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Usefulness of positron‐emission tomography for predicting the World Health Organization grade of thymic epithelial tumors

Abstract Background It is often difficult to distinguish between thymoma and thymic carcinoma by preoperative radiological tests. While there have been some reports that the maximum standardized uptake value (SUVmax) in positron emission tomography‐computed tomography (PET‐CT) is useful to this end, no large‐scale analysis has been performed. We therefore analyzed the usefulness of the SUVmax and tumor size (TS) for differentiating thymic epithelial tumors. Methods From 2011 to 2019, 129 patients with thymic epithelial tumor who underwent PET‐CT before surgical treatment were enrolled. The relevance of the SUVmax to the World Health Organization (WHO) histological type was assessed. To reduce the impact of the TS, the ratio of the SUVmax to the TS was also investigated. Results A total of 99 thymoma cases and 30 thymic carcinoma cases were enrolled into the study. The SUVmax and SUVmax/TS of thymic carcinoma were significantly higher than those of thymoma (SUVmax: 7.7 ± 3.4 vs. 3.3 ± 1.3, p < 0.01; SUVmax/TS: 1.5 ± 0.7 vs. 0.6 ± 0.4, p < 0.01). Focusing on the patients with a moderate SUVmax of ≤5 (84 thymoma and 4 thymic carcinoma), the SUVmax/TS values of thymic carcinoma were still significantly higher than those of thymoma (1.6 ± 0.8 vs. 0.6 ± 0.4, p < 0.01). Conclusions PET‐CT might provide significant information for differentiating images of thymoma and thymic carcinoma. We experienced several cases of thymic carcinoma with a moderate SUVmax of ≤5, and SUVmax/TS was considered a useful parameter for differentiating such cases.


INTRODUCTION
Thymic epithelial tumor is classified based on the World Health Organization (WHO) histological classification, which is known to be related to the prognosis after complete resection. 1 The treatment strategy is mostly dependent on the malignant potential of the thymic tumor. However, the precise imaging diagnosis of thymic epithelial tumor remains difficult.
Although computed tomography (CT) is the most prevalent imaging examination for mediastinal tumors, fluorine-18fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) has been considered a powerful diagnostic modality for anterior mediastinal masses. 2 Recently, several reports investigated the relationship between the maximum standardized uptake value (SUV max ) and the pathological diagnosis. A previous meta-analysis showed that the SUV max differed significantly among thymic epithelial tumors (low-grade thymomas, high-grade thymomas, and thymic carcinoma). 3 Some studies have examined the importance of the ratio of the SUV max to the tumor size (SUV max /TS) for distinguishing thymoma and thymic cancer based on radiological findings. 4,5 However, those reports had small cohort sizes, so further analyses, such as those involving tumors with a moderate SUV max , are required.
We therefore retrospectively analyzed the role of the SUV max and SUV max /TS in the pathological diagnosis of thymic epithelial tumors.

Study design
The clinical characteristics and imaging examinations of thymic epithelial tumors in our institution were investigated. The relationship between the pathological diagnosis of tumor and the results of imaging examinations were retrospectively analyzed.
The study protocol was approved by the Ethical Review Board for Clinical Studies at Osaka University (control no. 18297).

Patients
From April 2011 to December 2019, a total of 129 patients with anterior thymic epithelial tumors were examined by PET-CT and thereafter underwent surgical resection. The histological diagnosis and immunohistochemical examinations were performed by the pathologists in our institution. The tumors were divided into six subtypes (type A, AB, B1, B2, B3, C) based on the WHO classification. 6 These subtypes were further divided into three categories: low-grade thymoma (type A, AB, B1), high-grade thymoma (type B2, B3), and thymic carcinoma. Staging was performed in accordance with UICC TNM Classification of Malignant Tumors eighth edition and the Masaoka-Koga classification. 7

F-FDG-PET protocol
All patients underwent 18 F-FDG-PET as a preoperative imaging test with integrated PET-CT as previously described. 8 In brief, the patients fasted for at least 4 h prior to the injection of 18 F-FDG. The dose of 18 F-FDG was calculated by the bodyweight of the patients. PET-CT was performed with a whole body scanner equipped with a 16-slice CT 1 h after the administration of 18 F-FDG (activity: 4 MBq/kg). The SUV max was calculated using the commercially available software provided by the manufacturer. Tumor size (TS) was decided based on the maximum diameter that was described in the radiological report of thin slice computed tomography (CT) prior to any treatment.

