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Gastric gastrointestinal stromal tumours (2-5 cm): Correlation of CT features with malignancy and differential diagnosis
European Journal of Radiology 123 (2020) 108783
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Gastric gastrointestinal stromal tumours (2-5 cm): Correlation of CT features with malignancy and differential diagnosis
T
Zeyang Chena,1, Jiejin Yangb,1, Jiali Sunb, Pengyuan Wanga,* a b
Department of General Surgery, Peking University First Hospital, Peking University, 8 Xi ShiKu Street, Beijing 100034, People’s Republic of China Department of Radiology, Peking University First Hospital, Peking University, 8 Xi ShiKu Street, Beijing 100034, People’s Republic of China
ARTICLE INFO
ABSTRACT
Keywords: Gastrointestinal stromal tumours Computed tomography Schwannoma Leiomyoma Risk stratification
Purpose: The purpose of this study was to investigate the computed tomography (CT) features of 2−5 cm gastric gastrointestinal stromal tumors (GISTs), schwannomas and leimyomas which have close relationship with malignancy evaluation and differential diagnosis. Method: Seventy-six patients with pathologically confirmed gastric submucosal tumors (SMTs) between 2−5 cm were included in this study, including 60 GISTs, 10 schwannomas and 6 leiomyomas. CT imaging features were reviewed and quantitative parameters including CT values during nonenhanced phase (CTV-N), portal phase (CTV-P) and delayed phase (CTV-D) were recorded. The association of CT features with mitotic counts of GISTs and the significantly different CT features between GISTs and benign SMTs were analyzed. Results: The lobulated contour was significantly more common in GISTs with high mitoses (P < 0.05). The value of CTV-D/CTV-P was significantly lower in GISTs with high mitoses (P < 0.05) and it was an independent predictor for high-mitosis GISTs (P = 0.049, odds ratio [OR] = 186.445) with an area under the curve (AUC) of 0.722. CT features including heterogeneous enhancement and presence of necrosis or cystic degeneration were significantly suggestive of GISTs instead of benign SMTs (P < 0.05). The value of CTV-D/CTV-P was significantly higher in schwannomas than that in GISTs (P < 0.05) with an AUC of 0.853. The value of CTV-P/ CTV-N was significantly lower in leiomyomas than that in GISTs (P < 0.05) with an AUC of 0.883. Conclusions: Some qualitative and quantitative parameters on contrast-enhanced CT can be helpful in preoperative diagnosis and risk stratification of 2−5 cm gastric GISTs.
1. Introduction Recent developments in the field of minimally invasive surgical technology have led to an increasing interest in endoscopic surgery for gastric submucosal tumours (SMTs). The National Comprehensive Cancer Network (NCCN) guidelines recommend that gastrointestinal stromal tumours (GISTs) < 2 cm in size should be resected or accept surveillance, which depends on whether there are high-risk endoscopic ultrasonography (EUS) features, and that all GISTs > 2 cm should be resected [1]. Endoscopic resection is an effective and safe treatment for gastric GISTs < 2 cm, but may not be suitable for GISTs > 5 cm because it is difficult to remove large tumours from the stomach via the oral route [2–4]. Nevertheless, whether endoscopic surgery can be used in 2−5 cm gastric GISTs remains controversial considering the potential
risk of metastasis and recurrence [2,5]. For 2−5 cm gastric GISTs, metastasis rates for GISTs with mitotic counts > 5 per 50 high power fields (HPFs) and ≤ 5/50 HPFs are 16 % and 1.9 %, respectively [6]. Chen et al. indicated that CT features were more useful than EUS features for predicting mitotic counts [7]. Therefore, exploring the association between CT features and GIST risk stratification may influence the surgical treatment decision for 2−5 cm gastric GISTs. Gastric SMTs are divided into three major categories: GISTs, neurogenic tumours and myogenic tumours [8]. GISTs are the most common gastric SMTs. For benign gastric SMTs, schwannomas and leiomyomas are the most representative types of neurogenic and myogenic tumours, respectively. Each type of gastric SMT should be managed specifically according to its different biological behaviour [9]. Some studies have suggested that conservative and minimally invasive
Abbreviations: GISTs, gastrointestinal stromal tumours; SMTs, submucosal tumours; HU, Housefield unit; CTV-N, CT values during nonenhanced phase; CTV-P, CT values during portal phase; CTV-D, CT values during delayed phase ⁎ Corresponding author. E-mail address: [email protected] (P. Wang). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.ejrad.2019.108783 Received 5 September 2019; Received in revised form 20 October 2019; Accepted 24 November 2019 0720-048X/ © 2019 Elsevier B.V. All rights reserved.
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treatments are suitable for benign SMTs with clinically favourable outcomes, in contrast to GISTs with potential malignancy [9,10]. However, it is hard to distinguish gastric GISTs from benign SMTs preoperatively because they demonstrate similar CT features and clinical symptoms. Therefore, this study aimed to identify some qualitative and quantitative parameters on contrast-enhanced CT that may be useful in risk stratification, enabling identification of patients with clinically critical 2−5 cm gastric GISTs.
retrospectively by two experienced radiologists, who were blind to patients’ pathologic data. As for the result which they had originally disagreed, two radiologists reached agreement by negotiating together. CT SMT features included contour, margin, growth pattern, degree of enhancement, enhancement pattern, necrosis or cystic degeneration, calcification, surface ulceration, lymphadenopathy, organ invasion and distant or peritoneal metastasis. The contour of the tumour was divided into round (regular shape) and lobulated (irregular shape). A clear tumour margin was defined as well-defined, or, when the tumour infiltrated surrounding tissues or had a blurred border, as ill-defined. The growth pattern of the lesion was classified as endophytic, exophytic or mixed: endophytic growth signified the lesion was confined to the gastric cavity without expanding toward the extraluminal space; exophytic growth identified that a tumour was confined to the extraluminal space without bulging into the gastric cavity; mixed growth was defined as a pattern with endophytic and exophytic features. In the portal phase of contrast-enhanced CT, the degree of enhancement was evaluated by comparing CT values of the lesion with the liver or the muscle as described previously [12]. The enhancement pattern of the lesion was classified into homogeneous or heterogeneous. The region of necrosis or cystic degeneration was determined when its CT value was less than 20 HU in the portal phase. Degrees of necrosis or cystic degeneration were graded as absent, mild (< 50 % low-density areas of the lesion), and severe (> 50 % low-density areas of the lesion). The presence of calcification was determined by the presence of high-attenuation foci in the mass. The presence of surface ulceration was defined as some mucosal tissue defects on the intraluminal surface of the mass. If long-axis diameters of regional lymph nodes were larger than 1 cm, this was identified as lymphadenopathy [12].
2. Materials and methods 2.1. Patients selection The Institutional Ethics Committee of Peking University First Hospital approved this retrospective study and the need for informed consent was waived. The pathologic database at this institution was searched to identify 230 patients with GISTs, 15 patients with schwannomas and 27 patients with leiomyomas in the stomach from January 2008 to December 2018. 146 GISTs, 4 schwannomas and 16 leiomyomas were excluded because their longest diameters were greater than 5 cm or smaller than 2 cm. 18 patients with GISTs, one patient with schwannomas and 3 patients with leiomyomas were excluded due to unavailable or undetailed CT images. Additionally, 6 patients with GISTs and 2 patients with leiomyomas were excluded as they only accepted biopsy without surgical excision. Finally, 60 GISTs, 10 schwannomas and 6 leiomyomas met all of the inclusion criteria. The inclusion criteria were as follows: (a) patients with primary submucosal tumours (SMTs) in the stomach undergoing radical operation without rupture; (b) GISTs, schwannomas or leiomyomas confirmed by postoperative pathologic diagnosis and the diagnosis was made by two experienced pathologic doctors according to specimens’ morphologic assessment and immunohistochemistry results; (c) longest tumour diameter > 2 cm and < 5 cm confirmed by pathologic measurement; (d) abdominal contrast-enhanced CT performed within 1 month before operation; (e) CT images containing non-enhancing phase, portal phase and delayed phase available for analysis; (f) no neoadjuvant treatment; (g) detailed clinicopathological data. Subsequently, according to the latest National Comprehensive Cancer Network (NCCN) guidelines of soft tissue sarcoma [11], GISTs with mitotic counts ≤ 5/50 HPFs and > 5/50 HPFs have distinct biological behavior. Hence, patients with 2−5 cm gastric GISTs were divided into a low-mitosis group (≤ 5/50 HPFs) and high-mitosis group (> 5/50 HPFs).
