Utility of noncontrast MRI in the detection and risk grading of gastrointestinal stromal tumor: a comparison with contrast-enhanced CT

Introduction

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, with an estimated annual incidence of 6.8–14.5 cases per million (1). Adjuvant therapy has revolutionized the survival outcomes of metastatic GIST patients, with median survival duration having increased from approximately 20 months to more than 60 months (2,3). Contrast-enhanced computed tomography (CECT) is the standard imaging modality for diagnosing GIST and assessing the therapeutic response of GIST (4). According to the latest version of the National Comprehensive Cancer Network guidelines, for patients with resectable GISTs, regular follow-up CECT can be performed up to 20 times in the first 5 years, and even more frequent follow-ups may be required for those with unresectable GISTs, recurrence, or metastatic GISTs (5). Only in patients with low-risk GISTs can the number of follow-up CECT be reduced. The dangers and concerns related to ionizing radiation in CT examinations, along with patients’ desire to decrease ionizing radiation exposure, reduce patient compliance. The absence of ionizing radiation exposure and the foregoing of intravenous contrast agent administration make noncontrast magnetic resonance imaging (MRI) an increasingly flexible test in clinical practice that may potentially further improve the survival of GIST patients.

MRI has been introduced as an alternative or preferred imaging modality for gastrointestinal disease (6,7). Recurrent tumors with a cyst-like appearance without enhancement may occur in a significant proportion of GIST patients during therapy (8). T2-weighted imaging (T2WI) can clearly delineate the boundary of a cystic GIST and its response to adjuvant therapies (9); meanwhile, diffusion-weighted imaging (DWI) reflects pathological differences, including the risk grade of the primary GIST, through the calculation of apparent diffusion coefficient (ADC) values (10-13). Furthermore, volumetric ADC calculated by DWI histogram analysis has shown remarkable reproducibility in patients with other solid neoplasms (14,15). However, the role of noncontrast MRI combined with DWI in the management of GIST has remained unclear since the prolonged overall survival time of GIST patients and the variable appearance of GIST in imaging due to more widely applied adjuvant therapy.

The aim of this study was to investigate whether noncontrast MRI performed with DWI has comparable lesion detection performance to CECT in the detection of GIST, and whether volumetric ADC histogram parameters can identify GIST patients with moderate-to-high risk grades.

Methods

Patients

The study protocols were approved by the institutional ethics review board of our institution, and informed consent was waived because of the retrospective nature of this study. A medical record review was conducted from March 2012 to March 2018 using the institutional database, and patients with gastric or small intestinal GISTs were enrolled for qualitative analysis. For quantitative analyses, database research was performed from March 2012 to December 2019. Flow charts depicting the selection and inclusion of subjects for these two parts of the study are provided in Figure 1. The clinical information (age, sex, etc.) for all patients with pathologically confirmed GISTs by surgical or biopsy specimen were recorded by a reader blinded to the results of the imaging analysis.

Figure 1 Flowchart of the study population. (A) Flow diagram shows patient inclusion in the qualitative analysis. (B) Flow diagram shows patient selection in the quantitative analysis. GIST, gastrointestinal stromal tumor; MRI, magnetic resonance imaging; CT, computed tomography; mNIH, the modified National Institutes of Health criteria; DWI, diffusion-weighted imaging.

Consecutive patients with pathologically confirmed GISTs were enrolled for qualitative analysis. CECT and MRI performed both at the time of diagnosis (time interval within 2 weeks) or both during follow-up (time interval within 15 weeks) were included for analysis. GIST patients who underwent curative resection treatment or unresectable GIST patients on targeted therapy were the follow-up cases. All enrolled patients were followed-up for at least 6 months to confirm their disease status. After evaluation by a senior oncologist, including physical and imaging examinations, the status of no evidence of disease was determined, and the patient was grouped as without lesions. The exclusion criteria were the following: (I) changes in treatment strategy between the CECT and MRI examination, (II) patients with an additional non-GIST neoplasm.

For quantitative analysis, the inclusion criteria were as follows: (I) primary GIST patients pathologically confirmed by surgical specimens, (II) DWI performed with a b value of 0 and 800 sec/mm² on a 3T MR scanner, (III) no adjuvant therapy performed before DWI. The exclusion criteria were as follows: (I) DWI performed after surgery or adjuvant therapy, (II) insufficient image acquisition and quality, (III) patients with unresectable or metastatic tumors, (VI) patients with intussusception, (V) tumor diameter smaller than 1 cm.

