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Cine MR feature tracking analysis for diagnosing thymic epithelial tumors: a feasibility study

Cine MR feature tracking analysis for diagnosing thymic epithelial tumors: a feasibility study Background To assess the feasibility of the cine MR feature tracking technique for the evaluation of cardiovascular- induced morphological deformation in the diagnosis of thymic epithelial tumors ( TETs). Methods Our study population consisted of 43 patients with pathologically proven TETs including 10 low-grade thymomas, 23 high-grade thymomas, and 10 thymic carcinomas. Cine MR images were acquired using a balanced steady-state free precession sequence with short periods of breath-hold in the axial and oblique planes in the slice with the largest lesion cross-sectional area. The tumor margin was manually delineated in the diastolic phase and was automatically tracked for all other cardiac phases. The change rates of the long-to-short diameter ratio (∆LSR) and tumor area (∆area) associated with pulsation were compared between the three pathological groups using the Kruskal–Wallis H test and the Mann–Whitney U test. A receiver-operating characteristic (ROC) curve analysis was performed to assess the ability of each parameter to differentiate thymic carcinomas from thymomas. Results ∆LSR and ∆area were significantly different among the three groups in the axial plane (p = 0.028 and 0.006, respectively) and in the oblique plane (p = 0.034 and 0.043, respectively). ∆LSR and ∆area values were significantly lower in thymic carcinomas than in thymomas in the axial plane (for both, p = 0.012) and in the oblique plane (p = 0.015 and 0.011, respectively). The area under the ROC curves for ∆LSR and ∆area for the diagnosis of thymic carcinoma ranged from 0.755 to 0.764. Conclusions Evaluation of morphological deformation using cine-MR feature tracking analysis can help diagnose histopathological subtypes of TETs and identify thymic carcinomas preoperatively. Keywords Thymic epithelial tumors, Thymic cancer, Cine magnetic resonance imaging, Feature tracking *Correspondence: Koji Takumi takumi@m2.kufm.kagoshima-u.ac.jp Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544, Japan General Thoracic Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544, Japan Human Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544, Japan © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Takumi et al. Cancer Imaging (2023) 23:42 Page 2 of 10 Background surgical specimens. The tissues were fixed with 10% neu - y Th mic epithelial tumors (TETs) are the most common tral phosphate-buffered formalin, routinely processed for primary tumors in the anterior mediastinum, with an paraffin embedding, and sectioned for hematoxylin and incidence of approximately 1.3 per million person-years eosin (HE) staining. All TET lesions were classified into [1]. Clinically, TETs comprise three subgroups accord- six histological subtypes according to the 2015 WHO ing to the WHO classification: low-risk thymomas (type histological classification and divided into the following A, AB, and B1), high-risk thymomas (type B2 and B3), three subgroups: low-risk thymoma (types A, AB, and and thymic carcinomas. Subgroup is an independent B1), high-risk thymoma (types B2 and B3), and thymic prognostic factor for survival in patients with TETs [2] carcinoma. and is important information for optimizing treatment strategies. MR imaging protocol Cine MR imaging is widely used to evaluate cardiovas- All MR examinations were performed using 3T systems cular diseases by assessment of cardiac morphology and (Trio, Siemens Healthcare, Erlangen, Germany; or Inge- function [3] and can also be used to diagnose chest wall nia 3.0T, Philips Healthcare, Best, The Netherlands) using or cardiovascular invasion of thoracic masses by evalu- a 30-channel phased-array body coil during a breath hold. ating cardiovascular-induced sliding motion [4–6]. The Cine-MR imaging has been a part of our institute’s rou- MR feature tracking technique, a two-dimensional post- tine clinical pretreatment MR protocol for the evaluation processing algorithm based on cine MRI, has recently of chest wall or cardiovascular invasion in anterior medi- been introduced into clinical practice. It was developed astinal tumors. Cardiac-gated cine images were acquired to evaluate cardiac function and myocardial deforma- using a balanced steady-state free precession (bSSFP) tion, which are applied to the diagnosis and prediction sequence with short periods of breath holding in the axial of prognosis in cardiac diseases [7]. A recent report [8] and oblique planes. The oblique plane was applied per - showed that MR feature tracking analysis of cardiovas- pendicular to the interface between the thymic lesion and cular-induced liver deformation was correlated with liver the adjacent cardiovascular structures with reference to damage in patients with tetralogy of Fallot. Reduced pas- the axial image. The following parameters were used for sive deformity of the liver may be due to chronic liver imaging in both planes: repetition time, 10 to 48 ms; echo damage with fibrosis. Therefore, the feature tracking time, 1.5 ms; flip angle, 45 or 50°; turbo field echo factor, technique may have the potential to provide informa- 22; number of cardiac phases, 20–25; number of signal tion on tissue stiffness by evaluation of morphological averages, 1; field of view, 350 × 350  mm; in-plane spatial deformation of a mediastinal lesion (including TETs) that resolution, 1 to 2 × 1 to 2 mm; section thickness, 3–6 mm; occurs by the pulsation of adjacent cardiovascular struc- number of slices, 3–5. tures. The WHO classification of TETs is determined pathologically based on the morphological manifesta- Imaging analyses tions of epithelial cells and the ratio of lymphocytes to To evaluate cardiac-induced deformation with feature epithelial cells [9], which can impact tumor stiffness. We tracking evaluations, all