2.3.2. Quantitative analysis Two radiologist measured the mean CTV-N, CTV-P and CTV-D of tumours. Under the condition of avoiding heterogeneous regions, such as necrotic and cystic positions, larger than 10 mm2 circular regions of interests (ROIs) were placed at three different homogeneous sites of the lesion of the non-enhanced phase to measure CTV-N values. In the same way, CTV-P and CTV-D were evaluated in the same slice and location as in CTV-N in each of these three sites. Subsequently, the ratio of CTV-P to CTV-N and CTV-D to CTV-P was calculated in each site. Then averages of CTV-N, CTV-P, CTV-D, CTV-P/CTV-N and CTV-D/CTV-P were calculated in three homogeneous sites as the independently measured parameter. The average value of two radiologists’ independently measured parameters were used in the analysis.
2.2. CT acquisition Abdominal contrast-enhanced CT examinations had been performed using one of the following multislice spiral CT machines: Siemens Somatom Sensation 64 (Siemens, Forchheim, Germany); Philips Brilliance iCT, or Philips Brilliance 64 (Philips Medical Systems, Cleveland, OH, USA); GE Discovery CT750 m or GE LightSpeed VCT (GE Healthcare, Princeton, NJ, USA). The parameters of spiral CT were as follows: 120 kV tube voltage, 150−250 mA tube current, 0.5-0.8 s tube rotation time, 64 × 0.625 mm detector collimation, 350 × 350 mm field of view, 512 × 512 matrix, 5 mm section thickness and 1 mm reconstruction interval. Before CT examinations, patients were required to fast for at least 8 h. 500 ml of water was administered orally 5−10 min prior to scan. Subsequently, 80–100 ml iodinated contrast medium was injected intravenously at a rate of 3.0 ml/s. Portal phase and delayed phase images were obtained 60 s and 180 s after the injection of contrast medium.
2.4. Statistical analysis Univariate analysis using t test, chi-square test, Wilcoxon rank sum test and Fisher’s exact test was performed to compare CT features between the high-mitosis group and the low-mitosis group. Variables where P < 0.05 were included in the multivariate analysis. Subsequently, logistic regression was used for processing the multivariate analysis to select significant predictors for high mitotic counts. In multivariate analysis, a variable with two-sided P value < 0.05 was considered to be an independent predictor for mitoses. Odds ratios (OR) and 95 % confidence intervals (CIs) were also computed. The receiver operating characteristic (ROC) curve was drawn to evaluate the obtained variable from the multivariate analysis. CT features between GISTs and other benign SMTs (schwannomas and leiomyomas) were also compared by univariate analysis in the same way as previously described. The ROC was also calculated for some quantitative variables obtained from the univariate comparison between GISTs and benign SMTs. SPSS version 19.0 was used for statistical analysis. A statistically significant difference was defined as P value < 0.05.
2.3. CT imaging analysis 2.3.1. Qualitative analysis Abdominal contrast-enhanced
CT
images
were
reviewed 2
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3. Results
Table 1 Comparison of CT features in patients with 2−5 cm gastric GISTs.
3.1. Clinicopathological findings
Criteria
The clinicopathological findings of patients in the low-mitosis group (n = 47) and high-mitosis group (n = 13) were listed in Supplemental Table 1. Results of the univariate analysis indicated that patients had no significant difference in variables of age, tumour size, sex, type of operation and symptoms between the two groups (all P > 0.05). The clinicopathological data of 60 patients with GISTs, 10 patients with schwannomas, and 6 patients with leiomyomas were listed in Supplemental Table 2. The median age of patients with GISTs (65.0 years) was significantly older than that of patients in the schwannoma group (53.5 years, P = 0.005) and leiomyoma group (40.5 years, P = 0.002). Patients without symptoms in the schwannoma group (8/ 10, 80 %) were significantly more common than in the GIST group (21/ 60, 35 %) (P = 0.049). The ratio of patients being asymptomatic was higher in the leiomyoma group (4/6, 66.7 %) than in the GIST group (21/60, 35 %), but without statistical difference (P > 0.05). Before the operation, a patient with GIST was misdiagnosed as having a pancreatic tail lesion, and 10 patients with schwannomas and 5 patients with leiomyomas were misdiagnosed with GISTs. The preoperative misdiagnosis rate of the GIST group (1/60, 1.7 %) was significantly lower than in the schwannoma group (10/10, 100 %, P < 0.001) and leiomyoma group (5/6, 83.3 %, P < 0.001).
Mitotic indexa,b Low-mitosis group (n = 47)
Contour Round 41 (87.2) Lobulated 6 (12.8) Growth pattern Endophytic 23 (48.9) Mixed 7 (14.9) Exophytic 17 (36.2) Calcification Absent 43 (91.5) Present 4 (8.5) Surface ulceration Absent 37 (78.7) Present 10 (21.3) Necrosis or cystic degeneration Absent 22 (46.8) Mild 21 (44.7) Severe 4 (8.5) Degree of enhancement Low 23 (48.9) Iso 20 (42.6) High 4 (8.5) Enhancement pattern Homogeneous 26 (55.3) Heterogeneous 21 (44.7) CTV-N (HU) 31.56 ± 7.44 CTV-P (HU) 65.33 (53.33–74.67) CTV-D (HU) 70.52 ± 16.37 CTV-P/CTV-N 2.01 (1.87–2.29) CTV-D/CTV-P 1.10 ± 0.18
3.2. Association of CT features with malignancy of GISTs No patients with 2−5 cm gastric GISTs, schwannomas or leiomyomas had CT features of ill-defined margin, lymphadenopathy, organ invasion and distant or peritoneal metastasis, therefore these variables were not listed in Tables 1 and 3. According to the univariate analysis results (Table 1), growth pattern, calcification, surface ulceration, necrosis and cystic degeneration, degree of enhancement, enhancement pattern, CTV-N, CTV-P, CTV-D, and CTV-P/CTV-N were not significantly different between the low-mitosis and high-mitosis groups (P > 0.05). Tumours with lobulated contour were significantly more common in the high-mitosis group (5/13, 38.5 %) than in the lowmitosis group (6/60, 12.8 %, P = 0.034). Representative examples were illustrated in Figs. 2 and 3. The value of CTV-D/CTV-P in the highmitosis group was significantly smaller than in the low-mitosis group with means of 0.98 and 1.10, respectively (P = 0.032). The CT contour feature and the CTV-D/CTV-P parameter were included in the subsequent multivariate analysis (Table 2). The result of logistic regression indicated that only the value of CTV-D/CTV-P was an independent risk factor for malignancy in patients with 2−5 cm gastric GISTs (P = 0.049, OR = 186.445). Further ROC analysis was used to calculate the cut-off value and area under the curve (AUC) of CTVD/CTV-P (Fig. 1). The cut-off point was 0.99 and the AUC was 0.722 (95 % CI: 0.582-0.861) (Table 4), which suggested that the value of CTV-D/CTV-P was a reasonable indicator of the malignancy in patients with 2−5 cm gastric GISTs.
P-valuec High-mitosis group (n = 13) 8 (61.5) 5 (38.5) 8 (61.5) 3 (23.1) 2 (15.4) 11 (84.6) 2 (15.4) 8 (61.5) 5 (38.5) 6 (46.2) 7 (53.8) 0 6 (46.2) 6 (46.2) 1 (7.7) 6 (46.2) 7 (53.8) 35.46 ± 7.53 72 (64.83–82.67) 73.51 ± 15.28 2.25 (1.83–2.40) 0.98 ± 0.097
0.034 0.364
0.602 0.205 0.859
0.955
0.558 0.10 0.061 0.556 0.404 0.032
a For the qualitative analysis, data are numbers of patients with percentages in parentheses. b For the quantitative analysis, the normal distribution data are presented as mean ± standard deviation; the non-normal distribution data are presented as median (interquartile range). c P-values in bold indicate statistically significant difference between the tumours.
Table 2 Results of logistic regression for significant CT features of GIST risk stratification. CT features
P-valuea
Odds ratio (95 % CI)
CTV-D/CTV-P Contour (round)
0.049 0.071
186.445(1.035,33586.881) 3.901(0.890,17.099)
a P-value written in bold indicates statistically significant difference between the tumours.
