Combining amide proton transfer-weighted and arterial spin labeling imaging to differentiate solitary brain metastases from glioblastomas

doi:10.21203/rs.3.rs-2728624/v1

This study aimed to evaluate the clinical utility of amide proton transfer-weighted imaging (APTw) and arterial spin labeling (ASL) in differentiating solitary brain metastases (SBMs) from glioblastomas (GBMs). All patients underwent conventional MRI, APTw, and ASL scans on a 3.0 T MRI system. The mean APTw value and mean cerebral blood flow (CBF) value were measured. The differences in various parameters between GBMs and SBMs were assessed using the independent-samples t test. The quantitative performance of these MRI parameters in distinguishing between GBMs and SBMs was evaluated using receiver operating characteristic (ROC) curve analysis. Our results showed that GBMs exhibited significantly higher APTw and CBF values in peritumoral regions compared with SBMs (P<0.05). There was no significant difference between SBMs and GBMs in tumor cores. APTw MRI had a higher diagnostic efficiency in differentiating SBMs from GBMs (AUC: 0.864; 75.0% sensitivity and 81.8% specificity). Combined use of APTw and CBF value increased the AUC to 0.927. In conclusion, APTw may be superior to ASL for distinguishing between SBMs and GBMs. Combination of APTw and ASL showed better discrimination and a superior diagnostic performance.

Health sciences/Diseases

Health sciences/Diseases/Cancer

Health sciences/Diseases/Cancer/Cancer imaging

Adult glioblastomas and brain metastases are the most common malignant tumors of the central nervous system and are associated with high recurrence and mortality rate¹. The prevalence of these two malignancies has shown an increasing trend in recent decades². Distinguishing between solitary brain metastases (SBMs) and glioblastomas (GBMs) prior to treatment is of immense clinical significance owing to its implications for therapeutic decision-making and follow-up³. Nonsurgical therapy is preferred over traditional surgical resection for management of metastases⁴. However, in the vast majority of cases with clinically and radiographically suspected GBMs, surgical resection followed by temozolomide-based chemoradiotherapy is the standard approach⁵. Additionally, both tumors typically present as heterogeneously enhanced masses surrounded by significant peritumoral edema. The similar imaging findings of GBMs and metastases on conventional magnetic resonance imaging and post contrast T1-weighted images pose a great diagnostic challenge. Therefore, numerous studies have utilized advanced imaging techniques to differentiate SBMs from GBMs, including chemical exchange saturation transfer (CEST)⁶, magnetic resonance spectroscopy (MRS)^{7, 8}, diffusion-weighted imaging (DWI)^{9, 10}, and perfusion imaging (PWI)¹¹. However, these reports have mixed results for distinguishing between these two types of tumors. Hence, further studies of non-invasive imaging modalities are necessary to improve the diagnosis accuracy.

Proton transfer-weighted (APTw) imaging, a particular type of CEST technique, is used to demonstrate the exchangeable mobile proteins and peptides at low concentrations^{12, 13}, and a radio-frequency pulse is applied at the resonant frequency of 8.3 ppm to allow the exchange of amide protons with bulk water particles¹⁴, which enables indirect signal intensity acquisition. The APT value was shown to increase with the concentration of mobile proteins and peptides¹⁵, which was unrelated to gadolinium enhancement. Arterial spin labeling (ASL) perfusion imaging is one of the methods for diagnosis of malignant tumors^{16, 17}. It has a high sensitivity for evaluating microvascular proliferation in the tumor using an endogenous intravascular tracer-hydrogen nuclei in blood and allows for the measurement of CBF values in brain tissue¹⁸. Recent clinical studies have demonstrated the usefulness of APTw and CBF values for evaluating brain tumors, including glioma^{19, 20}, meningioma²¹, lymphoma^{22, 23}, and other systemic neoplasms^{12, 24}. However, to the best of our knowledge, there are no reports comparing the diagnostic performance of APTw and ASL MRI in differentiating SBMs and GBMs. In this study, APTw and ASL imaging were compared to identify which method is superior for distinguishing SBMs from GBMs.

Study population. This study was approved by the ethics committee of Liuzhou Workers Hospital, The Fourth Affiliated Hospital of Guangxi Medical University of China. This study was conducted from January 2021 to October 2022. Eighty-nine consecutive patients with brain tumors that were detected primarily on CT or MRI were collected. Of these, six patients were excluded due to motion artifacts (n = 2) and other histopathologic diagnoses (n = 4). Finally, 40 cases of glioblastomas (22 males, 18 females; mean age, 56.5 ± 14.0 years [range, 22–72]) and 43 cases of brain metastases (25males, 18 females; mean age, 62.7 ± 12.6 years [range 38–77]) were enrolled in this study. Surgical resection or stereotactic biopsy were used to confirm histopathology in all patients with GBMs and 20 with SBMS; the remaining 23 patients had a history of primary cancer (n = 8) and had MRI follow-ups (n = 15). The primary lesions were lung cancer (n = 25), liver cancer (n = 8), and breast cancer (n = 10).