cine images were transferred hypothesize that evaluation of cardiovascular-induced and analyzed using a workstation (Ziostation 2; Ziosoft morphological deformation using cine-MR feature track- Inc., Tokyo, Japan). All images were independently evalu- ing analysis can assist in diagnosing the histopathologi- ated by a radiologist (with 20 years of chest radiology cal classification of TETs. Therefore, the purpose of this experience) who was blinded to the final pathological study was to assess the diagnostic feasibility of feature results. All measurements were performed twice by the tracking analyses using pretreatment cine-MR images for same observer. The tumor margin was delineated manu - the evaluation of TETs. ally in the diastolic phase in the axial and oblique planes on the slice with the largest cross-sectional area of the Materials and methods lesion, and automatically tracked for all other cardiac Patients phases using feature-tracking methods based mainly on Institutional ethics review board approval was obtained a block-matching approach, which defines the region of and informed consent was waived for this retrospective interest for the target structure and tracks it along the study. Between February 2008 and April 2021, all patients cardiac cycle by searching for the most similar region in who met the following inclusion criteria were enrolled: the next image [10, 11]. Tumor sizes (longest and shortest (a) pathologically confirmed TET, (b) had undergone diameters) and lesion area were automatically measured cine-MR examination, (c) no history of treatment for for all cardiac phases. We calculated the long-to-short- TET before the MR examination, and (d) lesions larger diameter ratio, which was defined as the short diameter than 10  mm in short diameter. The final diagnosis was divided by the long diameter. Long diameter (LD and max determined by histological examination of biopsy or LD ), short diameter (SD and SD ), long-to-short min max min Takumi et al. Cancer Imaging (2023) 23:42 Page 3 of 10 diameter ratio (LSR and LSR ), and lesion area of P < 0.05 were considered indicative of significance in all max min (LA and LA ) were recorded in the two phases when analyses. Statistical analyses were performed using Med- max min the lesion areas were maximal and minimal, respectively. Calc version 19.6 (MedCalc Software, Mariakerke, Bel- We also calculated the change in the long-to-short-diam- gium) and SPSS version 28.0 (SPSS, Chicago, IL). eter ratio (∆long-to-short-diameter ratio [∆LSR]) and lesion area (∆area) between the two phases when the Results lesion areas were maximal and minimal. The length of Patients and thymic tumor classifications contact between the lesion and the adjacent cardiovascu- Forty-three eligible patients (18 men, 25 women; mean lar structures was measured in both planes. age, 62.3 ± 15.4 years; range, 25–85 years) were identi- fied and included in this study (Fig.  1). The clinical and Statistical analysis pathological characteristics of the study population are Intra-observer agreement was assessed by calculating summarized in Table  1. The subgroups of TETs were the intra-class correlation coefficient (ICC). ICCs were diagnosed pathologically as 10 low-risk thymomas (type considered to indicate excellent agreement when > 0.74 A [n = 4], AB [n = 3], type B1 [n = 3]), 23 high-risk thymo- [12]. Long diameter (LD and LD ), short diameter mas (type B2 [n = 8], type B3 [n = 15]), and 10 thymic car- max min (SD and SD ), long-to-short diameter ratio (LSR cinomas. All thymic tumors were located in the anterior max min max and LSR ), lesion area (LA and LA ), ∆LSR, and mediastinum. min max min ∆area were compared among the three groups (low- and high-risk thymomas and thymic carcinomas), between Feature tracking parameters among the three TET groups low- and high-risk thymomas, and between all thymomas Intra-observer variability was excellent for all parameters and thymic carcinomas using the Kruskal–Wallis H test (Online supplementary table). Table  2 lists the values or the Mann–Whitney U test. Receiver-operating char- of tracking parameters in the axial and oblique images acteristic (ROC) curve analysis was performed to evalu- according to group. There was no significant difference ate the ability of continuous values to differentiate thymic among the groups in terms of contact length between carcinomas from thymomas. Sensitivity and specificity the lesion and adjacent cardiovascular structures in were calculated using a threshold criterion that would either plane (both p > 0.05). ∆LSR and ∆area were signifi - maximize the Youden index. All data for continuous vari- cantly different among the three groups in the axial plane ables are presented as mean ± standard deviation. Values (p = 0.028 and 0.006, respectively) and in the oblique Fig. 1 Flow diagram of the study population. Abbreviation: TET = thymic epithelial tumor Takumi et al. Cancer Imaging (2023) 23:42 Page 4 of 10 Table 1 Clinical and demographic characteristics Variables N = 43 Gender (M: F) 18:25 Age (mean ± SD) 62.3 ± 15.4 Major clinical symptoms Pain or pressure in the chest 6 Shortness of breath 1 General fatigue 3 Facial swelling 2 Weight loss 1 Drooping eyelids 9 No symptom 21 Mosaoka-Koga stage I 9 II 19 III 9 IV 6 WHO classification A 4 AB 3 B1 3 B2 8 B3 15 Carcinoma 10 Fig. 2 ROC curve analysis of different parameters for diagnosing thymic carcinoma. The area under the ROC curve values were 0.761, 0.755, 0.761, and 0.764 for ∆LSR in the axial and oblique planes, and ∆area in the axial and oblique planes, respectively Takumi et al. Cancer Imaging (2023) 23:42 Page 5 of 10 Table 2 Clinical characteristics and cine MR feature tracking parameters Low-risk thymomas High-risk thymo- Thymic carcinomas P (among three P (Low- vs. high-risk P (all thy- (n = 10) mas (n = 23) (n = 10) groups) thymomas) momas vs. carcino- mas) Axial image Contact length (mm) 43.2 ± 14.6 33.9 ± 13.5 44.0 ± 16.3 0.101 0.089 0.204 