For GISTs versus leiomyomas, similarly to for schwannomas, lesions without necrosis or cystic degeneration and those with the presence of homogeneous enhancement were more common in the leiomyoma group than in patients with GISTs (P = 0.021 and 0.035, respectively). The value of CTV-P/CTV-N in leiomyomas was significantly smaller than in GISTs (1.52 versus 2.07, P = 0.002). The cut-off point was 1.68 and the AUC was 0.883 (95 % CI: 0.759–1.000) for CTV-P/CTV-N in the comparison between GISTs and leiomyomas (Fig. 1 and Table 4). Representative examples of the schwannoma with relatively high CTV-D/ CTV-P and leiomyoma with relatively low CTV-P/CTV-N were shown in Figs. 4 and 5.
3.3. GIST versus schwannoma and GIST versus leiomyomas Differences between GISTs and benign SMTs as determined by univariate analysis are listed in Table 3. For GISTs versus schwannomas, tumours without necrosis or cystic degeneration (p = 0.002), and those associated with a homogeneous enhancement pattern (P = 0.038), were more common in patients with schwannomas than in the GIST group. The CTV-D of schwannomas (89.33 ± 9.01 HU) was significantly higher than that of GISTs (71.17 ± 16.06 HU) (P < 0.0001). The value of CTV-D/CTV-P in the schwannoma group was significantly higher than in the GIST group (1.24 versus 1.06, P < 0.0001). The cut-off point was 1.13 and the AUC was 0.853 (95 % CI: 0.763-0.944) for CTV-D/CTVP in the comparison between GISTs and schwannomas (Fig. 1 and Table 4).
4. Discussion With the increasing popularity of endoscopic techniques, especially in the East, more than half of gastric tumours smaller than 5 cm in 3
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Table 3 Comparison of CT features in patients with 2−5 cm gastric SMTs. GIST (n = 60)
Contour Round Lobulated Growth pattern Endophytic Mixed Exophytic Calcification Absent Present Sulface ulceration Absent Present Necrosis or cystic degeneration Absent Mild Severe Degree of enhancement Low Iso High Enhancement pattern Homogeneous Heterogeneous CTV-N(Hu) CTV-P(Hu) CTV-D(Hu) CTV-P/CTV-N CTV-D/CTV-P
Non-GIST (n = 16)a,b
P-valuec
Schwannoma (n = 10)
Leiomyoma (n = 6)
49 (81.7) 11 (18.3)
10 (100.0) 0 (0.0)
5 (83.3) 1 (16.7)
31 (51.7) 10 (16.7) 19 (31.7)
3 (30.0) 2 (20.0) 5 (50.0)
3 (50.0) 0 (0.0) 3 (50.0)
54 (90.0) 6 (10.0)
10 (100.0) 0 (0.0)
6 (100) 0 (0.0)
45 (75.0) 15 (25.0)
8 (80.0) 2 (20.0)
5 (83.3) 1 (16.7)
28 (46.7) 28 (46.7) 4 (6.7)
10 (100.0) 0 (0.0) 0 (0.0)
6 (100.0) 0 (0.0) 0 (0.0)
29 (48.3) 26 (43.3) 5 (8.3)
2 (20.0) 8 (80.0) 0 (0.0)
5 (83.3) 1 (16.7) 0 (0.0)
32 (53.3) 28 (46.7) 32.41 ± 7.57 66.33 (54.83–78.83) 71.17 ± 16.06 2.07 (1.88–2.34) 1.06 (0.95–1.17)
9 (90.0) 1 (10.0) 35.9 ± 4.46 70.83 (62.33–80.25) 89.33 ± 9.01 2.05 (1.77–2.27) 1.24 (1.17–1.31)
6 (100.0) 0 (0.0) 36.94 ± 8.54 53.00 (47.83–63.92) 63.11 ± 9.67 1.52 (1.32–1.81) 1.17 (1.04–1.27)
GIST versus schwannoma
GIST versus leiomyoma
0.344
1.000
0.392
0.618
0.583
1.000
1.000
1.000
0.002
0.021
0.289
0.154
0.038
0.035
0.162 0.306
0.171 0.067
< 0.001 0.626
0.234 0.002
< 0.001
0.124
a
For the qualitative analysis, data are numbers of patients with percentages in parentheses. For the quantitative analysis, the normal distribution data is presented as mean ± standard deviation; the non-normal distribution data is presented as median (interquartile range). c P-values written in bold indicate statistically significant difference between the tumours. b
qualitative data available for this study, the presence of lobulated shape was significantly more frequent in GISTs with high mitoses (P = 0.034). This result was partially consistent with a retrospective study that indicated that only tumour shape and growth pattern on CT were significant in predicting mitotic index [7]. Recently, some studies demonstrated that the presence of heterogeneous enhancement, necrosis and surface ulceration on CT were closely related to the higher risk stratification of GISTs, including of tumours larger than 5 cm [13,15,16]. However, as previously described, there were no significant differences in CT features of 2−5 cm GISTs in the current study between the high-mitosis and low-mitosis groups (all P > 0.05). This lack of difference could be explained by the occurrence of some CT features not just being associated with the biological behaviour of tumours; for example, Choi et al. identified that the presence of surface ulceration had no direct correlation with aggressive tumoral behaviour and originated from the ischemic mucosa pressed by the enlarging SMT [17]. From the quantitative data, CTV-D/CTV-P was an independent indicator for 2−5 cm GISTs risk stratification. The heterogeneous enhancement pattern of GISTs could be explained by the theory of neovascularisation [17,18]. The lower value of CTV-D/CTV-P in GISTs with high mitoses may also be due to neovascularization: the mismatch between the rapid speed of tumour growth and relatively slow speed of neovascularization in high-mitosis GISTs can induce the formation of necrosis or cystic degeneration, which is sometimes invisible to the naked eye on CT. The decrease of the solid component in GISTs results in less pressure being imposed upon the intra-tumoral blood vessel and
diameter are diagnosed and treated [12,13]. Therefore, it is important to make correct diagnoses and therapeutic strategies for small gastric lesions. GIST is the most common gastric SMT, which originates from mesenchyme [12]. The majority of GISTs less than 2 cm are usually without the risk of metastasis and their mitotic counts are less than 5 per 50 HPFs in general; conversely, for GISTs between 2 cm and 5 cm, there is a ten-fold difference in rates of metastasis between low-mitosis and high-mitosis groups [6]. Counts of mitoses are usually unknown before operation due to endoscopic biopsy not being conventionally performed in SMTs because of its high false negative rate, which is caused by SMT locations and insufficient tissue for pathological examinations [10,14]. Consequently, if contrasted-enhanced CT, a frequently used and non-invasive examination for gastric tumours, can be used to predict the malignancy of 2−5 cm gastric GISTs, this could be used to inform treatment measures, and especially to promote minimally-invasive procedures. In this research, the location and size of the 2−5 cm gastric GISTs were certain. Hence, according to the NCCN guideline, the malignancy potential of 2−5 cm gastric GISTs mainly depends on mitotic counts [1]. Tateishi et al. indicated that hepatic metastasis, presence of wall invasion and tumours larger than 11.1 cm were CT features of highgrade GISTs [13]. However, only tumours between 2 cm and 5 cm, which were in their early stages and without CT features characteristic of advanced tumours such as ill-defined margin, organ invasion and distant or peritoneal metastasis, were included in this analysis. A previous study showed that CT was not suitable for predicting the malignancy of GISTs 5 cm or smaller [12]. Nevertheless, with the 4
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Fig. 1. ROC curves. a. ROC curve of CTV-D/CTV-P for differentiation between GISTs in the high-mitosis and low-mitosis groups. b. ROC curve of CTV-D/CTV-P for differentiation between GISTs and schwannomas. c. ROC curve of CTV-P/CTV-N for differentiation between GISTs and leiomyomas.
more rapid washout of contrast medium from the tumour. This proposed mechanism is reflected in the lower value of CTV-D/CTV-P in high-mitosis GISTs. Different pathological types of SMTs exhibit different biological behaviour [17]. As two representative types of benign SMTs, almost without any risk of metastasis, schwannomas and leiomyomas should be treated via different methods than GISTs [9,19]. Benign SMTs usually have similar CT features as GISTs and are nearly always preoperatively diagnosed as GISTs [8]. Rates of preoperative misdiagnosis for schwannomas and leiomyomas in the current study were 100 % and 83.3 %, respectively. Taken together, if benign SMTs are distinguished from GISTs before the operation, more suitable, individualised treatment can be used in patients with SMTs.
