The value of adding DWI and FLAIR signal changes in the resection cavity on the diagnostic performance of BT-RADS category 3 for tumor progression prediction in post-treated glioma patients: a prospective pilot study
Egyptian Journal of Radiology and Nuclear Medicine volume 54, Article number: 52 (2023)
BT-RADS is a structured reporting system of post-treatment glioma. BT-RADS category 3 carries a probability of recurrent malignancy versus treatment-related changes. The aim of this study is to evaluate the additive value of DWI and resection cavity FLAIR signal changes to BT-RADS category 3 in the prediction of tumor progression. We prospectively evaluated follow-up contrast-enhanced MR imaging where 27 post-treated glioma patients were assigned BT-RADS category 3. In all images, FLAIR signal, enhancement component, mass effect, and ADCmean were assessed. We used imaging follow-up from the second stage of the study as the gold standard for comparing the diagnostic performance of BT-RADS category 3 for predicting tumor recurrence before and after the addition of DWI and resection cavity FLAIR signal changes. ROC curves analyses were assessed and compared using the Delong test.
48.1% of patients had tumor recurrence and 51.9% of patients had treatment-related changes. There was significant difference between ADCmean in recurrent and non-recurrent groups measuring 0.9 and 1.15 × 10−3mm2/s, respectively (p value < 0.001). BT-RADS, BT-RADS added DWI, and BT-RADS added DWI and resection cavity FLAIR signal had a specificity of 64.3, 71.4, and 71.4%, sensitivity of 76.9, 84.6, and 92.3%, and accuracy of 70.5, 77.8, and 81.5%, with improved AUC from 0.706 (95% CI of 0.50–0.86) to 0.78 (95% CI of 0.58–0.92) to 0.819 (95% CI of 0.64–0.94), respectively.
Adding DWI and resection cavity FLAIR signal alteration improves the diagnostic performance of BT-RADS category 3.
Glioma accounts for about 80% of all malignant primary tumors of the brain  with the highest incidence for glioblastoma multiforme (GBM), representing about 60% of adult primary brain tumors . High-grade primary brain tumors are characterized by aggressive behavior without significant difference in incidence rate between females and males . GBM carries the poorest prognosis with a 40% survival rate during the first year post-diagnosis . The standard treatment protocol for glioma is the resection with concomitant chemoradiotherapy followed by adjuvant chemotherapy . Unfortunately, the prognosis of GBM is still poor with no improvements in outcome since the combined treatment with chemoradiotherapy in 2005 . The radiation therapy oncology group had held a trial to compare survival between conventional adjuvant and dense-dose temozolomide; however, no significant difference regarding the survival improvement between both groups was concluded. The incorporation of Bevacizumab in management protocol yielded improvement in progression-free survival without change in overall survival [7, 8]. Meanwhile, a recent meta-analysis detected an association between prolonged temozolomide and elongated survival in comparison to standard six cycles of temozolomide therapy .
One of the recognized complications of radiotherapy is post-radiation brain necrosis. It can occur 6 to 36 months post-radiation, and cause radiological changes at the radiation zone that look similar to a recurrent tumor .
Differentiation between radiation-induced changes and recurrent brain tumors is sometimes a challenging matter for radiologists, so several series of response evaluation criteria applied to conventional MRI were held for the precise assessment of the post-treated glioma response and differentiation between radiation-induced changes and recurrent brain tumors. Lastly, these trials concluded with Brain Tumor Reporting and Data System (BT-RADS) which categorizes post-treated glioma response into 4 groups according to the enhanced component and the non-enhanced FLAIR signal abnormality, and mass effect in correlation with patients’ clinical states and received treatment . However, BT-RADS neglects the effect of FLAIR signal changes within the resection cavity which has been proved by another research  to be an early and specific sign in predicting tumor recurrence in operated high-grade glioma.
Albeit restricted signal on the diffusion-weighted image (DWI) characterizes high cellular tumor tissue , DWI was not included within the criteria of BT-RADS categorization.
As BT-RADS category 3 has an intermediate probability of recurrent neoplastic activity , so in our study, we evaluated the added value of DWI and resection cavity FLAIR signal changes on the diagnostic performance of BT-RADS category 3 for a more precise distinction between post-treatment changes and recurrent tumor in post-treated glioma.
Approval was procured from the Institutional review board and research ethics committee. A written informed consent was taken from the included patients in the study.