CT and MRI imaging protocols

Images were acquired with five CT scanners and two 3.0 T MR scanners (MR system 1 and 2), and all platforms and techniques adhered to the recommendations of the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and the European Society of Pediatric Radiology (ESPR) (16). The detailed protocols and vendors for CECT and MRI devices are provided in Tables S1,S2. Patients fasted for 4–6 hours, and approximately 1,200–1,500 mL drinking water for CECT and isosmotic mannitol solution for noncontrast MRI were orally administered 30 minutes to 1 hour before scanning. Intravenous contrast agents were only administered for CT. The iodinated contrast agent (Optiray, 350 mgI/mL; Mallinckrodt, Canada) was infused using an automatic power injector (Stellant; Medrad, USA) at a rate of 4 mL/s, followed by a 20-mL saline solution flush. The total contrast volume varied according to the patient’s weight at 1.5 mL/kg. Using a bolus tracking technique, arterial phase acquisition began 6 seconds after the threshold enhancement of the abdominal aorta reached 120 HU. The venous phase started 20–25 seconds after the completion of the arterial phase. The DWI sequence used for quantitative analysis was performed with a b value of 0 and 800 sec/mm² on the same two 3T MR scanners.

Image interpretation

Two abdominal radiologists (YQS and XMH, with 10 and 12 years of experience in clinical CT and MRI respectively) independently analyzed CECT and noncontrast MRI in two sessions using the Digital Imaging and Communications in Medicine (DICOM) data of CT and MR image sets of each patient. CT image sets included arterial and venous phase scanning, and multiplanar reconstruction was available to further differentiate lesions from normal tissues. The four pulse sequences listed in Table S2 constitute the MR image sets. Axial and coronal planes for T1-weighted imaging (T1WI), T2WI, fast imaging employing steady-state acquisition (FIESTA), or true fast imaging with steady-state free precession (TRUFI) were available for the MR dataset. The radiologists were blinded to detailed clinical information, and only know that the images were from GIST patients. Each session was performed 4 weeks apart to minimize recall bias. Combined CECT and noncontrast MRI were reviewed by radiologist YQS in a third reading session.

The radiologists were instructed to record their certainty with regards to the GISTs according to the following scoring system: 1= definitely no neoplasm, 2= probably no neoplasm, 3= indeterminate, 4= probably neoplasm, 5= definitely neoplasm (17,18). Imaging features for establishing the existence of a single GIST included tumor originating from the muscularis propria layer of the gastrointestinal tract, well-defined margins, intratumoral attenuation or signal pattern related to possible necrosis, cystic degeneration, and hemorrhage. Metastatic lesions were confirmed when more than 1 new mass presented in the liver or peritoneum with or without a lesion located in the gastrointestinal tract. Patients scoring 1 or 2 in the group of patients with no evidence of disease status represented true negatives, and patients scoring 4 or 5 in the group of patients with reference-confirmed existence of GIST lesions represented true positives. Because each individual metastasis could not be pathologically confirmed, a per-lesion analysis was not performed.

DWI was processed with FireVoxel (an open source software, https://wp.nyu.edu/firevoxel/) for quantitative analysis (19). Another two radiologists (ZLZ and JYL, with 3 and 5 years of experience in reading gastrointestinal images, respectively) manually contoured the three-dimensional volume of interest along the margin of the entire neoplasm on each slice of the DWI on which the tumor was present (b=800 sec/mm²), excluding the adjacent normal bowel contents and wall. T2-weighted images were used to assist with identifying the contours of the tumors. Examples showing representative volume of interest placement are provided in Figure S1. The ADC map was constructed automatically by using the following monoexponential model:

S=S0×e-b×ADC[1]

where S and S0 represent the signal intensities with and without diffusion sensitization and b represents the diffusion-weighting factor. Histogram parameters derived from DWI were as follows: ADC_mean, ADC_median, ADC_min, ADC_max, and ADC_Stdev; 5^th, 10^th, 25^th, 75^th, 90^th, and 95^th percentiles; inhomogeneity, skewness, kurtosis, and entropy. The results of these histogram parameters were calculated as mean values of the two radiologists.

Reference standards

Diagnostic confirmation was obtained by histopathological examination for cases with CECT and MRI performed before surgery or adjuvant therapy. For cases with CECT and MRI acquired during follow-up, diagnostic confirmation was performed by serial follow-up imaging after the index test in combination with clinical information (20). Clinical follow-up lasted for at least 6 months after performance of the index test for all follow-up cases.