Similarly to the present study, previous studies have demonstrated that, under normal conditions, the age of onset of benign SMTs, which are usually asymptomatic, is younger than of GISTs [9,17]. Unlike GISTs with potential malignancies, benign SMTs grow slowly and neovascularisation can provide enough blood supply for their growth; insufficient blood supply is the reason for necrosis or cystic degeneration [8,17]. Hence, in this study, the presence of necrosis or cystic degeneration and a heterogeneous enhancement pattern was more likely to indicate GISTs than schwannomas or leiomyomas. These results corroborated many earlier findings [8,9,17,19,20]. Liu et al. [21] showed that lymphadenopathy was more common in patients with schwannomas, which was caused by the inflammation process [22]. This differs from findings presented here, and a possible explanation for
Fig. 2. a–c. CT images of a 46-year-old woman pathologically diagnosed with gastric GIST with high mitosis. The lesion (arrow) shows lobulated shape, heterogeneous enhancement and presence of necrosis. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase. 5
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Fig. 3. a–c. CT images of a 70-year-old man pathologically diagnosed with gastric GIST with low mitosis. The lesion (arrow) shows round shape and homogeneous enhancement. The enhancement of the lesion occurred over time with peak enhancement during the delayed phase. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase.
using CTV-D/CTV-P for schwannomas, and 0.883 using CTV-P/CTV-N for leiomyomas. Therefore, ratios of CT values in different phases on contrast-enhanced CT have potential value in clinical application for risk stratification and identification of 2−5 cm gastric GISTs. However, our study has several limitations. Firstly, it is a retrospective study using different CT machines and having unavoidable selection bias. Secondly, because of the low incidence of certain types of SMTs, even though the current study included the largest series of patients with 2−5 cm SMTs to our knowledge, the number of patients were different within different types and not large for some types of SMTs. With the limited sample size, the multivariate analysis was not performed between GISTs and benign SMTs and the generalisability of some quantitative parameters needs to be verified. Thirdly, our study only focused on SMTs between 2 and 5 cm, and a large portion of patients with SMTs was excluded. Nevertheless, taking into consideration the high detection rate of small gastric tumours and poor ability to appropriately differentiate therapies among patients with 2−5 cm GISTs, these results may have potential clinical value. Taken together, further prospective and multi-centre studies with larger sample size are needed. In conclusion, 2−5 cm GISTs with high mitoses have characteristic CT features including a lobulated contour and lower value of CTV-D/ CTV-P, which may be used to differentiate them from GISTs with low mitoses. In terms of 2−5 cm benign SMTs, schwannomas and leiomyomas are more likely to have homogeneous enhancement without the presence of necrosis or cystic degeneration. The higher value of CTVD/CTV-P in schwannomas and lower value of CTV-P/CTV-N in leiomyomas, respectively, may enable these to be distinguished from GISTs. Thus, the combination of qualitative and quantitative parameters on contrast-enhanced CT may be helpful for 2−5 cm GIST risk stratification and identification.
Table 4 Parameters of ROC curves. AUC
SE
P value
High-mitosis group versus low-mitosis group CTV-D/CTV-P 0.722 0.071 0.015
95 % CI
Cut-off point
0.5820.861
0.99
Schwannoma versus GIST CTV-D/CTV-P 0.853
0.046
< 0.001
1.13
Leiomyoma versus GIST CTV-P/CTV-N 0.883
0.7630.944
0.063
0.002
0.7591.000
1.68
this may be that 2−5 cm schwannomas with relatively small size may be unable to cause enough inflammatory activities to induce the enlargement of lymph nodes. It has been suggested that enhancement of gastric schwannomas occurs over time, with peak enhancement during the delayed phase [20,23]; on the other hand, as previously mentioned, the CTV-D may decline in GISTs because of the quick washout of intratumoral contrast agent. These rationales could reasonably explain the finding of the current study that the value of CTV-D/CTVP was significantly higher in schwannomas than in GISTs (P < 0.0001). The poor enhancement caused by low vascularity is one of the characteristic imaging features of leiomyomas [9,10]. In other words, there is no great difference between CTV-N and CTV-P in leiomyomas. This inference supports the finding in our research that the value of CTV-P/CTV-N was significantly lower in leiomyomas than in GISTs. Ultimately, multiphasic enhanced-CT scanning can provide useful information for distinguishing disease in SMTs, and the outcome of our study was contrary to that of previous research done by Liu et al. [21]. The quantitative data of CTV-D/CTV-P and CTV-P/CTV-N can reflect the intra-tumoral dynamic change of the contrast medium. Results of ROC analyses are listed in Table 4. An AUCs of 0.722 was obtained using CTV-D/CTV-P to identify 2−5 cm high-mitosis GISTs, 0.853
Funding This work is supported by the Cross-subject Program of Peking University First Hospital (No. 2018CR38)
Fig. 4. a–c. CT images of a 45-year-old woman pathologically diagnosed with gastric schwannoma. The lesion (arrow) shows homogeneous enhancement. The enhancement of the lesion occurred over time with peak enhancement during the delayed phase. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase. 6
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Fig. 5. a–c. CT images of a 34-year-old man pathologically diagnosed with gastric leiomyoma. The lesion (arrow) shows homogeneous enhancement. The enhancement of the lesion was not obvious. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase.
Declaration of Competing Interest
(2015) 1694–1700. [10] M.J. Lee, J.S. Lim, J.E. Kwon, et al., Gastric true leiomyoma: computed tomographic findings and pathological correlation, J. Comput. Assist. Tomogr. 31 (2) (2007) 204–208. [11] M. Mehren, J.M. Kane III, R.S. Benjamin, Soft tissue sarcoma, version 2.2019, NCCN clinical practice guidelines in oncology, J. Compr. Canc. Netw. 16 (5) (2018) 536–563. [12] H.C. Kim, J.M. Lee, K.W. Kim, et al., Gastrointestinal stromal tumors of the stomach: CT findings and prediction of malignancy, AJR Am. J. Roentgenol. 183 (4) (2004) 893–898. [13] U. Tateishi, T. Hasegawa, M. Satake, N. Moriyama, Gastrointestinal stromal tumor. Correlation of computed tomography findings with tumour grade and mortality, J. Comput. Assist. Tomogr. 27 (5) (2003) 792–798. [14] J.Y. Kim, J.M. Lee, K.W. Kim, et al., Ectopic pancreas: CT findings with emphasis on differentiation from small gastrointestinal stromal tumor and leiomyoma, Radiology 252 (1) (2009) 92–100. [15] C. Zhou, X. Duan, X. Zhang, H. Hu, D. Wang, J. Shen, Predictive features of CT for risk stratifications in patients with primary gastrointestinal stromal tumour, Eur. Radiol. 26 (9) (2016) 3086–3093. [16] H. Li, G. Ren, R. Cai, J. Chen, X. Wu, J. Zhao, A correlation research of Ki67 index, CT features, and risk stratification in gastrointestinal stromal tumor, Cancer Med. 7 (9) (2018) 4467–4474. [17] Y.R. Choi, S.H. Kim, S.A. Kim, et al., Differentiation of large (≥ 5 cm) gastrointestinal stromal tumors from benign subepithelial tumors in the stomach: radiologists’ performance using CT, Eur. J. Radiol. 83 (2) (2014) 250–260. [18] M.H. Yu, J.M. Lee, J.H. Baek, J.K. Han, B.I. Choi, MRI features of gastrointestinal stromal tumors, AJR Am. J. Roentgenol. 203 (5) (2014) 980–991. [19] H.S. Hong, H.K. Ha, H.J. Won, et al., Gastric schwannomas: radiological features with endoscopic and pathological correlation, Clin. Radiol. 63 (5) (2008) 536–542. [20] A.D. Levy, A.M. Quiles, M. Miettinen, L.H. Sobin, Gastrointestinal schwannomas: CT features with clinicopathologic correlation, AJR Am. J. Roentgenol. 184 (3) (2005) 797–802. [21] M. Liu, L. Liu, E. Jin, Gastric sub-epithelial tumors: identification of gastrointestinal stromal tumors using CT with a practical scoring method, Gastric Cancer 22 (4) (2019) 769–777. [22] M.Y. He, R. Zhang, Z. Peng, et al., Differentiation between gastrointestinal schwannomas and gastrointestinal stromal tumors by computed tomography, Oncol. Lett. 13 (5) (2017) 3746–3752. [23] J.S. Ji, C.Y. Lu, W.B. Mao, Z.F. Wang, M. Xu, Gastric schwannoma: CT findings and clinicopathologic correlation, Abdom. Imaging 40 (5) (2015) 1164–1169.