Study design and population
Our pilot prospective study dealt with imaging of post-treated glioma patients. It consisted of two stages, the first one was concerned with the collection of data and classification of two consecutive post-treated glioma MR imaging acquired between May 2019 and December 2020 according to BT-RADS categorization. The second stage was concerned with the evaluation of first stage patients’ imaging follow-up and it was held during the period from January 2021 to December 2021 and served as the reference standard for the given BT-RADS category. A preliminary sample included 63 patients. Inclusion and exclusion criteria are shown in the flowchart of the recruited patient (Fig. 1). The final sample entailed 27 patients.
MR image acquisition
All contrast-enhanced MR imaging were obtained on GE Healthcare and Siemens 1.5T MR machine using 8 channels head coil. The brain tumor MR protocol included axial T1weighted-image (WI), axial and coronal T2WIs, and axial FLAIR. By intravenous injection of 0.1 mmol/kg of gadopentetate dimeglumine at a rate of 2 ml/s, post-contrast axial, sagittal, and coronal T1WIs were acquired. DWI was done at b value (0 and 1000) with automatically calculated ADC map by the software. Table 1 shows the parameters of acquired MR sequences.
Image analysis and BT-RADS implementation
All first-stage MR studies were independently interpreted by two neuroradiologists (who were already implementing BT-RADS in their daily practice) on a PACS system (Paxera Ultima-Paxeramed) according to the BT-RADS scoring system, and their results were compared and the final BT-RADS category was confirmed consensually in cases with different ratings. They were informed about all patients' clinical states and previous treatment regimens. BT-RADS categorization was based on the tumors’ FLAIR/T2 component, mass effect, and enhanced component . Studies were classified into BT-RADS 3a, 3b, and 3c as following:
BT-RADS 3a (image worsening favoring treatment effect): within 3 months following completed chemoradiotherapy with increase T2/FLAIR component or increase enhancing component < 25%, and increase mass effect in a clinically stable patient.
BT-RADS 3b (indeterminate): beyond 3 months following completed chemoradiotherapy with increase T2/FLAIR component or increase enhancing component < 25%, and increase mass effect in a clinically stable patient.
BI-RADS 3c (image worsening favoring tumor progression): beyond 3 months following completed chemoradiotherapy with increase T2/FLAIR component, increase enhancing component < 25%, and increase mass effect in a clinically worse patient and/or demonstration of a new indeterminate lesion outside the zone of radiation.
Adding DWI and resection cavity FLAIR signal to BT-RADS categorization
After interpretation of ADCmean, lowering ADCmean upgraded the BT-RADS categorization, whereas stable or increasing ADCmean stabilized or downgraded the BT-RADS categorization. Also, resection cavity FLAIR signal change into a higher signal upgraded BT-RADS categorization.
The imaging of each enrolled patient in the first stage was followed in the second stage of the study. The second stage follow-up studies were used to determine the diagnostic performance of previous BT-RADS categorization and the additive value of ADCmean and resection cavity FLAIR signal change on the diagnostic performance of BT-RADS category 3.
Analyses were done using SPSS version 28.0 (IBM, Armonk, NY). The normality of distribution was assessed using the Kolmogorov–Smirnov test. Normally distributed data were presented as mean and standard deviation (SD), and categorical data as frequency and percentage. The difference between groups was analyzed by using Chi-square and Fisher exact tests (for categorical data). The correlation was done to detect the linear relationship between ADC value and tumor recurrence using the Pearson correlation coefficient. The accuracy, sensitivity, specificity, PPV and NPP before and after addition of ADCmean and resection cavity FLAIR signal change were calculated. ROC curve analyses were done to determine the diagnostic performance of BT-RADS implementation before and after addition of ADCmean and resection cavity FLAIR signal change in detection of tumor recurrence. Comparison of AUC was interpreted by Delong test. A statistical difference was significant as long as the P-value ≤ 0.05.
Patient demographic and clinical characteristics
Twenty-seven patients (male, 62.9%, mean age ± SD, 50.1 ± 3.5; female, 37.1%, mean age ± SD, 35 ± 3.6) were included in our study. Table 2 shows the demographic and clinical data of the included patients. The primary tumor was resected either totally in 55.6% or partially in 44.4%, the rate of tumor recurrence was insignificantly related to the surgical tumor resection pattern measuring 46.2% and 53.8% in both groups, respectively. On resection cavity FLAIR signal assessment, all the five cases (38.5%) who developed a higher signal in the resection cavity on follow-up study proved to have tumor progression (Table 3).
