0	0	Yes	7	23	30
14	Necrosis	34	363	9	1.9	0.6	0	0	0	Yes	0	0	Yes	10	23	43
15	GFAP	23	363	6	1.5	0.6	Yes	Yes	Yes	Yes	Yes	Yes	Yes	21	23	91
16	NogoA	2	363	1	1.5	0.6	0	Yes	0	0	0	Yes	0	2	23	9
17	MAP2	3	363	1	1.2	0.6	0	Yes	0	0	0	Yes	0	3	23	13
18	Olig2	17	363	5	2.2	0.6	0	0	0	Yes	0	0	Yes	2	23	9
19	p53	15	363	4	1.3	0.6	Yes	Yes	Yes	Yes	Yes	Yes	Yes	11	23	48
20	Tibor PAP silver impregnation for reticulin	13	363	4	1.3	0.6	0	Yes	0	Yes	0	Yes	Yes	5	23	22
21	Vimentin	2	363	1	1.5	0.2	0	Yes	0	Yes	0	Yes	Yes	2	23	9
22	Strong gliosis	3	363	1	2	0.1	0	Yes	0	0	0	Yes	0	1	23	4
23	CNS with cell proliferation	9	363	2	1.6	0.6	0	Yes	Yes	0	Yes	Yes	Yes	4	23	17
24	Macrophages	7	363	2	1.6	0.6	0	Yes	Yes	0	Yes	Yes	Yes	4	23	17
25	LFP- or PAS positive myelin	5	363	1	1.8	0.6	0	Yes	0	0	0	Yes	0	2	23	9
26	Reactive changes	7	363	2	1.3	0.6	0	0	Yes	0	Yes	0	Yes	2	23	9
27	Lymphocyte infiltrates (TILs)	6	363	2	1.3	0.6	0	0	Yes	0	Yes	0	Yes	2	23	9

Abbreviations: UR, uptake ratio; SD, standard deviation; LGG, low-grade glioma; HGG, high-grade glioma; WHO, World Health Organization; PAP, peroxidase–antiperoxidase; CNS, central nervous system; LFP, lateral fluid percussion; PAS, periodic acid–Schiff; TILs, tumor-infiltrating lymphocytes; No, number.

Table S2 Analysis of variance (descriptive per group)

Tumor grade	UR average	UR median	UR SD
WHO-I	0.68	0.6	0.18
WHO-II	1.34	1.18	0.53
WHO-III	1.26	1.22	0.46
WHO-IV	1.87	1.89	0.52
Other	1.34	1.21	0.52
LGG	1.18	1.06	0.55
HGG	1.7	1.68	0.57
All	1.5	1.52	0.61

Abbreviations: UR, uptake ratio; SD, standard deviation; WHO, World Health Organization; LGG, low-grade glioma; HGG, high-grade glioma.

WessaPFree Statistics Software, Office for Research Development and Education, version 1.1.23-r72015 Avaiable from: http://www.wessa.net/

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