There is no conflict of interest in this manuscript. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.ejrad.2019.108783. References [1] G.D. Demetri, M. von Mehren, C.R. Antonescu, et al., NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors, J. Compr. Canc. Netw. 8 (Suppl 2) (2010) S1–S41 quiz S42-4. [2] W. An, P.B. Sun, J. Gao, et al., Endoscopic submucosal dissection for gastric gastrointestinal stromal tumors: a retrospective cohort study, Surg. Endosc. 31 (11) (2017) 4522–4531. [3] C. Shen, H. Chen, Y. Yin, et al., Endoscopic versus open resection for small gastric gastrointestinal stromal tumors: safety and outcomes, Medicine (Baltimore) 94 (1) (2015) e376. [4] I. Andalib, D. Yeoun, R. Reddy, S. Xie, S. Iqbal, Endoscopic resection of gastric gastrointestinal stromal tumors originating from the muscularis propria layer in North America: methods and feasibility data, Surg. Endosc. 32 (4) (2018) 1787–1792. [5] M.Y. Kim, Y.S. Park, K.D. Choi, et al., Predictors of recurrence after resection of small gastric gastrointestinal stromal tumors of 5 cm or less, J. Clin. Gastroenterol. 46 (2) (2012) 130–137. [6] M. Miettinen, J. Lasota, Gastrointestinal stromal tumors: pathology and prognosis at different sites, Semin. Diagn. Pathol. 23 (2) (2006) 70–83. [7] T. Chen, L. Xu, X. Dong, et al., The roles of CT and EUS in the preoperative evaluation of gastric gastrointestinal stromal tumors larger than 2 cm, Eur. Radiol. 29 (5) (2019) 2481–2489. [8] J.W. Choi, D. Choi, K.M. Kim, et al., Small submucosal tumors of the stomach: differentiation of gastric schwannoma from gastrointestinal stromal tumor with CT, Korean J. Radiol. 13 (4) (2012) 425–433. [9] H.K. Yang, Y.H. Kim, Y.J. Lee, et al., Leiomyomas in the gastric cardia: CT findings and differentiation from gastrointestinal stromal tumors, Eur. J. Radiol. 84 (9)
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Gastric gastrointestinal stromal tumours (2-5 cm): Correlation of CT features with malignancy and differential diagnosis
T
Zeyang Chena,1, Jiejin Yangb,1, Jiali Sunb, Pengyuan Wanga,* a b
Department of General Surgery, Peking University First Hospital, Peking University, 8 Xi ShiKu Street, Beijing 100034, People’s Republic of China Department of Radiology, Peking University First Hospital, Peking University, 8 Xi ShiKu Street, Beijing 100034, People’s Republic of China
ARTICLE INFO
ABSTRACT
Keywords: Gastrointestinal stromal tumours Computed tomography Schwannoma Leiomyoma Risk stratification
Purpose: The purpose of this study was to investigate the computed tomography (CT) features of 2−5 cm gastric gastrointestinal stromal tumors (GISTs), schwannomas and leimyomas which have close relationship with malignancy evaluation and differential diagnosis. Method: Seventy-six patients with pathologically confirmed gastric submucosal tumors (SMTs) between 2−5 cm were included in this study, including 60 GISTs, 10 schwannomas and 6 leiomyomas. CT imaging features were reviewed and quantitative parameters including CT values during nonenhanced phase (CTV-N), portal phase (CTV-P) and delayed phase (CTV-D) were recorded. The association of CT features with mitotic counts of GISTs and the significantly different CT features between GISTs and benign SMTs were analyzed. Results: The lobulated contour was significantly more common in GISTs with high mitoses (P < 0.05). The value of CTV-D/CTV-P was significantly lower in GISTs with high mitoses (P < 0.05) and it was an independent predictor for high-mitosis GISTs (P = 0.049, odds ratio [OR] = 186.445) with an area under the curve (AUC) of 0.722. CT features including heterogeneous enhancement and presence of necrosis or cystic degeneration were significantly suggestive of GISTs instead of benign SMTs (P < 0.05). The value of CTV-D/CTV-P was significantly higher in schwannomas than that in GISTs (P < 0.05) with an AUC of 0.853. The value of CTV-P/ CTV-N was significantly lower in leiomyomas than that in GISTs (P < 0.05) with an AUC of 0.883. Conclusions: Some qualitative and quantitative parameters on contrast-enhanced CT can be helpful in preoperative diagnosis and risk stratification of 2−5 cm gastric GISTs.
1. Introduction Recent developments in the field of minimally invasive surgical technology have led to an increasing interest in endoscopic surgery for gastric submucosal tumours (SMTs). The National Comprehensive Cancer Network (NCCN) guidelines recommend that gastrointestinal stromal tumours (GISTs) < 2 cm in size should be resected or accept surveillance, which depends on whether there are high-risk endoscopic ultrasonography (EUS) features, and that all GISTs > 2 cm should be resected [1]. Endoscopic resection is an effective and safe treatment for gastric GISTs < 2 cm, but may not be suitable for GISTs > 5 cm because it is difficult to remove large tumours from the stomach via the oral route [2–4]. Nevertheless, whether endoscopic surgery can be used in 2−5 cm gastric GISTs remains controversial considering the potential
risk of metastasis and recurrence [2,5]. For 2−5 cm gastric GISTs, metastasis rates for GISTs with mitotic counts > 5 per 50 high power fields (HPFs) and ≤ 5/50 HPFs are 16 % and 1.9 %, respectively [6]. Chen et al. indicated that CT features were more useful than EUS features for predicting mitotic counts [7]. Therefore, exploring the association between CT features and GIST risk stratification may influence the surgical treatment decision for 2−5 cm gastric GISTs. Gastric SMTs are divided into three major categories: GISTs, neurogenic tumours and myogenic tumours [8]. GISTs are the most common gastric SMTs. For benign gastric SMTs, schwannomas and leiomyomas are the most representative types of neurogenic and myogenic tumours, respectively. Each type of gastric SMT should be managed specifically according to its different biological behaviour [9]. Some studies have suggested that conservative and minimally invasive
Abbreviations: GISTs, gastrointestinal stromal tumours; SMTs, submucosal tumours; HU, Housefield unit; CTV-N, CT values during nonenhanced phase; CTV-P, CT values during portal phase; CTV-D, CT values during delayed phase ⁎ Corresponding author. E-mail address: [email protected] (P. Wang). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.ejrad.2019.108783 Received 5 September 2019; Received in revised form 20 October 2019; Accepted 24 November 2019 0720-048X/ © 2019 Elsevier B.V. All rights reserved.
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treatments are suitable for benign SMTs with clinically favourable outcomes, in contrast to GISTs with potential malignancy [9,10]. However, it is hard to distinguish gastric GISTs from benign SMTs preoperatively because they demonstrate similar CT features and clinical symptoms. Therefore, this study aimed to identify some qualitative and quantitative parameters on contrast-enhanced CT that may be useful in risk stratification, enabling identification of patients with clinically critical 2−5 cm gastric GISTs.
retrospectively by two experienced radiologists, who were blind to patients’ pathologic data. As for the result which they had originally disagreed, two radiologists reached agreement by negotiating together. CT SMT features included contour, margin, growth pattern, degree of enhancement, enhancement pattern, necrosis or cystic degeneration, calcification, surface ulceration, lymphadenopathy, organ invasion and distant or peritoneal metastasis. The contour of the tumour was divided into round (regular shape) and lobulated (irregular shape). A clear tumour margin was defined as well-defined, or, when the tumour infiltrated surrounding tissues or had a blurred border, as ill-defined. The growth pattern of the lesion was classified as endophytic, exophytic or mixed: endophytic growth signified the lesion was confined to the gastric cavity without expanding toward the extraluminal space; exophytic growth identified that a tumour was confined to the extraluminal space without bulging into the gastric cavity; mixed growth was defined as a pattern with endophytic and exophytic features. In the portal phase of contrast-enhanced CT, the degree of enhancement was evaluated by comparing CT values of the lesion with the liver or the muscle as described previously [12]. The enhancement pattern of the lesion was classified into homogeneous or heterogeneous. The region of necrosis or cystic degeneration was determined when its CT value was less than 20 HU in the portal phase. Degrees of necrosis or cystic degeneration were graded as absent, mild (< 50 % low-density areas of the lesion), and severe (> 50 % low-density areas of the lesion). The presence of calcification was determined by the presence of high-attenuation foci in the mass. The presence of surface ulceration was defined as some mucosal tissue defects on the intraluminal surface of the mass. If long-axis diameters of regional lymph nodes were larger than 1 cm, this was identified as lymphadenopathy [12].