Diagnostic performance of BT-RADS category 3
Twenty-seven patients were classified as BT-RADS category 3 using the BT-RADS classification system. Recurrent glioma was found in 9/20 BT-RADS 3b cases and 4/5 BT-RADS 3c cases. On follow-up studies, the two BT-RADS 3a cases showed regression, with no evidence of recurrent glioma (Table 2). BT-RADS category 3 could truly detect tumor recurrence in 10 out of 13 cases, and to eliminate tumor recurrence in 9 out of 14 cases reaching 76.9% sensitivity, 64.3% specificity, and 70.4% accuracy (Table 4).
Relation between ADC value and tumor recurrence
The recurrence group had a significantly lower ADCmean (0.9 × 10−3mm2/s) than the non-recurrence group (1.15 × 10−3mm2/s). A significant correlation existed between ADC value and tumor recurrence (p˂ 0.001) (Table 3).
Additive value of DWI to the diagnostic performance of BT-RADS category 3
After incorporation of ADCmean to BT-RADS category 3, the diagnostic performance for differentiating tumor recurrence and non-recurrence increased from 64.3 to 71.4%, 76.9 to 84.6%, 66.7 to 73.3%, 79.5 to 83.3%, and 70.4 to 77.8% in terms of specificity, sensitivity, PPV, NPV, and Accuracy, respectively, with increased AUC from 0.706 (95% CI: 50–86%) to 0.780 (95% CI: 58–92%) (Table 4).
Additive value of DWI and resection cavity FLAIR signal to the diagnostic performance of BT-RADS category 3
After integration of both ADCmean and resection cavity FLAIR signal change to BT-RADS category 3, AUC increased to 0.819 (95% CI: 62–94%) with increased specificity, sensitivity, PPV, NPV and accuracy to 71.4%, 92.3%, 75%, 90.9%, and 81.5%, respectively (Table 4).
Figure 2 displays the comparison between Roc curves.
The interpretation of post-treated glioma is daily encountered in routine neuroimaging practice. Despite advances in treatment of high-grade glioma, it still has a tendency for recurrence. Moreover, it is sometimes hardly differentiated form treatment-related effect. Structured reporting of post-treated brain tumors imaging underwent several trials that ended with BT-RADS classification. BT-RADS classified the probability of tumor recurrence in post-treated glioma into 4 categories tied to suggested management strategy according to MR imaging features, clinical states of the patients, and the time elapsed since last received chemoradiotherapy . However, BT-RADS category 3 had the intermediate probability of tumor recurrence and treatment-related changes. We concluded that adding ADCmean and resection cavity FLAIR signal changes could improve the diagnostic performance of BT-RADS category 3in the prediction capability of tumor recurrence.
DWI represents visual and quantitative assessment of water diffusion in extracellular space through creation of DWI (typically at b-value 0 and 1000) and ADC map, so high cellular tumors impair diffusivity of water resulting in decrease ADCmean and diffusion restriction . Similar to Yang et al. study  who reported statistically significant difference of ADCmean between recurrent (0.8, IQR: 0.7–1.0 × 10–3 mm2/s) and non-recurrent groups (1.3, IQR: 1.2–1.4 × 10–3 mm2/s), we reported statistically significant difference of ADCmean in recurrent (0.9, IQR: 0.7–1.4) × 10–3 mm2/s) and non-recurrent groups (1.15, IQR: 1.04–1.6 × 10–3 mm2/s).
In Yang et al. study , specificity and accuracy of BT-RADS increased after adding DWI from 0.55 to 0.83%, and 0.7 to 0.8%, respectively, while sensitivity decreased from 0.88 to 0.78%.
It is worth noting that even after incorporating DWI into the classification system in our study, three cases classified as BT-RADS 3b and one case classified as BT-RADS 3c were falsely positive interpreted as tumor progression while was confirmed on follow-up to be delayed radiation necrosis, this was attributed to the inflammation accompanied radiation-induced brain injury, which can cause alteration in diffusion signal and restriction . Moreover, radiation-induced changes are not limited to 3 months post-treatment, but radiation-induced brain injury has wide time range to occur either from days to weeks or weeks to months or months to years ascribed as acute, early delayed, and late delayed effects, respectively .