Long diameter with maximum lesion area (mm) 49.5 ± 16.4 45.2 ± 16.8 52.9 ± 22.9 0.721 0.524 0.702 Short diameter with maximum lesion area (mm) 30.5 ± 12.0 23.3 ± 9.1 33.5 ± 18.7 0.123 0.105 0.249 Long-to-short ratio with maximum lesion area 0.6 ± 0.1 0.5 ± 0.1 0.6 ± 0.1 0.193 0.133 0.386 Long diameter with minimum lesion area (mm) 48.6 ± 16.7 44.7 ± 16.7 52.5 ± 23.0 0.724 0.550 0.661 Short diameter with minimum lesion area (mm) 28.7 ± 11.5 22.5 ± 9.4 32.9 ± 18.9 0.140 0.155 0.194 Long-to-short ratio with minimum lesion area 0.6 ± 0.1 0.5 ± 0.2 0.6 ± 0.1 0.241 0.207 0.273 ∆Long-to-short ratio (%) 4.7 ± 3.5 4.1 ± 5.8 1.4 ± 1.4 0.028 0.253 0.012 Maximum lesion area (mm ) 1349.8 ± 918.3 964.7 ± 654.0 1747.0 ± 1942.0 0.294 0.269 0.313 Minimum lesion area (mm ) 1270.0 ± 885.9 929.8 ± 649.0 1717.5 ± 1939.1 0.310 0.305 0.286 ∆Area (%) 6.8 ± 4.2 4.9 ± 4.5 2.6 ± 1.6 0.006 0.038 0.012 Oblique image Contact length (mm) 54.1 ± 24.1 43.6 ± 16.2 51.2 ± 23.2 0.524 0.269 0.702 Long diameter with maximum lesion area (mm) 51.3 ± 19.5 42.6 ± 14.5 53.8 ± 25.7 0.477 0.305 0.487 Short diameter with maximum lesion area (mm) 30.4 ± 12.5 23.8 ± 10.9 31.7 ± 19.4 0.2829 0.133 0.681 Long-to-short ratio with maximum lesion area 0.6 ± 0.1 0.6 ± 0.2 0.6 ± 0.1 0.800 0.524 0.788 Long diameter with minimum lesion area (mm) 50.1 ± 19.5 42.6 ± 14.5 53.3 ± 25.8 0.533 0.343 0.487 Short diameter with minimum lesion area (mm) 30.4 ± 12.5 23.8 ± 10.9 31.0 ± 18.7 0.266 0.133 0.542 Long-to-short ratio with minimum lesion area 0.6 ± 0.2 0.6 ± 0.2 0.6 ± 0.1 0.772 0.524 0.810 ∆Long-to-short ratio (%) 6.5 ± 5.9 4.6 ± 4.2 1.6 ± 1.0 0.034 0.363 0.015 Maximum lesion area (mm ) 1339.5 ± 1003.0 950.2 ± 642.4 1704.9 ± 1962.3 0.421 0.305 0.435 Minimum lesion area (mm ) 1336.9 ± 984.0 900.5 ± 637.4 1670.7 ± 1947.7 0.354 0.384 0.356 ∆Area (%) 5.7 ± 3.7 6.5 ± 4.8 2.8 ± 1.4 0.043 0.862 0.011 Takumi et al. Cancer Imaging (2023) 23:42 Page 6 of 10 Table 3 Area under the ROC curve values for the diagnosis of thymic carcinoma Parameters AUC Threshold Value Sensitivity (%) Specificity (%) ∆Long-to-short ratio in the axial plane 0.761 ≤ 0.90 70.0 90.9 ∆Long-to-short ratio in the oblique plane 0.755 ≤ 3.53 100.0 45.5 ∆Area in the axial plane 0.761 ≤ 3.39 90.0 63.6 ∆Area in the oblique plane 0.764 ≤ 5.04 100.0 45.5 plane (p = 0.034 and 0.043, respectively), whereas there Comparison between thymomas and thymic carcinomas was no significant difference in long diameter (LD The ∆LSR and ∆area of thymic carcinomas were signifi - max and LD ), short diameter (SD and SD ), long-to- cantly smaller than those of thymomas in the axial plane min max min short diameter ratio (LSR and LSR ), or lesion area (4.26 ± 5.13% vs. 1.45 ± 1.42%, p = 0.012; 5.47 ± 4.43% vs. max min (LA and LA ) between the groups in either plane (all 2.58 ± 1.55%, p = 0.012, respectively) and in the oblique max min p > 0.05). plane (5.19 ± 4.78% vs. 1.65 ± 0.99%, p = 0.015; 6.21 ± 4.43% vs. 2.82 ± 1.41%, p = 0.011, respectively). For diagnosing Fig. 3 A 64-year-old woman with low-risk thymoma (type A). Axial (a) and oblique (c) cine MR images of low-risk thymoma (type A) in the right anterior mediastinum, accompanied by graphs representing the time course of area and long-to-short diameter ratio in axial (b) and oblique planes (d). In the axial plane, ∆long-to-short diameter ratio and ∆area were 10.58% and 5.89%, respectively. In the oblique plane, ∆long-to-short diameter ratio and ∆area were 10.50% and 8.14%, respectively Takumi et al. Cancer Imaging (2023) 23:42 Page 7 of 10 thymic carcinomas, the values of the area under the ROC (sensitivity, 100% with 95%CI of 69.2–100.0; specificity, curve (AUC) were 0.761 (95% confidential interval [CI], 45.5% with 95%CI of 28.1–63.6), respectively (Table 3). 0.606–0.877), 0.755 (95%CI, 0.600–0.873), 0.761 (95%CI, Representative cases are shown in Figs.  3 and 4, and 0.606–0.877), and 0.764 (95%CI, 0.610–0.880) for ∆LSR online-supplementary videos. in the axial and oblique planes, and ∆area in the axial and oblique planes, respectively (Fig.  2; Table  3). The opti - Association between feature tracking parameters and mal cutoff values of ∆LSR and ∆area in the axial plane cystic/necrotic changes or adjacent cardiovascular to differentiate thymic carcinoma from thymomas were structures 0.90% (sensitivity, 70.0% with 95%CI of 34.8–93.3; speci- Cystic/necrotic changes were present in 10 lesions (3 ficity, 90.9% with 95%CI of 75.7–98.1) and 3.39% (sensi - low-risk thymomas, 4 high-risk thymomas, and 3 thymic tivity, 90% with 95%CI of 55.5–99.7; specificity, 63.6% carcinomas), and in all cases, these changes occupied less with 95%CI of 45.1–79.6), respectively (Table  3). The than half of the lesion. There was no significant difference optimal cutoff values of ∆LSR and ∆area in the oblique between the lesions with and without cystic/necrotic plane to differentiate thymic carcinoma from thymomas changes in ∆LSR and ∆area in both planes (all, p > 0.05). were 3.53% (sensitivity, 100.0% with 95%CI of 69.2–100.0; Twenty-five lesions (3 low-risk thymomas, 17 high-risk specificity, 45.5% with 95%CI of 28.1–63.6) and 5.04% thymomas, and 5 thymic carcinomas) predominantly Fig. 4 A 57-year-old woman with thymic carcinoma. Axial (a) and oblique (c) cine MR images show an irregularly shaped and ill-defined tumor in the anterior mediastinum. Graphs represent the time course of area and long-to-short diameter ratio in axial (b) and oblique planes (d). In the axial plane, ∆long-to-short diameter ratio and ∆area were 0.52% and 3.39%, respectively. In the oblique plane, ∆long-to-short diameter ratio and ∆area were 2.05% and 3.74%, respectively Takumi et al. Cancer Imaging (2023) 23:42 Page 8 of 10 contacted the aorta, 12 (4 low-risk thymomas, 5 high- which can result in lower tumor stiffness compared with risk thymomas, and 3 thymic carcinomas) predominantly lymphocyte-sparse TETs such as B3 thymoma and thy- contacted the pulmonary artery, and 6 (3 low-risk thymo- mic carcinomas. Therefore, the