Risk stratification of each primary GIST was defined on the basis of histopathological reports which were graded using the modified National Institutes of Health criteria, including factors such as tumor diameter, site, mitotic index, and presence of rupture at surgery (21). Patients with moderate-to-high risk GISTs were categorized into the high-risk recurrence group (H-group, higher recurrence rate within 5 years) and patients with very-low-and-low risk GISTs were assigned to a low-risk recurrence group (L-group, lower recurrence rate within 5 years) (22,23).

Statistical analysis

The sensitivity, specificity, and accuracy for identifying GISTs, along with their corresponding 95% confidence intervals (CIs), were calculated for each imaging technique. Positive and negative predictive values were not computed due to the scoring system defining a score of 3 as neither a true-positive nor a true-negative imaging finding. The differences in sensitivity and specificity between CECT and noncontrast MRI were assessed using the extended paired McNemar test (24). Given a power of 0.95, a type I error of 0.05, a total sample size of 83, and the fixed paired McNemar statistical model, the calculated effect size was moderate, with a value of 0.49 (a range of 0.3 to 0.5 indicated medium effect size). Interobserver agreement between the two readers was assessed using the weighted kappa value. Agreement was defined as follows: ≤0.20, poor; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, good; and >0.80, excellent.

The volumetric ADC histogram parameters were compared to the modified National Institutes of Health criteria risk grading system. Reliability between the two readers was calculated using the interclass correlation coefficient. For each lesion, mean values of the parameters measured by the two radiologists were analyzed if interobserver agreement was strong (11). After testing the normality of each parameter with the Shapiro-Wilk test, univariate analysis, including the independent Student’s t-test or Mann-Whitney U test, was used for the comparison of parameters between the H- and L-groups. Correlations between histogram parameters and risk grades were evaluated using Spearman’s rank correlation. The receiver operator characteristic analyses for univariate variables were performed for histograms that significantly differed between the two different prognostic groups. The optimal cutoff point value of each parameter was calculated by the Youden index. The sensitivity and specificity were estimated for each univariate parameter.

Data management and analyses were performed using SPSS software v.23.0 (IBM Corp., USA) and R software v.3.6.0 (R Project for Statistical Computing). All statistical significance levels were set at a P value <0.05. Effect size was calculated by using G*power software v.3.1.9.4 (25).

Results

Clinical characteristics

For the qualitative analysis, there were 55 patients with GIST lesions (28 males, 27 females, with a mean age of 52.82±10.5) and 28 patients with no evidence of disease (16 males, 12 females, with a mean age of 51.29±10.16). For patients with GIST lesions, we enrolled CECT and noncontrast MRI data from patients with primary gastric GISTs (n=12), small bowel GISTs (n=21), locally advanced GISTs in the small intestine (n=3), recurrent GISTs in the stomach (n=2), and metastatic GISTs (n=17). The distribution of patients for the qualitative analysis is detailed in Table 1. The distribution of age and sex were comparable between the groups of patients with GISTs and patients with no evidence of disease (P=0.523 and P=0.591, respectively; both >0.05). The CECT and noncontrast MRI in 42 patients (cases with images acquired before the surgery or targeted therapy) were performed with a median of 3 days apart (range from 0 to 11 days). For the 41 patients with CECT and noncontrast MRI performed after surgery, the median time interval between the tests was 16 days (range from 1 to 105 days, 39 cases within 90 days, 2 cases within 105 days).

Table 1 Clinicopathological distribution of 83 patients for qualitative analysis
Full table

For the quantitative analysis, 28 patients with a single primary GIST (28 tumors for analysis) were enrolled. There were 11 patients with gastric GISTs and 17 patients with small intestinal GISTs. The mean diameter of the 28 tumors was 4.74±2.93 cm (range, 1.5–15 cm). The clinicopathological characteristics of these 28 GIST patients are shown in Table 2. According to the modified National Institutes of Health criteria, 12 patients with tumors were categorized as high risk, 3 as intermediate risk, 9 as low risk, and 4 as very low risk. Based on the group criteria above, 15 patients were assigned to the H-group and 13 to the L-group.

Table 2 Clinicopathological characteristics of 28 patients with primary GISTs for quantitative analysis
Full table

Comparison of CECT and noncontrast MRI in the qualitative analysis

For the 83 patients who underwent matched CECT and noncontrast MRI, detailed scores reflecting the probability of a GIST are shown in Table S3. Subgroup scores of detection performance with CECT and noncontrast MRI based on patients with primary gastric GISTs, primary small bowel GISTs, and patients with metastatic GISTs are presented in Table S4. For both readers, the group of patients with GIST lesions included cases with findings not well-visualized by CECT but more clearly depicted by MRI (Figure 2 and Figure S2).