MRI protocol. All patients underwent conventional MRI, APTw, and ASL scans on a 3.0 T MRI system (Ingenia CX, Philips Medical Systems, Best, The Netherlands). A 32-channel head coil was used to perform the MRI scans. The conventional MRI sequences included T1WI (TR = 1980 ms, TE = 19 ms, FOV = 24×24 cm, section thickness = 4 mm, NEX = 1, matrix = 256×256), T2WI (TR = 1980 ms, TE = 19 ms, FOV = 240×240 mm², section thickness = 4 mm, NEX = 1, matrix = 256×256) and T2 fluid-attenuated inversion recovery (FLAIR) imaging (TR = 1980 ms, TE = 19 ms, FOV = 240×240 mm², section thickness = 4 mm, NEX = 1, matrix = 256×256) sequences. After intravenous injection of Gadoterate meglumine (0.2 mL/kg body weight, at a flow rate of 2 mL/second) through the median cubital vein, post contrast T1-weighted images were obtained.

In addition, the following parameters were utilized for the whole brain three-dimensional pseudocontinuous ASL (3D PCASL) sequence prior to the injection of contrast medium: post labeling delay = 1.5s, TR = 4.4 s, TE = 9.2 ms, acquisition matrix = 8 arms with 512 spiraling points, NEX = 3, section thickness = 32 mm, FOV = 240×240 mm², band width = 62.5, plane = axial). The total scan time was 4 minutes.

Three-dimensional APTw (3D APTw) imaging was carried out using a multiple source transmitting technology, which has the potential to both extend the radio frequency saturation time and boost APT efficiency. 3D mDIXON TSE sequence was used. The radio frequency pulse's saturation map and the unsaturated saturation map before the Gd-T1 weighted image can be used to calculate APTw. APTw refers to asymmetry in the magnetization transfer ratio at 3.5 ppm offsets from saturation frequency:

where Ssat (-3.5ppm), Ssat (+ 3.5ppm), and S₀ are the signal intensities obtained at -3.5, + 3.5, and − 1560 ppm, respectively. The acquisition parameters were: TR = 1980 ms, TE = 19 ms, FOV = 240×240 mm², section thickness = 4 mm, NEX = 1, matrix = 256×256, voxel size = 1.65×3.15×6.00 mm³; the total scan time was 192 ms.

Image processing and analysis. Image processing was performed on the workstation using a commercially-available software (Ingenia, Philips Medical Systems, CX, Intellispace Portal 10.1) which automatically generates the APT-weight images. The arterial spin labeling mapping was created by subtracting the unlabeled image from the labeled image. All MRI data were examined for tumor location, heterogeneity, peritumoral edema, and contrast-enhancement pattern by two neuroradiologists (nine and ten years of expertise, respectively) who were blinded to the histopathological results. The region with the largest area of tumor core was chosen for the manually drawn region of interest (ROI). Six ROIs (area 0.50 cm²) were placed within the tumor core area (including enhanced or unenhanced regions). A copy of the ROI was manually placed within the contralateral normal appearing white matter (CNAWM) and the peritumoral high-intensity brain zone (PBZ). Each ROI had a 20-pixel size. We excluded parts of the lesion that were cystic, necrotic, or bleeding to minimize error. The APTw and CBF values for each ROI were recorded for each patient. Subsequently, the mean APTw value and the mean CBF value were determined. To minimize the error, we also logged relative APTw (rCBF) and relative CBF (rCBF).

Statistical analysis. SPSS 27.0 software was used for statistical analyses. The sex distributions in the GBMs and SBMs groups were compared using the Mann-Whitney U test, while the mean age, APTw, rAPTw, CBF, and rCBF values were compared using the independent samples t test. The diagnostic efficacy of the parameters for distinguishing GBMs from SBMs was evaluated using ROC curve analysis. The AUC of these parameters were evaluated. AUC values are compared using a nonparametric method. Additionally, binary logistic regression analysis was utilized to determine whether any pairwise combination of parameters could increase the diagnostic performance. P value < 0.05 was considered to be statistically significant.