Previously reported that progressive contrast enhancement occurred within 2 months of chemoradiotherapy in approximately 21% of high-grade glioma patients, which was defined as pseudoprogression and resulted in imaging that mimicked tumor progression [17, 18]. This was explained by the treatment-induced local inflammation, glial and white matter damage, and vascular injury caused by a temporary increase of the blood brain barrier permeability at tumor bed . In comparison to viable tumor progression, this phenomenon was described radiologically as thick peripheral fluffy-like enhancement with facilitated diffusion . The late effects of radiation caused parenchymal and vascular injury and resulted in radiation necrosis of normal brain tissue or tumor  can occur from 2 to 32 months after radiotherapy with up to 85% of cases occur after 2 years of completed radiation . Also, Shah et al.  concluded that imaging worsening occurred 3 years after completed radiation was a combined effect of tumor progression and radiation necrosis. Remarkably, pseudoprogression was associated with improved survival and better prognosis, while late radiation necrosis required further treatment with higher morbidity [14, 22, 23].
In our study, DWI could not detect the tumor progression in two BT-RADS 3b cases, this was attributed to the variable recurrent tumor cellularity and mixed effect of tumor recurrence and necrosis .
Yang et al.  found that BT-RADS category 3 alone had sensitivity, specificity, and accuracy of 88%, 55% and 74% with AUC 0.76 (95% CI 0.66–0.84), while adding DWI improved diagnostic performance of BT-RADS to 78%, 83%, and 80%, respectively with AUC 0.88 (95% CI 0.80–0.94). Similarly, by adding DWI to BT-RADS category 3 in our study, an improvement of the diagnostic performance of BT-RADS category 3 was noted with increasing sensitivity, specificity and accuracy from 76.9 to 84.6%, 64.3 to 71.4%, and 70.4 to 77.8%, respectively.
Notably, increased or decreased FLAIR component size and development of new signal outside radiation zone were the main concern in BT-RADS categorization  neglecting FLAIR signal changes within the resection cavity, whereas the development of hyperintense fluid signal in the resection cavity on follow-up FLAIR sequence was previously reported to be allied with a poorer prognosis and disease progression in high-grade glioma with a positive predictive value 90.6% (95% CI, 79.3–96.3%), and it was higher for grade IV glioma approaching 93.2% (95% CI, 87.3–99.1%) . Bette et al.  confirmed the significance of FLAIR signal change assessment within the resection cavity that could differentiate between post-radiation changes and tumor recurrence in operated high-grade glioma with 80% specificity and 96.3% positive predictive value.
In our study, Integration of resection cavity FLAIR signal alteration and DWI to BT-RADS improved AUC with enhanced diagnostic performance.
In our study, we faced limitations. First, since re-surgical evaluation of post-treated glioma patients is not frequently performed in daily clinical practice, we depended on the second stage imaging follow-up as a reference standard in conjunction with clinical data. Second, we did not investigate the utility of adding perfusion weighted image to BT-RADS since it is not regularly acquired in radiological centers and has different image acquisition techniques. Third, our sample size is relatively small, this was explained by the nature of our study design, inclusion and exclusion criteria.
Diagnostic performance of BT-RADS category 3 for tumor recurrence prediction improved whenever it is combined with DWI and FLAIR signal assessment within the resection cavity. We recommend BT-RADS category 3 modification to avoid the necessity for treatment protocol adjustment and the hazards of unnecessary re-surgical interference.
Availability of data and materials
All data are available on a software system owned by each of the authors and the corresponding author has the authority to respond if there is any query.
Brain tumor reporting and data system
Diffusion weighted image
- ADCmean :
Mean apparent diffusion coefficient
Fluid attenuation inversion recovery
Receiver operating characteristics
Area under the curve
Positive predicative value
Negative predicative value
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Special thanks and hope for cure to all patients incorporated in our study.
The authors declare that this work has not received any funding.
Ethics approval and consent to participate
Zagazig University Institutional review board approval was obtained. Approval number is # 6184-14-6-2020. Written informed consent was obtained from all patients.
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All patients included in this research gave written informed consent to publish the data contained within the study.
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Metwally, M.I., Hafez, F.F.M., Ibrahim, S.A. et al. The value of adding DWI and FLAIR signal changes in the resection cavity on the diagnostic performance of BT-RADS category 3 for tumor progression prediction in post-treated glioma patients: a prospective pilot study. Egypt J Radiol Nucl Med 54, 52 (2023). https://doi.org/10.1186/s43055-023-00993-3