cine-MR feature tracking mas, 1 high-risk thymomas, and 2 thymic carcinomas) technique may enable the assessment of stromal condi- predominantly contacted the right atrium. No significant tions within a lesion and could be particularly useful for difference was observed among the predominantly con - evaluating lesions in which the stromal features vary by tacted adjacent cardiovascular structures in ∆LSR and histological subtype, such as TETs. ∆area in both planes (all, p > 0.05). Evaluation of lesion stiffness was reported to be useful for differentiation between benign and malignant lesions Discussion [22–24]. Malignant tumors tend to have an abundant The results of the present study demonstrate the fea - extracellular matrix, and increased vascularity and inter- sibility of cine MRI-based feature tracking analysis for stitial pressure [25]. These characteristics, along with assessing cardiac-induced deformation to diagnose TETs. increased cellularity, may cause increased stiffness. In Values of ∆LSR and ∆area were significantly different addition, intratumoral fibrosis is highly associated with between the TET subtypes, and those of thymic carcino- cancer [26], which can result in increased lesion stiffness mas were significantly smaller than those of thymomas. compared with benign lesions. In organs such as breast, AUCs for ∆LSR and ∆area to diagnose thymic carci - pancreas, prostate, and lymph nodes, malignant lesions nomas ranged from 0.755 to 0.764. To the best of our were reported to be stiffer than benign lesions or adja - knowledge, this potential role of cine-MR feature track- cent parenchymal organ tissue on ultrasound elastogra- ing analysis for diagnosing TETs has not been demon- phy [22–24, 27]. In the thoracic space, US elastography strated previously. demonstrated that malignant pleural-based masses were Tissue stiffness can provide additional information also stiffer than benign masses [ 28]. A preliminary study in evaluating several organs [13–17], and radiologi- focused on MR elastography demonstrated that the stiff - cal approaches such as ultrasound and MR elastogra- ness level of thymic carcinoma had a tendency to be phies have been developed for such evaluation [15, 16]. higher than that of thymoma and lymphoma [29]. In the Measurement of liver stiffness using MR elastography present results, ∆LSR and ∆area values of thymic carci - is useful to predict the stage of liver fibrosis and long- nomas were significantly lower than those of thymomas, term progression and outcome in chronic liver dis- which suggests that the stiffness of thymic carcinoma is ease [15, 17]. Stiffness of the thymus in healthy children higher than that of thymomas, possibly due to the abun- evaluated by MR elastography presented a mild nega- dant fibrous tissues in these lesions. Cine MRI is a com - tive correlation with age, height, and weight, which can monly used MR sequence that can be performed on be influenced by changes in the thymic epithelial space almost any MR device without additional expensive func- and the perivascular space [18]. Cine-MR feature track- tions. Therefore, it is clinically useful to be able to predict ing analysis can also provide information on tissue stiff - histopathological characteristics by evaluating cardiovas- ness [8, 19–21], in which tissue deformation is inversely cular-induced deformation of TETs at the same time as proportional to tissue stiffness. Cardiovascular MR fea - evaluating cardiovascular invasion [4–6]. ture tracking to quantify myocardial strain has been There are limitations in the present study. First, we reported to be associated with ventricular stiffness [ 19], included only a small number of patients with TET from and cardiac-induced deformation using cine-MR tag- a single institute, which limited the statistical power and ging analysis has been used to assess liver stiffness [ 20, universality of the study. In addition, it was a retrospec- 21]. Ohashi et al. reported that cardiac-induced liver tive study that may have been subject to selection bias deformation evaluated by the cine-MR feature tracking due to the unbalanced number of patients for each TET technique was associated with liver function in patients subtype. We believe that our pilot study will encourage with adult congenital heart disease [8]. In the present future research and that a well-designed prospective results, imaging parameters associated with cardiac- study with a large number of cases is needed to con- induced deformation of TETs, such as ∆LSR and ∆area firm our findings. Second, cardiac-induced deformation obtained from cine-MR feature tracking analysis, were of TETs can be affected by the stiffness of the adjacent significantly different between the histopathological TET cardiovascular structures and by blood pressure. Further groups. The pathological subtypes of TETs according to research is needed to clarify the relationship between the WHO classification are characterized by the content the state of adjacent structures and cardiac-induced of neoplastic epithelial cells and non-neoplastic imma- deformation. ture T cells. Typical thymomas, especially type AB, B1, and B2 thymomas, contain an abundance of immature T cells and fewer interstitial cells within the lesion [9], Takumi et al. Cancer Imaging (2023) 23:42 Page 9 of 10 Competing interests Conclusion Authors have no conflict of interest. The present results suggest that cardiac-induced defor - Received: 8 January 2023 / Accepted: 19 April 2023 mation of TETs evaluated using the cine-MR-based feature tracking technique may reflect differences in his - topathological characteristics among TETs. Evaluation of morphological deformation using cine MRI can help diagnose histopathological subtypes of TET and identify References thymic carcinomas preoperatively. 1. 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Sci Am. 1994;271:58–65. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Imaging Springer Journals