Comparison of conventional MRI, APTw and ASL images

For the 43 SBMs cases (43 lesions), lesions were located in the frontal (n=6), parietal (n=18), temporal (n=7), basal ganglia regions (n=5), and the cerebellar hemisphere (n=7). Sixteen cases showed mild edema, 8 cases showed moderate edema, and 17 cases showed severe edema. On the Gd-T1WI sequence, tumors displayed ring-like (n=28) and nodular (n=15) enhancement. In forty cases, the tumor cores showed hyperintensities on the ASL images, and the hyperintense areas were roughly equivalent to the lesions observed on the APTw and Gd-T1WI sequences. Besides, there were three cases with low signals on the ASL images, which was contrary to the high signal shown by APTw and Gd-T1WI.

For the 40 GBMs cases (40 lesions), the lesions were located in the frontal lobe (n=19), parietal lobe (n=7), temporal lobe (n=11), basal ganglia region (n=1), and the cerebellar hemisphere (n=2). The corpus callosum was invaded by three frontal lesions. Eight cases showed no edema, 7 cases showed mild edema, 15 cases showed moderate edema, and 10 cases showed severe edema. The Gd-T1WI sequence showed ring-like (n=15), nodular (n=9), and patchy (n=16) enhancement in tumors. In all cases, the tumor cores displayed heterogenous hyperintensities on APTw and ASL images. The areas of two diffuse infiltrating lesions identified by the APTw image were larger than those identified by the ASL and Gd-T1WI. Fig. 1 shows the findings of a patient with SBM, and Fig. 2 shows the findings of a patient with GBM.

Quantitative APTw and ASL imaging analysis

There was no significant difference between GBMs and SBMs groups with respect to sex or age (P=0.651, 0.908, respectively). The APTw and CBF values in tumor core and peritumoral part for the GBMs and SBMs groups are compared in Table 1 and Fig. 3 (a and b). The GBMs group had significantly higher APTw and rAPTw values in peritumoral part than in the SBMs group (1.906±0.512 vs. 1.195±0.351, P<0.001, P=0.002, respectively). The CBF and rCBF values of the peritumoral parts for GBMs and SBMs were 18.78±4.77 (mL/100 g/minute) and 13.73±5.06 (mL/100 g/minute), 2.34±1.54 and 1.36±0.65, with significant difference (P=0.002 and 0.004, respectively). There were no significant between-group differences with respect to any of the tumor core parameters (P>0.05).

The results of ROC curve analysis showing the diagnostic performance of the parameters in peritumoral parts are shown in Table 2. The APTw value had the greatest area under the ROC curve (AUC=0.864). APTw value > 1.54% had a 75% sensitivity and 81.8% specificity for the diagnosis of GBM. A significant difference in each pairwise comparison was observed in Table 3 (P < 0.001). Use of the combination of APTw and CBF increased the AUC value to 0.927 (Fig. 4).

Statement. The institutional review board approved this retrospective study and informed consent was waived. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

In the present study, there was no significant difference between SBMs and GBMs with respect to sex or age, although male sex is a risk factor for these two tumor types. This finding was consistent with a previous study²⁵. Both SBMs and GBMs showed the highest intensity in the tumor core, followed by peritumoral edema, compared to the CNAWM. On ROC curve analysis, APTw MRI was found to have a higher diagnostic efficiency in differentiating SBMs from GBMs (AUC=0.864). When used in combination with ASL, the AUC increased to 0.927. To the best of our knowledge, this is the first study to investigate the use of combination of APTw and ASL imaging for differentiating SBMs from GBMs. Our result reveals that APTw may be superior to ASL for distinguishing SBMs and GBMs, and the combination of both techniques demonstrated a more satisfactory discrimination and a superior diagnostic performance.

In our research, the APTw and CBF values in tumor core could not provide useful information to distinguish between GBMs and SBMs. These two parameters are related to different pathophysiological background but have their own advantages. As malignant tumors, SBMs and GBMs have rapid cell proliferation and microvascular hyperplasia²⁵. In previous studies, APTw signal intensity showed a significant positive correlation with cellularity and proliferation index^{15, 26, 27}. Other reports suggested that ASL is a sensitive modality for detecting hyper vascularity and blood perfusion of the tumor²³. According to those points, we posited that the absence of difference in APTw and ASL parameters between SBMs and GBMs could be attributed to similar degree of cell hyperplasia and microvascular hyperplasia in the tumor core. However, unlike in the tumor core, there were significant differences in peritumoral parts between the two groups, which was partially consistent with the findings of previous studies^{6, 28, 29}. Different pathophysiological changes in the peritumoral parts may be mainly responsible for the significant difference between these two tumors^{30, 31}. Peritumoral hyperintensity in GBM is caused by tumor cells infiltrating into the surrounding brain tissue through the damaged blood-brain barrier, while peritumoral edema in SBM is simply vasogenic edema caused by tumor compression of veins^{32, 33}. This may explain why APTw and ASL were found to be more sensitive to peritumoral edema than tumor core in our study.