2. Materials and methods 2.1. Patients selection The Institutional Ethics Committee of Peking University First Hospital approved this retrospective study and the need for informed consent was waived. The pathologic database at this institution was searched to identify 230 patients with GISTs, 15 patients with schwannomas and 27 patients with leiomyomas in the stomach from January 2008 to December 2018. 146 GISTs, 4 schwannomas and 16 leiomyomas were excluded because their longest diameters were greater than 5 cm or smaller than 2 cm. 18 patients with GISTs, one patient with schwannomas and 3 patients with leiomyomas were excluded due to unavailable or undetailed CT images. Additionally, 6 patients with GISTs and 2 patients with leiomyomas were excluded as they only accepted biopsy without surgical excision. Finally, 60 GISTs, 10 schwannomas and 6 leiomyomas met all of the inclusion criteria. The inclusion criteria were as follows: (a) patients with primary submucosal tumours (SMTs) in the stomach undergoing radical operation without rupture; (b) GISTs, schwannomas or leiomyomas confirmed by postoperative pathologic diagnosis and the diagnosis was made by two experienced pathologic doctors according to specimens’ morphologic assessment and immunohistochemistry results; (c) longest tumour diameter > 2 cm and < 5 cm confirmed by pathologic measurement; (d) abdominal contrast-enhanced CT performed within 1 month before operation; (e) CT images containing non-enhancing phase, portal phase and delayed phase available for analysis; (f) no neoadjuvant treatment; (g) detailed clinicopathological data. Subsequently, according to the latest National Comprehensive Cancer Network (NCCN) guidelines of soft tissue sarcoma [11], GISTs with mitotic counts ≤ 5/50 HPFs and > 5/50 HPFs have distinct biological behavior. Hence, patients with 2−5 cm gastric GISTs were divided into a low-mitosis group (≤ 5/50 HPFs) and high-mitosis group (> 5/50 HPFs).
2.3.2. Quantitative analysis Two radiologist measured the mean CTV-N, CTV-P and CTV-D of tumours. Under the condition of avoiding heterogeneous regions, such as necrotic and cystic positions, larger than 10 mm2 circular regions of interests (ROIs) were placed at three different homogeneous sites of the lesion of the non-enhanced phase to measure CTV-N values. In the same way, CTV-P and CTV-D were evaluated in the same slice and location as in CTV-N in each of these three sites. Subsequently, the ratio of CTV-P to CTV-N and CTV-D to CTV-P was calculated in each site. Then averages of CTV-N, CTV-P, CTV-D, CTV-P/CTV-N and CTV-D/CTV-P were calculated in three homogeneous sites as the independently measured parameter. The average value of two radiologists’ independently measured parameters were used in the analysis.
2.2. CT acquisition Abdominal contrast-enhanced CT examinations had been performed using one of the following multislice spiral CT machines: Siemens Somatom Sensation 64 (Siemens, Forchheim, Germany); Philips Brilliance iCT, or Philips Brilliance 64 (Philips Medical Systems, Cleveland, OH, USA); GE Discovery CT750 m or GE LightSpeed VCT (GE Healthcare, Princeton, NJ, USA). The parameters of spiral CT were as follows: 120 kV tube voltage, 150−250 mA tube current, 0.5-0.8 s tube rotation time, 64 × 0.625 mm detector collimation, 350 × 350 mm field of view, 512 × 512 matrix, 5 mm section thickness and 1 mm reconstruction interval. Before CT examinations, patients were required to fast for at least 8 h. 500 ml of water was administered orally 5−10 min prior to scan. Subsequently, 80–100 ml iodinated contrast medium was injected intravenously at a rate of 3.0 ml/s. Portal phase and delayed phase images were obtained 60 s and 180 s after the injection of contrast medium.
2.4. Statistical analysis Univariate analysis using t test, chi-square test, Wilcoxon rank sum test and Fisher’s exact test was performed to compare CT features between the high-mitosis group and the low-mitosis group. Variables where P < 0.05 were included in the multivariate analysis. Subsequently, logistic regression was used for processing the multivariate analysis to select significant predictors for high mitotic counts. In multivariate analysis, a variable with two-sided P value < 0.05 was considered to be an independent predictor for mitoses. Odds ratios (OR) and 95 % confidence intervals (CIs) were also computed. The receiver operating characteristic (ROC) curve was drawn to evaluate the obtained variable from the multivariate analysis. CT features between GISTs and other benign SMTs (schwannomas and leiomyomas) were also compared by univariate analysis in the same way as previously described. The ROC was also calculated for some quantitative variables obtained from the univariate comparison between GISTs and benign SMTs. SPSS version 19.0 was used for statistical analysis. A statistically significant difference was defined as P value < 0.05.
2.3. CT imaging analysis 2.3.1. Qualitative analysis Abdominal contrast-enhanced
CT
images
were
reviewed 2
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3. Results
Table 1 Comparison of CT features in patients with 2−5 cm gastric GISTs.
3.1. Clinicopathological findings
Criteria
The clinicopathological findings of patients in the low-mitosis group (n = 47) and high-mitosis group (n = 13) were listed in Supplemental Table 1. Results of the univariate analysis indicated that patients had no significant difference in variables of age, tumour size, sex, type of operation and symptoms between the two groups (all P > 0.05). The clinicopathological data of 60 patients with GISTs, 10 patients with schwannomas, and 6 patients with leiomyomas were listed in Supplemental Table 2. The median age of patients with GISTs (65.0 years) was significantly older than that of patients in the schwannoma group (53.5 years, P = 0.005) and leiomyoma group (40.5 years, P = 0.002). Patients without symptoms in the schwannoma group (8/ 10, 80 %) were significantly more common than in the GIST group (21/ 60, 35 %) (P = 0.049). The ratio of patients being asymptomatic was higher in the leiomyoma group (4/6, 66.7 %) than in the GIST group (21/60, 35 %), but without statistical difference (P > 0.05). Before the operation, a patient with GIST was misdiagnosed as having a pancreatic tail lesion, and 10 patients with schwannomas and 5 patients with leiomyomas were misdiagnosed with GISTs. The preoperative misdiagnosis rate of the GIST group (1/60, 1.7 %) was significantly lower than in the schwannoma group (10/10, 100 %, P < 0.001) and leiomyoma group (5/6, 83.3 %, P < 0.001).