Figure 2 A 52-year-old man with a primary ileal GIST. (A) T2WI showed a round, well-circumscribed small-bowel mass (circle). (B) The mass (circle) demonstrates high signal intensity on DWI. (C) Arterial phase CT images illustrate a poorly defined mildly enhancing ileal lesion (circle). (D) In the venous phase of the CECT, the lesion (circle) remains poorly defined. GIST, gastrointestinal stromal tumor; T2WI, T2-weighted imaging; DWI, diffusion-weighted imaging; CT, computed tomography; CECT, contrast-enhanced computed tomography.

As previously defined, the true-negatives and true-positives, sensitivity, specificity, and accuracy for detecting GIST lesions with CECT versus noncontrast MRI for reader 1 and reader 2 were calculated and are detailed in Table 3. The extended paired McNemar exact test showed no statistically significant differences overall in the sensitivity and specificity of CECT and noncontrast MRI (P=0.607 by radiologist 1; P=1.000 by radiologist 2). The concordance of the two readers was good for both CECT (weighted kappa value: 0.691; CI: 0.598–0.783; P<0.001) and noncontrast MRI (weighted kappa value: 0.762, CI: 0.666–0.858; P<0.001).

Table 3 Summary of GIST lesion detection performance of CECT and noncontrast MRI
Full table

When CECT and noncontrast MRI were analyzed together by radiologist 1, the number of indeterminate cases decreased from 8 to 3 cases. In the group of patients with GIST lesions, the number of cases with scores of 4–5 increased from 42 to 50 cases. In the group of patients with no evidence of disease, the number of cases with a score of 1 increased from 4 to 12 cases. Table 3 summarizes the GIST lesion detection performance of CECT and noncontrast MRI.

Correlation between volumetric ADC histogram parameters and risk grade in the quantitative analysis

Strong interobserver agreement was reached between the two readers, with interclass correlation coefficients ranging from 0.828 to 0.997. Table 4 presents the further analysis results of the averaged data of the two readers’ measurements for each volumetric ADC parameter between the H- and L-groups. The H-group showed higher ADC_max and ADC_stdev; 75^th, 90^th, and 95^th percentiles; and inhomogeneity and entropy values than the L-group. Differences in ADC_min, ADC_mean, and ADC_median; 5^th, 10^th, and 25^th percentiles; and skewness and kurtosis values between the groups did not reach statistical significance.

Table 4 Comparisons of volumetric ADC histogram parameters between the H- and L-groups
Full table

Diagnostic performance of volumetric ADC histogram parameters for discrimination of prognosis in the quantitative analysis

Univariate ADC_max had the highest area under the curve (0.938) in discriminating between the H- and L-groups of patients with the optimal cutoff value of 2.685×10^–3 mm²/s (Table 5). The corresponding receiver operator characteristic curves for univariate parameters are shown in Figure S3.

Table 5 Area under the curve and cutoff points of ADC histogram parameters for discrimination of the H- and L-groups of patients
Full table

Discussion

This study evaluated the performance of CECT and noncontrast MRI with respect to their sensitivity and specificity for the detection of GIST lesions. The results showed no significant differences in sensitivity and specificity for the detection performance of CECT and noncontrast MRI (P=0.607 by radiologist 1; P=1.000 by radiologist 2). In addition, the interobserver variability and the capability of volumetric ADC histogram parameters to discriminate moderate-to-high risk and very-low-to-low risk patients was assessed. Excellent agreement between the two radiologists was reached in the quantitative analysis. Patients with moderate-to-high risk GISTs had overall higher volumetric ADC parameters (ADC_max value of 3.319±0.580×10^–3 mm²/s) than patients with very-low-to-low risk GISTs (ADC_max value of 2.254±0.458×10^–3 mm²/s).

Noncontrast MRI and CECT demonstrated comparable performance for the detection of GIST lesions in our study. The present study extends the use of noncontrast MRI to assess small bowel GIST. GIST in the small intestine shows greater enhancement than other tumors in the small intestine (26,27) and gastric GIST (28). According to these previous studies, GIST should demonstrate avid contrast enhancement and be easily detected on CECT. Nevertheless, noncontrast MRI demonstrated equal detectability with CECT even without contrast media. Noncontrast MRI is advantageous over CECT as there is no concern about radiation exposure in patients. In patients with allergies to iodinated contrast media or renal disease, noncontrast MRI can be recommended as an alternative safe imaging modality. The lack of intravenous gadolinium contrast also avoids the risk of adverse reactions from contrast injection, the increase in overhead on scanning workflow (having a provider on site in case of contrast reaction), and the introduction of nonessential medications with unknown implications of gadolinium deposition.