Cine MR feature tracking analysis for diagnosing thymic epithelial tumors: a feasibility study

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Abstract

Background To assess the feasibility of the cine MR feature tracking technique for the evaluation of cardiovascular- induced morphological deformation in the diagnosis of thymic epithelial tumors ( TETs). Methods Our study population consisted of 43 patients with pathologically proven TETs including 10 low-grade thymomas, 23 high-grade thymomas, and 10 thymic carcinomas. Cine MR images were acquired using a balanced steady-state free precession sequence with short periods of breath-hold in the axial and oblique planes in the slice with the largest lesion cross-sectional area. The tumor margin was manually delineated in the diastolic phase and was automatically tracked for all other cardiac phases. The change rates of the long-to-short diameter ratio (∆LSR) and tumor area (∆area) associated with pulsation were compared between the three pathological groups using the Kruskal–Wallis H test and the Mann–Whitney U test. A receiver-operating characteristic (ROC) curve analysis was performed to assess the ability of each parameter to differentiate thymic carcinomas from thymomas. Results ∆LSR and ∆area were significantly different among the three groups in the axial plane (p = 0.028 and 0.006, respectively) and in the oblique plane (p = 0.034 and 0.043, respectively). ∆LSR and ∆area values were significantly lower in thymic carcinomas than in thymomas in the axial plane (for both, p = 0.012) and in the oblique plane (p = 0.015 and 0.011, respectively). The area under the ROC curves for ∆LSR and ∆area for the diagnosis of thymic carcinoma ranged from 0.755 to 0.764. Conclusions Evaluation of morphological deformation using cine-MR feature tracking analysis can help diagnose histopathological subtypes of TETs and identify thymic carcinomas preoperatively. Keywords Thymic epithelial tumors, Thymic cancer, Cine magnetic resonance imaging, Feature tracking *Correspondence: Koji Takumi takumi@m2.kufm.kagoshima-u.ac.jp Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544, Japan General Thoracic Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544, Japan Human Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544, Japan © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Takumi et al. Cancer Imaging (2023) 23:42 Page 2 of 10 Background surgical specimens. The tissues were fixed with 10% neu - y Th mic epithelial tumors (TETs) are the most common tral phosphate-buffered formalin, routinely processed for primary tumors in the anterior mediastinum, with an paraffin embedding, and sectioned for hematoxylin and incidence of approximately 1.3 per million person-years eosin (HE) staining. All TET lesions were classified into [1]. Clinically, TETs comprise three subgroups accord- six histological subtypes according to the 2015 WHO ing to the WHO classification: low-risk thymomas (type histological classification and divided into the following A, AB, and B1), high-risk thymomas (type B2 and B3), three subgroups: low-risk thymoma (types A, AB, and and thymic carcinomas. Subgroup is an independent B1), high-risk thymoma (types B2 and B3), and thymic prognostic factor for survival in patients with TETs [2] carcinoma. and is important information for optimizing treatment strategies. MR imaging protocol Cine MR imaging is widely used to evaluate cardiovas- All MR examinations were performed using 3T systems cular diseases by assessment of cardiac morphology and (Trio, Siemens Healthcare, Erlangen, Germany; or Inge- function [3] and can also be used to diagnose chest wall nia 3.0T, Philips Healthcare, Best, The Netherlands) using or cardiovascular invasion of thoracic masses by evalu- a 30-channel phased-array body coil during a breath hold. ating cardiovascular-induced sliding motion [4–6]. The Cine-MR imaging has been a part of our institute’s rou- MR feature tracking technique, a two-dimensional post- tine clinical pretreatment MR protocol for the evaluation processing algorithm based on cine MRI, has recently of chest wall or cardiovascular invasion in anterior medi- been introduced into clinical practice. It was developed astinal tumors. Cardiac-gated cine images were acquired to evaluate cardiac function and myocardial deforma- using a balanced steady-state free precession (bSSFP) tion, which are applied to the diagnosis and prediction sequence with short periods of breath holding in the axial of prognosis in cardiac diseases [7]. A recent report [8] and oblique planes. The oblique plane was applied per - showed that MR feature tracking analysis of cardiovas- pendicular to the interface between the thymic lesion and cular-induced liver deformation was correlated with liver the adjacent cardiovascular structures with reference to damage in patients with tetralogy of Fallot. Reduced pas- the axial image. The following parameters were used for sive deformity of the liver may be due to chronic liver imaging in both planes: repetition time, 10 to 48 ms; echo damage with fibrosis. Therefore, the feature tracking time, 1.5 ms; flip angle, 45 or 50°; turbo field echo factor, technique may have the potential to provide informa- 22; number of cardiac phases, 20–25; number of signal tion on tissue stiffness by evaluation of morphological averages, 1; field of view, 350 × 350  mm; in-plane spatial deformation of a mediastinal lesion (including TETs) that resolution, 1 to 2 × 1 to 2 mm; section thickness, 3–6 mm; occurs by the pulsation of adjacent cardiovascular struc- number of slices, 3–5. tures. The WHO classification of TETs is determined pathologically based on the morphological manifesta- Imaging analyses tions of epithelial cells and the ratio of lymphocytes to To evaluate cardiac-induced deformation with feature epithelial cells [9], which can impact tumor stiffness. We tracking evaluations, all cine images were transferred hypothesize that evaluation of cardiovascular-induced and analyzed