Mitotic indexa,b Low-mitosis group (n = 47)
Contour Round 41 (87.2) Lobulated 6 (12.8) Growth pattern Endophytic 23 (48.9) Mixed 7 (14.9) Exophytic 17 (36.2) Calcification Absent 43 (91.5) Present 4 (8.5) Surface ulceration Absent 37 (78.7) Present 10 (21.3) Necrosis or cystic degeneration Absent 22 (46.8) Mild 21 (44.7) Severe 4 (8.5) Degree of enhancement Low 23 (48.9) Iso 20 (42.6) High 4 (8.5) Enhancement pattern Homogeneous 26 (55.3) Heterogeneous 21 (44.7) CTV-N (HU) 31.56 ± 7.44 CTV-P (HU) 65.33 (53.33–74.67) CTV-D (HU) 70.52 ± 16.37 CTV-P/CTV-N 2.01 (1.87–2.29) CTV-D/CTV-P 1.10 ± 0.18
3.2. Association of CT features with malignancy of GISTs No patients with 2−5 cm gastric GISTs, schwannomas or leiomyomas had CT features of ill-defined margin, lymphadenopathy, organ invasion and distant or peritoneal metastasis, therefore these variables were not listed in Tables 1 and 3. According to the univariate analysis results (Table 1), growth pattern, calcification, surface ulceration, necrosis and cystic degeneration, degree of enhancement, enhancement pattern, CTV-N, CTV-P, CTV-D, and CTV-P/CTV-N were not significantly different between the low-mitosis and high-mitosis groups (P > 0.05). Tumours with lobulated contour were significantly more common in the high-mitosis group (5/13, 38.5 %) than in the lowmitosis group (6/60, 12.8 %, P = 0.034). Representative examples were illustrated in Figs. 2 and 3. The value of CTV-D/CTV-P in the highmitosis group was significantly smaller than in the low-mitosis group with means of 0.98 and 1.10, respectively (P = 0.032). The CT contour feature and the CTV-D/CTV-P parameter were included in the subsequent multivariate analysis (Table 2). The result of logistic regression indicated that only the value of CTV-D/CTV-P was an independent risk factor for malignancy in patients with 2−5 cm gastric GISTs (P = 0.049, OR = 186.445). Further ROC analysis was used to calculate the cut-off value and area under the curve (AUC) of CTVD/CTV-P (Fig. 1). The cut-off point was 0.99 and the AUC was 0.722 (95 % CI: 0.582-0.861) (Table 4), which suggested that the value of CTV-D/CTV-P was a reasonable indicator of the malignancy in patients with 2−5 cm gastric GISTs.
P-valuec High-mitosis group (n = 13) 8 (61.5) 5 (38.5) 8 (61.5) 3 (23.1) 2 (15.4) 11 (84.6) 2 (15.4) 8 (61.5) 5 (38.5) 6 (46.2) 7 (53.8) 0 6 (46.2) 6 (46.2) 1 (7.7) 6 (46.2) 7 (53.8) 35.46 ± 7.53 72 (64.83–82.67) 73.51 ± 15.28 2.25 (1.83–2.40) 0.98 ± 0.097
0.034 0.364
0.602 0.205 0.859
0.955
0.558 0.10 0.061 0.556 0.404 0.032
a For the qualitative analysis, data are numbers of patients with percentages in parentheses. b For the quantitative analysis, the normal distribution data are presented as mean ± standard deviation; the non-normal distribution data are presented as median (interquartile range). c P-values in bold indicate statistically significant difference between the tumours.
Table 2 Results of logistic regression for significant CT features of GIST risk stratification. CT features
P-valuea
Odds ratio (95 % CI)
CTV-D/CTV-P Contour (round)
0.049 0.071
186.445(1.035,33586.881) 3.901(0.890,17.099)
a P-value written in bold indicates statistically significant difference between the tumours.
For GISTs versus leiomyomas, similarly to for schwannomas, lesions without necrosis or cystic degeneration and those with the presence of homogeneous enhancement were more common in the leiomyoma group than in patients with GISTs (P = 0.021 and 0.035, respectively). The value of CTV-P/CTV-N in leiomyomas was significantly smaller than in GISTs (1.52 versus 2.07, P = 0.002). The cut-off point was 1.68 and the AUC was 0.883 (95 % CI: 0.759–1.000) for CTV-P/CTV-N in the comparison between GISTs and leiomyomas (Fig. 1 and Table 4). Representative examples of the schwannoma with relatively high CTV-D/ CTV-P and leiomyoma with relatively low CTV-P/CTV-N were shown in Figs. 4 and 5.
3.3. GIST versus schwannoma and GIST versus leiomyomas Differences between GISTs and benign SMTs as determined by univariate analysis are listed in Table 3. For GISTs versus schwannomas, tumours without necrosis or cystic degeneration (p = 0.002), and those associated with a homogeneous enhancement pattern (P = 0.038), were more common in patients with schwannomas than in the GIST group. The CTV-D of schwannomas (89.33 ± 9.01 HU) was significantly higher than that of GISTs (71.17 ± 16.06 HU) (P < 0.0001). The value of CTV-D/CTV-P in the schwannoma group was significantly higher than in the GIST group (1.24 versus 1.06, P < 0.0001). The cut-off point was 1.13 and the AUC was 0.853 (95 % CI: 0.763-0.944) for CTV-D/CTVP in the comparison between GISTs and schwannomas (Fig. 1 and Table 4).
4. Discussion With the increasing popularity of endoscopic techniques, especially in the East, more than half of gastric tumours smaller than 5 cm in 3
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Table 3 Comparison of CT features in patients with 2−5 cm gastric SMTs. GIST (n = 60)
Contour Round Lobulated Growth pattern Endophytic Mixed Exophytic Calcification Absent Present Sulface ulceration Absent Present Necrosis or cystic degeneration Absent Mild Severe Degree of enhancement Low Iso High Enhancement pattern Homogeneous Heterogeneous CTV-N(Hu) CTV-P(Hu) CTV-D(Hu) CTV-P/CTV-N CTV-D/CTV-P
Non-GIST (n = 16)a,b
P-valuec
Schwannoma (n = 10)
Leiomyoma (n = 6)
49 (81.7) 11 (18.3)
10 (100.0) 0 (0.0)
5 (83.3) 1 (16.7)
31 (51.7) 10 (16.7) 19 (31.7)
3 (30.0) 2 (20.0) 5 (50.0)
3 (50.0) 0 (0.0) 3 (50.0)
54 (90.0) 6 (10.0)
10 (100.0) 0 (0.0)
6 (100) 0 (0.0)
45 (75.0) 15 (25.0)
8 (80.0) 2 (20.0)
5 (83.3) 1 (16.7)
28 (46.7) 28 (46.7) 4 (6.7)
10 (100.0) 0 (0.0) 0 (0.0)
6 (100.0) 0 (0.0) 0 (0.0)
29 (48.3) 26 (43.3) 5 (8.3)
2 (20.0) 8 (80.0) 0 (0.0)
5 (83.3) 1 (16.7) 0 (0.0)
32 (53.3) 28 (46.7) 32.41 ± 7.57 66.33 (54.83–78.83) 71.17 ± 16.06 2.07 (1.88–2.34) 1.06 (0.95–1.17)
9 (90.0) 1 (10.0) 35.9 ± 4.46 70.83 (62.33–80.25) 89.33 ± 9.01 2.05 (1.77–2.27) 1.24 (1.17–1.31)
6 (100.0) 0 (0.0) 36.94 ± 8.54 53.00 (47.83–63.92) 63.11 ± 9.67 1.52 (1.32–1.81) 1.17 (1.04–1.27)
GIST versus schwannoma
GIST versus leiomyoma
0.344
1.000
0.392
0.618
0.583
1.000
1.000
1.000
0.002
0.021
0.289
0.154
0.038
0.035
0.162 0.306
0.171 0.067
< 0.001 0.626
0.234 0.002
< 0.001
0.124
a
For the qualitative analysis, data are numbers of patients with percentages in parentheses. For the quantitative analysis, the normal distribution data is presented as mean ± standard deviation; the non-normal distribution data is presented as median (interquartile range). c P-values written in bold indicate statistically significant difference between the tumours. b
qualitative data available for this study, the presence of lobulated shape was significantly more frequent in GISTs with high mitoses (P = 0.034). This result was partially consistent with a retrospective study that indicated that only tumour shape and growth pattern on CT were significant in predicting mitotic index [7]. Recently, some studies demonstrated that the presence of heterogeneous enhancement, necrosis and surface ulceration on CT were closely related to the higher risk stratification of GISTs, including of tumours larger than 5 cm [13,15,16]. However, as previously described, there were no significant differences in CT features of 2−5 cm GISTs in the current study between the high-mitosis and low-mitosis groups (all P > 0.05). This lack of difference could be explained by the occurrence of some CT features not just being associated with the biological behaviour of tumours; for example, Choi et al. identified that the presence of surface ulceration had no direct correlation with aggressive tumoral behaviour and originated from the ischemic mucosa pressed by the enlarging SMT [17]. From the quantitative data, CTV-D/CTV-P was an independent indicator for 2−5 cm GISTs risk stratification. The heterogeneous enhancement pattern of GISTs could be explained by the theory of neovascularisation [17,18]. The lower value of CTV-D/CTV-P in GISTs with high mitoses may also be due to neovascularization: the mismatch between the rapid speed of tumour growth and relatively slow speed of neovascularization in high-mitosis GISTs can induce the formation of necrosis or cystic degeneration, which is sometimes invisible to the naked eye on CT. The decrease of the solid component in GISTs results in less pressure being imposed upon the intra-tumoral blood vessel and
diameter are diagnosed and treated [12,13]. Therefore, it is important to make correct diagnoses and therapeutic strategies for small gastric lesions. GIST is the most common gastric SMT, which originates from mesenchyme [12]. The majority of GISTs less than 2 cm are usually without the risk of metastasis and their mitotic counts are less than 5 per 50 HPFs in general; conversely, for GISTs between 2 cm and 5 cm, there is a ten-fold difference in rates of metastasis between low-mitosis and high-mitosis groups [6]. Counts of mitoses are usually unknown before operation due to endoscopic biopsy not being conventionally performed in SMTs because of its high false negative rate, which is caused by SMT locations and insufficient tissue for pathological examinations [10,14]. Consequently, if contrasted-enhanced CT, a frequently used and non-invasive examination for gastric tumours, can be used to predict the malignancy of 2−5 cm gastric GISTs, this could be used to inform treatment measures, and especially to promote minimally-invasive procedures. In this research, the location and size of the 2−5 cm gastric GISTs were certain. Hence, according to the NCCN guideline, the malignancy potential of 2−5 cm gastric GISTs mainly depends on mitotic counts [1]. Tateishi et al. indicated that hepatic metastasis, presence of wall invasion and tumours larger than 11.1 cm were CT features of highgrade GISTs [13]. However, only tumours between 2 cm and 5 cm, which were in their early stages and without CT features characteristic of advanced tumours such as ill-defined margin, organ invasion and distant or peritoneal metastasis, were included in this analysis. A previous study showed that CT was not suitable for predicting the malignancy of GISTs 5 cm or smaller [12]. Nevertheless, with the 4
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Fig. 1. ROC curves. a. ROC curve of CTV-D/CTV-P for differentiation between GISTs in the high-mitosis and low-mitosis groups. b. ROC curve of CTV-D/CTV-P for differentiation between GISTs and schwannomas. c. ROC curve of CTV-P/CTV-N for differentiation between GISTs and leiomyomas.