The quantitative results of volumetric ADC histogram parameters showed moderate sensitivity and specificity for identifying patients with moderate-to-high risk GISTs requiring higher frequency follow-up. Our study demonstrated higher volumetric ADC values with higher risk GISTs as per the modified National Institutes of Health grade. Generally speaking, ADC values reflect the cellularity of the tumor through diffusion of water molecules within tissue, and lower ADC values correspond to the most solid components and high proliferation rates (29). Correspondingly, Zhou et al. and Kang et al. reported that lower mean ADC values are negatively correlated with the modified National Institutes of Health risk stratification of GIST (11,13). However, histogram parameters reflect the distribution of signal intensity over the delineated volume of interest in the tumor, and are independent of absolute measures of signal intensity (30). Underlying molecular diversity is paralleled with the clinicopathological heterogeneity of GISTs. High-risk GISTs have a higher mean size, and pathologically have more heterogeneous composition, such as hemorrhagic foci, central cystic degenerative changes, or necrosis (31). In our study, higher percentile volumetric ADC parameters which corresponded to higher percentiles reflecting cystic or necrotic tissue showed significant differences in discriminating patient groups with different risk grades. Methodological differences may account for the discrepancies with previous studies, as the ADC values in both previous studies were derived from a single slice of tumor, as opposed to the histogram distribution parameters obtained from ADC volumetry in our study. Second, cystic areas or hemorrhage components scattered in the tumor parenchyma represented by the histogram volumetric ADC values such as entropy and inhomogeneity reflected the heterogeneous composition within the tumors. The tumor volume ADC analysis demonstrated strong interobserver reliability in this study, a feature which has been shown in the literature for other neoplasms (14,32). Finally, differences in the study cohort, criteria for risk stratification, b values used, and tumor grade grouping methods may also account for the discrepancies between our results and previous findings.

Previous studies have suggested that dynamic contrast-enhanced MRI could play an important role in characterizing GISTs and assessing therapeutic response (33). The efficacy of DWI for the evaluation of therapeutic response has now been demonstrated by several studies (34,35). Furthermore, DWI texture extracted from patients with metastatic GISTs has the potential to serve as a predictor for overall survival (36). CECT was performed for each patient in our study, and thus, noncontrast MRI with DWI, as opposed to contrast-enhanced MRI, could avoid duplicate infusion of contrast materials, and can be used as a supplemental diagnostic test when needed. Our study presented the complementary roles of noncontrast MRI and CECT for the detection of GIST lesions. Through providing evidence of morphological and functional changes during the entire medical treatment process of GIST, this study suggests that noncontrast MRI with DWI may prove to be an important tool for radiologists and oncologists attempting to formulate an optimal follow-up imaging strategy for GIST.

There are some limitations in this study. First, the relatively small patient population might have caused overestimation of the accuracy of noncontrast MRI in the qualitative analysis, and might have introduced bias in the results of the quantitative analysis. However, the relatively low incidence of GIST and guidelines recommending CECT as the imaging study of choice make it difficult to include patients on a larger scale. Second, overall detection performance rather than separate assessment based on different sites or metastatic lesions was performed in our study, which might have caused bias in the results of the qualitative analysis. Third, the combined reading process of CECT and noncontrast MRI was only performed by 1 radiologist, which meant we were unable to assess the impact of the reader’s experience on the results of the performance of combined CECT and noncontrast MRI. Selection bias could not be avoided due to the retrospective nature of this study, leading to overrepresentation of certain populations in this analysis. Per-lesion analysis was not performed in this study.

In conclusion, in the management of patients with GISTs, noncontrast MRI helps detect lesions and predict pathological risk classification. The performance of noncontrast MRI was comparable to that of CECT for the detection of GIST lesions, and noncontrast MRI has a complementary role to CECT in the detection of GISTs. Quantitative noncontrast MRI evaluation through volumetric ADC histogram analysis was useful in predicting modified National Institutes of Health tumor risk grade, offering important prognostic information, and potentially guiding follow-up.

Acknowledgments

The authors thank Mrs. Fangqin Tan at the technological Department of Radiology for her technical assistance.

Funding: This work was supported by the National Scientific foundation of China (No. 81701657, 81571642, 81771801, and 81801695).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-578). The authors have no conflicts of interest to declare.

Ethical Statement: The study was approved by the Institutional Ethics Review Board of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, and informed written consent was waived due to the retrospective nature of this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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