using a workstation (Ziostation 2; Ziosoft morphological deformation using cine-MR feature track- Inc., Tokyo, Japan). All images were independently evalu- ing analysis can assist in diagnosing the histopathologi- ated by a radiologist (with 20 years of chest radiology cal classification of TETs. Therefore, the purpose of this experience) who was blinded to the final pathological study was to assess the diagnostic feasibility of feature results. All measurements were performed twice by the tracking analyses using pretreatment cine-MR images for same observer. The tumor margin was delineated manu - the evaluation of TETs. ally in the diastolic phase in the axial and oblique planes on the slice with the largest cross-sectional area of the Materials and methods lesion, and automatically tracked for all other cardiac Patients phases using feature-tracking methods based mainly on Institutional ethics review board approval was obtained a block-matching approach, which defines the region of and informed consent was waived for this retrospective interest for the target structure and tracks it along the study. Between February 2008 and April 2021, all patients cardiac cycle by searching for the most similar region in who met the following inclusion criteria were enrolled: the next image [10, 11]. Tumor sizes (longest and shortest (a) pathologically confirmed TET, (b) had undergone diameters) and lesion area were automatically measured cine-MR examination, (c) no history of treatment for for all cardiac phases. We calculated the long-to-short- TET before the MR examination, and (d) lesions larger diameter ratio, which was defined as the short diameter than 10  mm in short diameter. The final diagnosis was divided by the long diameter. Long diameter (LD and max determined by histological examination of biopsy or LD ), short diameter (SD and SD ), long-to-short min max min Takumi et al. Cancer Imaging (2023) 23:42 Page 3 of 10 diameter ratio (LSR and LSR ), and lesion area of P < 0.05 were considered indicative of significance in all max min (LA and LA ) were recorded in the two phases when analyses. Statistical analyses were performed using Med- max min the lesion areas were maximal and minimal, respectively. Calc version 19.6 (MedCalc Software, Mariakerke, Bel- We also calculated the change in the long-to-short-diam- gium) and SPSS version 28.0 (SPSS, Chicago, IL). eter ratio (∆long-to-short-diameter ratio [∆LSR]) and lesion area (∆area) between the two phases when the Results lesion areas were maximal and minimal. The length of Patients and thymic tumor classifications contact between the lesion and the adjacent cardiovascu- Forty-three eligible patients (18 men, 25 women; mean lar structures was measured in both planes. age, 62.3 ± 15.4 years; range, 25–85 years) were identi- fied and included in this study (Fig.  1). The clinical and Statistical analysis pathological characteristics of the study population are Intra-observer agreement was assessed by calculating summarized in Table  1. The subgroups of TETs were the intra-class correlation coefficient (ICC). ICCs were diagnosed pathologically as 10 low-risk thymomas (type considered to indicate excellent agreement when > 0.74 A [n = 4], AB [n = 3], type B1 [n = 3]), 23 high-risk thymo- [12]. Long diameter (LD and LD ), short diameter mas (type B2 [n = 8], type B3 [n = 15]), and 10 thymic car- max min (SD and SD ), long-to-short diameter ratio (LSR cinomas. All thymic tumors were located in the anterior max min max and LSR ), lesion area (LA and LA ), ∆LSR, and mediastinum. min max min ∆area were compared among the three groups (low- and high-risk thymomas and thymic carcinomas), between Feature tracking parameters among the three TET groups low- and high-risk thymomas, and between all thymomas Intra-observer variability was excellent for all parameters and thymic carcinomas using the Kruskal–Wallis H test (Online supplementary table). Table  2 lists the values or the Mann–Whitney U test. Receiver-operating char- of tracking parameters in the axial and oblique images acteristic (ROC) curve analysis was performed to evalu- according to group. There was no significant difference ate the ability of continuous values to differentiate thymic among the groups in terms of contact length between carcinomas from thymomas. Sensitivity and specificity the lesion and adjacent cardiovascular structures in were calculated using a threshold criterion that would either plane (both p > 0.05). ∆LSR and ∆area were signifi - maximize the Youden index. All data for continuous vari- cantly different among the three groups in the axial plane ables are presented as mean ± standard deviation. Values (p = 0.028 and 0.006, respectively) and in the oblique Fig. 1 Flow diagram of the study population. Abbreviation: TET = thymic epithelial tumor Takumi et al. Cancer Imaging (2023) 23:42 Page 4 of 10 Table 1 Clinical and demographic characteristics Variables N = 43 Gender (M: F) 18:25 Age (mean ± SD) 62.3 ± 15.4 Major clinical symptoms Pain or pressure in the chest 6 Shortness of breath 1 General fatigue 3 Facial swelling 2 Weight loss 1 Drooping eyelids 9 No symptom 21 Mosaoka-Koga stage I 9 II 19 III 9 IV 6 WHO classification A 4 AB 3 B1 3 B2 8 B3 15 Carcinoma 10 Fig. 2 ROC curve analysis of different parameters for diagnosing thymic carcinoma. The area under the ROC curve values were 0.761, 0.755, 0.761, and 0.764 for ∆LSR in the axial and oblique planes, and ∆area in the axial and oblique planes, respectively Takumi et al. Cancer Imaging (2023) 23:42 Page 5 of 10 Table 2 Clinical characteristics and cine MR feature tracking parameters Low-risk thymomas High-risk thymo- Thymic carcinomas P (among three P (Low- vs. high-risk P (all thy- (n = 10) mas (n = 23) (n = 10) groups) thymomas) momas vs. carcino- mas) Axial image Contact length (mm) 43.2 ± 14.6 33.9 ± 13.5 44.0 ± 16.3 0.101 0.089 0.204 Long diameter with maximum lesion area (mm) 49.5 ± 16.4 45.2 ± 16.8 52.9 ± 22.9 0.721 0.524 0.702 Short