We discovered that both APTw and ASL imaging showed excellent performance in identifying the heterogenous hyperintensities. According to related published reports, the most active portion of the tumor, where there may be more tumor cells and vascular components, is charactered by heterogeneous hyperintensity^{34, 35}. Signal intensity may be a reflection of significant changes in amino acid concentrations and an overall upregulation of protein expression in more aggressive brain tumors, as these patients are more likely to progress quickly and live shorter^{36, 37}. In our study, we also found that the heterogenous areas of two diffuse infiltrating GBM lesions identified by APTw imaging were larger than those identified by ASL and Gd-T1WI. In this regard, APTw images may be more sensitive in identifying regions of high invasiveness within heterogeneous GBMs.

Compared with previous reports^{26, 38}, we used a three-dimensional APTw sequence with multi-source emission technology to greatly extend the RF saturation time (2 s) to improve the characterization of heterogeneous tumors and their surrounding tissues and enhance the APTw contrast. Furthermore, we measured a total of six ROIs in enhanced and non-enhanced areas at the largest layer of each lesion, unlike in previous studies in which the ROIs were measured only in the enhanced areas. However, roughly 10 percent of GBMs demonstrate no enhancement²³. Moreover, tumor enhancement only indicates the destruction of the tumor blood-brain barrier and non-enhanced areas also contain important tumor information³⁸. Therefore, our measurements maximized the coverage of all tumor information, resulting in more comprehensive and reliable data.

Some limitations of this study should be considered while interpreting the results. First, the sample size was small. We did not further analyze the SBMs according to the different primary sites or pathological types. Future studies should examine this aspect in larger cohorts. Second, in this work, the diagnostic efficacy of APTw and ASL was evaluated using a straightforward statistical analysis. However, a more sophisticated multiple regression analysis may provide more robust results. Third, this study was unable to quantitatively analyze the MRI information of tumors in other layers because we only selected a single slice with the largest area for manual measurement of the ROI.

In conclusion, APTw may be superior to ASL for distinguishing between SBMs and GBMs. Combination of APTw and CBF values demonstrated a more satisfactory discrimination and a higher diagnostic performance.

Data availability

All available data is presented in the manuscript.

Acknowledgements

This study was partially supported by grants from Guangxi Liuzhou Science and Technology Planning Project (2021CBC0128), Guangxi Zhuang Autonomous Region self-funded project (Z20210919).

Author contributions

C.L. and L.Y. wrote the main manuscript text and L.S.H. and Z.J.H. prepared figures 1-4. L.T. conceived the study. Z.Z.S. and Z.L. reviewed the literature and provided the idea of the study. H.L.Z., T.L.F. and W.M. performed the statistical analysis and interpreted the results. All authors reviewed the manuscript.

Competing interests

The authors declare no competing interests.

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Table 1 Parameters of the tumor core and peritumoral part in GBMs and SBMs.

Parameters	Tumor core	P	Peritumoral part	P
	GBMs SBMs		GBMs SBMs
APTw	2.92±0.73 2.50±0.62	0.053	1.91±0.51 1.20±0.35	<0.001
rAPTw	4.64±2.67 3.35±2.18	0.092	3.86±2.10 2.08±1.22	0.002
CBF	37.45±12.34 31.48±10.63	0.100	18.78±4.77 13.73±5.06	0.002
rCBF	3.83±1.95 3.09±2.44	0.292	2.34±1.54 1.36±0.65	0.009

Table 2 Results of ROC curve analysis based on APTw and ASL MRI in peritumoral part of SBMs and GBMs.

Parameters	AUC	95% CI	P	Cut-off	Sensitivity	Specificity
APTw	0.864	0.76–0.97	0.000	1.54	75.0	81.8
rAPTw	0.805	0.67–0.94	0.015	2.41	80.0	68.2
CBF	0.743	0.60–0.89	0.007	15.42	80.0	63.6
rCBF	0.720	0.57–0.88	0.015	1.49	65.0	72.7

Table 3 The combination of various parameters in peritumoral part

Parameters	AUC	P
APTw, rAPTw	0.870	0.000
APTw, CBF	0.927	0.000
APTw, rCBF	0.911	0.000
rAPTw, CBF	0.886	0.000
rAPTw, rCBF	0.893	0.000
CBF, rCBF	0.780	0.002

No competing interests reported.

Combining amide proton transfer-weighted and arterial spin labeling imaging to differentiate solitary brain metastases from glioblastomas

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Abstract

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Introduction

Materials And Methods

Results

Discussion

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