more rapid washout of contrast medium from the tumour. This proposed mechanism is reflected in the lower value of CTV-D/CTV-P in high-mitosis GISTs. Different pathological types of SMTs exhibit different biological behaviour [17]. As two representative types of benign SMTs, almost without any risk of metastasis, schwannomas and leiomyomas should be treated via different methods than GISTs [9,19]. Benign SMTs usually have similar CT features as GISTs and are nearly always preoperatively diagnosed as GISTs [8]. Rates of preoperative misdiagnosis for schwannomas and leiomyomas in the current study were 100 % and 83.3 %, respectively. Taken together, if benign SMTs are distinguished from GISTs before the operation, more suitable, individualised treatment can be used in patients with SMTs.
Similarly to the present study, previous studies have demonstrated that, under normal conditions, the age of onset of benign SMTs, which are usually asymptomatic, is younger than of GISTs [9,17]. Unlike GISTs with potential malignancies, benign SMTs grow slowly and neovascularisation can provide enough blood supply for their growth; insufficient blood supply is the reason for necrosis or cystic degeneration [8,17]. Hence, in this study, the presence of necrosis or cystic degeneration and a heterogeneous enhancement pattern was more likely to indicate GISTs than schwannomas or leiomyomas. These results corroborated many earlier findings [8,9,17,19,20]. Liu et al. [21] showed that lymphadenopathy was more common in patients with schwannomas, which was caused by the inflammation process [22]. This differs from findings presented here, and a possible explanation for
Fig. 2. a–c. CT images of a 46-year-old woman pathologically diagnosed with gastric GIST with high mitosis. The lesion (arrow) shows lobulated shape, heterogeneous enhancement and presence of necrosis. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase. 5
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Fig. 3. a–c. CT images of a 70-year-old man pathologically diagnosed with gastric GIST with low mitosis. The lesion (arrow) shows round shape and homogeneous enhancement. The enhancement of the lesion occurred over time with peak enhancement during the delayed phase. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase.
using CTV-D/CTV-P for schwannomas, and 0.883 using CTV-P/CTV-N for leiomyomas. Therefore, ratios of CT values in different phases on contrast-enhanced CT have potential value in clinical application for risk stratification and identification of 2−5 cm gastric GISTs. However, our study has several limitations. Firstly, it is a retrospective study using different CT machines and having unavoidable selection bias. Secondly, because of the low incidence of certain types of SMTs, even though the current study included the largest series of patients with 2−5 cm SMTs to our knowledge, the number of patients were different within different types and not large for some types of SMTs. With the limited sample size, the multivariate analysis was not performed between GISTs and benign SMTs and the generalisability of some quantitative parameters needs to be verified. Thirdly, our study only focused on SMTs between 2 and 5 cm, and a large portion of patients with SMTs was excluded. Nevertheless, taking into consideration the high detection rate of small gastric tumours and poor ability to appropriately differentiate therapies among patients with 2−5 cm GISTs, these results may have potential clinical value. Taken together, further prospective and multi-centre studies with larger sample size are needed. In conclusion, 2−5 cm GISTs with high mitoses have characteristic CT features including a lobulated contour and lower value of CTV-D/ CTV-P, which may be used to differentiate them from GISTs with low mitoses. In terms of 2−5 cm benign SMTs, schwannomas and leiomyomas are more likely to have homogeneous enhancement without the presence of necrosis or cystic degeneration. The higher value of CTVD/CTV-P in schwannomas and lower value of CTV-P/CTV-N in leiomyomas, respectively, may enable these to be distinguished from GISTs. Thus, the combination of qualitative and quantitative parameters on contrast-enhanced CT may be helpful for 2−5 cm GIST risk stratification and identification.
Table 4 Parameters of ROC curves. AUC
SE
P value
High-mitosis group versus low-mitosis group CTV-D/CTV-P 0.722 0.071 0.015
95 % CI
Cut-off point
0.5820.861
0.99
Schwannoma versus GIST CTV-D/CTV-P 0.853
0.046
< 0.001
1.13
Leiomyoma versus GIST CTV-P/CTV-N 0.883
0.7630.944
0.063
0.002
0.7591.000
1.68
this may be that 2−5 cm schwannomas with relatively small size may be unable to cause enough inflammatory activities to induce the enlargement of lymph nodes. It has been suggested that enhancement of gastric schwannomas occurs over time, with peak enhancement during the delayed phase [20,23]; on the other hand, as previously mentioned, the CTV-D may decline in GISTs because of the quick washout of intratumoral contrast agent. These rationales could reasonably explain the finding of the current study that the value of CTV-D/CTVP was significantly higher in schwannomas than in GISTs (P < 0.0001). The poor enhancement caused by low vascularity is one of the characteristic imaging features of leiomyomas [9,10]. In other words, there is no great difference between CTV-N and CTV-P in leiomyomas. This inference supports the finding in our research that the value of CTV-P/CTV-N was significantly lower in leiomyomas than in GISTs. Ultimately, multiphasic enhanced-CT scanning can provide useful information for distinguishing disease in SMTs, and the outcome of our study was contrary to that of previous research done by Liu et al. [21]. The quantitative data of CTV-D/CTV-P and CTV-P/CTV-N can reflect the intra-tumoral dynamic change of the contrast medium. Results of ROC analyses are listed in Table 4. An AUCs of 0.722 was obtained using CTV-D/CTV-P to identify 2−5 cm high-mitosis GISTs, 0.853
Funding This work is supported by the Cross-subject Program of Peking University First Hospital (No. 2018CR38)
Fig. 4. a–c. CT images of a 45-year-old woman pathologically diagnosed with gastric schwannoma. The lesion (arrow) shows homogeneous enhancement. The enhancement of the lesion occurred over time with peak enhancement during the delayed phase. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase. 6
European Journal of Radiology 123 (2020) 108783
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Fig. 5. a–c. CT images of a 34-year-old man pathologically diagnosed with gastric leiomyoma. The lesion (arrow) shows homogeneous enhancement. The enhancement of the lesion was not obvious. a. Image of the nonenhanced phase. b. Image of the portal phase. c. Image of the delayed phase.
Declaration of Competing Interest
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