diameter with maximum lesion area (mm) 30.5 ± 12.0 23.3 ± 9.1 33.5 ± 18.7 0.123 0.105 0.249 Long-to-short ratio with maximum lesion area 0.6 ± 0.1 0.5 ± 0.1 0.6 ± 0.1 0.193 0.133 0.386 Long diameter with minimum lesion area (mm) 48.6 ± 16.7 44.7 ± 16.7 52.5 ± 23.0 0.724 0.550 0.661 Short diameter with minimum lesion area (mm) 28.7 ± 11.5 22.5 ± 9.4 32.9 ± 18.9 0.140 0.155 0.194 Long-to-short ratio with minimum lesion area 0.6 ± 0.1 0.5 ± 0.2 0.6 ± 0.1 0.241 0.207 0.273 ∆Long-to-short ratio (%) 4.7 ± 3.5 4.1 ± 5.8 1.4 ± 1.4 0.028 0.253 0.012 Maximum lesion area (mm ) 1349.8 ± 918.3 964.7 ± 654.0 1747.0 ± 1942.0 0.294 0.269 0.313 Minimum lesion area (mm ) 1270.0 ± 885.9 929.8 ± 649.0 1717.5 ± 1939.1 0.310 0.305 0.286 ∆Area (%) 6.8 ± 4.2 4.9 ± 4.5 2.6 ± 1.6 0.006 0.038 0.012 Oblique image Contact length (mm) 54.1 ± 24.1 43.6 ± 16.2 51.2 ± 23.2 0.524 0.269 0.702 Long diameter with maximum lesion area (mm) 51.3 ± 19.5 42.6 ± 14.5 53.8 ± 25.7 0.477 0.305 0.487 Short diameter with maximum lesion area (mm) 30.4 ± 12.5 23.8 ± 10.9 31.7 ± 19.4 0.2829 0.133 0.681 Long-to-short ratio with maximum lesion area 0.6 ± 0.1 0.6 ± 0.2 0.6 ± 0.1 0.800 0.524 0.788 Long diameter with minimum lesion area (mm) 50.1 ± 19.5 42.6 ± 14.5 53.3 ± 25.8 0.533 0.343 0.487 Short diameter with minimum lesion area (mm) 30.4 ± 12.5 23.8 ± 10.9 31.0 ± 18.7 0.266 0.133 0.542 Long-to-short ratio with minimum lesion area 0.6 ± 0.2 0.6 ± 0.2 0.6 ± 0.1 0.772 0.524 0.810 ∆Long-to-short ratio (%) 6.5 ± 5.9 4.6 ± 4.2 1.6 ± 1.0 0.034 0.363 0.015 Maximum lesion area (mm ) 1339.5 ± 1003.0 950.2 ± 642.4 1704.9 ± 1962.3 0.421 0.305 0.435 Minimum lesion area (mm ) 1336.9 ± 984.0 900.5 ± 637.4 1670.7 ± 1947.7 0.354 0.384 0.356 ∆Area (%) 5.7 ± 3.7 6.5 ± 4.8 2.8 ± 1.4 0.043 0.862 0.011 Takumi et al. Cancer Imaging (2023) 23:42 Page 6 of 10 Table 3 Area under the ROC curve values for the diagnosis of thymic carcinoma Parameters AUC Threshold Value Sensitivity (%) Specificity (%) ∆Long-to-short ratio in the axial plane 0.761 ≤ 0.90 70.0 90.9 ∆Long-to-short ratio in the oblique plane 0.755 ≤ 3.53 100.0 45.5 ∆Area in the axial plane 0.761 ≤ 3.39 90.0 63.6 ∆Area in the oblique plane 0.764 ≤ 5.04 100.0 45.5 plane (p = 0.034 and 0.043, respectively), whereas there Comparison between thymomas and thymic carcinomas was no significant difference in long diameter (LD The ∆LSR and ∆area of thymic carcinomas were signifi - max and LD ), short diameter (SD and SD ), long-to- cantly smaller than those of thymomas in the axial plane min max min short diameter ratio (LSR and LSR ), or lesion area (4.26 ± 5.13% vs. 1.45 ± 1.42%, p = 0.012; 5.47 ± 4.43% vs. max min (LA and LA ) between the groups in either plane (all 2.58 ± 1.55%, p = 0.012, respectively) and in the oblique max min p > 0.05). plane (5.19 ± 4.78% vs. 1.65 ± 0.99%, p = 0.015; 6.21 ± 4.43% vs. 2.82 ± 1.41%, p = 0.011, respectively). For diagnosing Fig. 3 A 64-year-old woman with low-risk thymoma (type A). Axial (a) and oblique (c) cine MR images of low-risk thymoma (type A) in the right anterior mediastinum, accompanied by graphs representing the time course of area and long-to-short diameter ratio in axial (b) and oblique planes (d). In the axial plane, ∆long-to-short diameter ratio and ∆area were 10.58% and 5.89%, respectively. In the oblique plane, ∆long-to-short diameter ratio and ∆area were 10.50% and 8.14%, respectively Takumi et al. Cancer Imaging (2023) 23:42 Page 7 of 10 thymic carcinomas, the values of the area under the ROC (sensitivity, 100% with 95%CI of 69.2–100.0; specificity, curve (AUC) were 0.761 (95% confidential interval [CI], 45.5% with 95%CI of 28.1–63.6), respectively (Table 3). 0.606–0.877), 0.755 (95%CI, 0.600–0.873), 0.761 (95%CI, Representative cases are shown in Figs.  3 and 4, and 0.606–0.877), and 0.764 (95%CI, 0.610–0.880) for ∆LSR online-supplementary videos. in the axial and oblique planes, and ∆area in the axial and oblique planes, respectively (Fig.  2; Table  3). The opti - Association between feature tracking parameters and mal cutoff values of ∆LSR and ∆area in the axial plane cystic/necrotic changes or adjacent cardiovascular to differentiate thymic carcinoma from thymomas were structures 0.90% (sensitivity, 70.0% with 95%CI of 34.8–93.3; speci- Cystic/necrotic changes were present in 10 lesions (3 ficity, 90.9% with 95%CI of 75.7–98.1) and 3.39% (sensi - low-risk thymomas, 4 high-risk thymomas, and 3 thymic tivity, 90% with 95%CI of 55.5–99.7; specificity, 63.6% carcinomas), and in all cases, these changes occupied less with 95%CI of 45.1–79.6), respectively (Table  3). The than half of the lesion. There was no significant difference optimal cutoff values of ∆LSR and ∆area in the oblique between the lesions with and without cystic/necrotic plane to differentiate thymic carcinoma from thymomas changes in ∆LSR and ∆area in both planes (all, p > 0.05). were 3.53% (sensitivity, 100.0% with 95%CI of 69.2–100.0; Twenty-five lesions (3 low-risk thymomas, 17 high-risk specificity, 45.5% with 95%CI of 28.1–63.6) and 5.04% thymomas, and 5 thymic carcinomas) predominantly Fig. 4 A 57-year-old woman with thymic carcinoma. Axial (a) and oblique (c) cine MR images show an irregularly shaped and ill-defined tumor in the anterior mediastinum. Graphs represent the time course of area and long-to-short diameter ratio in axial (b) and oblique planes (d). In the axial plane, ∆long-to-short diameter ratio and ∆area were 0.52% and 3.39%, respectively. In the oblique plane, ∆long-to-short diameter ratio and ∆area were 2.05% and 3.74%, respectively Takumi et al. Cancer Imaging (2023) 23:42 Page 8 of 10 contacted the aorta, 12 (4 low-risk thymomas, 5 high- which can result in lower tumor stiffness compared with risk thymomas, and 3 thymic carcinomas) predominantly lymphocyte-sparse TETs such as B3 thymoma and thy- contacted the pulmonary artery, and 6 (3 low-risk thymo- mic carcinomas. Therefore, the cine-MR feature tracking mas, 1 high-risk thymomas, and 2 thymic carcinomas) technique may enable the assessment of stromal condi- predominantly contacted the right atrium. No significant tions within a lesion and could be particularly useful for difference was observed among the predominantly con - evaluating lesions in which the stromal features vary by tacted adjacent cardiovascular structures in ∆LSR and histological subtype, such as TETs. ∆area in both planes (all, p > 0.05). Evaluation of lesion stiffness was reported to be useful for differentiation between benign and malignant lesions Discussion [22–24]. Malignant tumors tend to have an abundant The results of the present study demonstrate the fea - extracellular matrix, and increased vascularity and inter- sibility of cine MRI-based feature tracking analysis for stitial pressure [25]. These characteristics, along with assessing cardiac-induced deformation to diagnose TETs. increased cellularity, may cause increased stiffness. In Values of ∆LSR and ∆area were significantly different addition, intratumoral fibrosis is highly associated with between the TET subtypes, and those of thymic carcino- cancer [26], which can result in increased lesion stiffness mas were significantly smaller than those of thymomas. compared with benign lesions. In organs such as breast, AUCs for ∆LSR and ∆area to diagnose thymic carci - pancreas, prostate, and lymph nodes, malignant lesions nomas ranged from 0.755 to 0.764. To the best of our were reported to be stiffer than benign lesions or adja - knowledge, this potential role of cine-MR feature track- cent parenchymal organ tissue on ultrasound elastogra- ing analysis for diagnosing TETs has not been demon- phy [22–24, 27]. In the thoracic space, US elastography strated previously. demonstrated that malignant pleural-based masses were Tissue stiffness can provide additional information also stiffer than benign masses [ 28]. A preliminary study in evaluating several organs [13–17], and radiologi- focused on MR elastography demonstrated that the stiff - cal approaches such as ultrasound and MR elastogra- ness level of thymic carcinoma had a tendency to be phies have been developed for such evaluation [15, 16]. higher than that of thymoma and lymphoma [29]. In the Measurement of liver stiffness using MR elastography present results, ∆LSR and ∆area values of thymic carci - is useful to predict the stage of liver fibrosis and long- nomas were significantly lower than those of thymomas, term progression and outcome in chronic liver dis- which suggests that the stiffness of thymic carcinoma is ease [15, 17]. Stiffness of the thymus in healthy children higher than that of thymomas, possibly due to the abun- evaluated by MR elastography presented a mild nega- dant fibrous tissues in these lesions. Cine MRI is a com - tive correlation with age, height, and weight, which can monly used MR sequence that can be performed on be influenced by changes in the thymic epithelial space almost any MR device without additional expensive func- and the perivascular space [18]. Cine-MR feature track- tions. Therefore, it is clinically useful to be able to predict ing analysis can also provide information on tissue stiff - histopathological characteristics by evaluating cardiovas- ness [8, 19–21], in which tissue deformation is inversely cular-induced deformation of TETs at the same time as proportional to tissue stiffness. Cardiovascular MR fea - evaluating cardiovascular invasion [4–6]. ture tracking to quantify myocardial strain has been There are limitations in the present study. First, we reported to be associated with ventricular stiffness [ 19], included only a small number of patients with TET from and cardiac-induced deformation using cine-MR tag- a single institute, which limited the statistical power and ging analysis has been used to assess liver stiffness [ 20, universality of the study. In addition, it was a retrospec- 21]. Ohashi et al. reported that cardiac-induced liver tive study that may have been subject to selection bias deformation evaluated by the cine-MR feature tracking due to the unbalanced number of patients for each TET technique was associated with liver function in patients subtype. We believe that our pilot study will encourage with adult congenital heart disease [8]. In the present future research and that a well-designed prospective results, imaging parameters associated with cardiac- study with a large number of cases is needed to con- induced deformation of TETs, such as ∆LSR and ∆area firm our findings. Second, cardiac-induced deformation obtained from cine-MR feature tracking analysis, were of TETs can be affected by the stiffness of the adjacent significantly different between the histopathological TET cardiovascular structures and by blood pressure. Further groups. The pathological subtypes of TETs according to research is needed to clarify the relationship between the WHO classification are characterized by the content the state of adjacent structures and cardiac-induced of neoplastic epithelial cells and non-neoplastic imma- deformation. ture T cells. Typical thymomas, especially type AB, B1, and B2 thymomas, contain an abundance of immature T cells and fewer interstitial cells within the lesion [9], Takumi et al. Cancer Imaging (2023) 23:42 Page 9 of 10 Competing interests Conclusion Authors have no conflict of interest. The present results suggest that cardiac-induced defor - Received: 8 January 2023 / Accepted: 19 April 2023 mation of TETs evaluated using the cine-MR-based feature tracking technique may reflect differences in his - topathological characteristics among TETs. Evaluation of morphological deformation using cine MRI can help diagnose histopathological subtypes of TET and identify References thymic carcinomas preoperatively. 1. 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Journal

Cancer Imaging – Springer Journals

Published: May 1, 2023

Keywords: Thymic epithelial tumors; Thymic cancer; Cine magnetic resonance imaging; Feature tracking

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