Statistical analysis
Statistical analyses were performed using the JMP software program for Windows version 14 (SAS Institute Inc.). Continuous variables are expressed as the median AE standard deviation (SD), and categorical variables as numbers. The SUV max /TS was calculated using the following formula: SUV max / longest diameter on axial CT (cm). To determine the predictive value of parameters, including the SUV max and SUV max /TS, the area under the curve (AUC) was scored by a receiver operating characteristic (ROC) analysis. The Mann-Whitney test was used to compare the numerical variables between two groups. A p-value of ≤0.05 was considered statistically significant in all comparisons.

Patients
A total of 129 patients were enrolled in the current study. The clinical characteristics of the cohort are shown in Table 1

SUV max and SUV max /TS in thymic epithelial tumors
We investigated the relationship between the SUV max of each tumor and the pathological findings, with a focus on the differentiation of thymoma and thymic carcinoma (Figure 1a). The SUV max scores in thymoma were significantly lower than those in thymic carcinoma (3.3 AE 1.3 vs. 7.7 AE 3.4, p < 0.01). The cutoff value for the SUV max was 5.0, and the sensitivity and specificity for differentiating thymoma and thymic carcinoma were 0.90 and 0.75, respectively. The SUV max /TS of thymoma was also significantly lower than that of thymic carcinoma (0.6 AE 0.4 vs. 1.5 AE 0.7, p < 0.01) (Figure 1b). The cutoff value for the SUV max /TS was 1.0, and the sensitivity and specificity for differentiating thymoma and thymic carcinoma were 0.93 and 0.73, respectively. The AUC of each parameter was calculated as 0.93 for the SUV max and 0.90 for the SUV max /TS (Figure 1c,d).

FDG-PET/CT parameters and tumor classification
The SUV max and SUV max /TS in thymic epithelial tumors according to the WHO classification were shown in Figure 2a,b, respectively. The scores of SUV max in thymic carcinoma were significantly higher than those in low-and high-grade thymoma (p < 0.01, p < 0.01, respectively). Similarly, the SUV max /TS values of thymic carcinoma were significantly higher than those of low-and high-grade thymoma (p < 0.01, p < 0.01, respectively).

Relationship between the tumor stage and FDG-PET/CT parameters
Next, the patients were divided into two categories: Masaoka stage 1 and stage 2-4. The SUV max and SUV max /TS values were plotted in accordance with the Masaoka stage (Figure 3a,  b). The scores of SUV max in Masaoka stage 1 were significantly lower than those in Masaoka stage 2-4 (2.9 AE 1.5 vs. 4.7 AE 3.1, p < 0.05). In addition, the SUV max /TS values in Masaoka stage 1 were significantly lower than those in Masaoka stage 2-4 (0.7 AE 0.5 vs. 0.9 AE 0.7, p < 0.05).

FDG-PET/CT parameters in tumors show a moderate SUV max
To investigate the relevance of SUV max /TS to the prediction of thymic carcinoma with a moderate SUV max of ≤5.0,  Figure 4a). Furthermore, the SUV max /TS values of thymoma tended to be lower than those of thymic carcinoma (0.6 AE 0.4 and 1.6 AE 0.8) (Figure 4b). An ROC curve analysis was performed in this cohort, and the AUC of the SUV max /TS was 0.86 ( Figure 4c). Using the cutoff value of SUV max /TS as 1.0, the sensitivity and specificity for differentiating thymoma and thymic cancer were 0.75 and 0.86, respectively.

DISCUSSION
We found that both the SUV max and SUV max /TS were associated with the pathological differentiation of thymic epithelial tumors. Both of those scores in thymic carcinoma were significantly higher than those in thymoma. Furthermore, to our knowledge, this is the first report to investigate the role of the SUV max /TS in the differentiation of thymic epithelial tumor, especially in tumors with a moderate SUV max of ≤5.0. A preoperative diagnosis is very important to determine the appropriate treatment strategy against thymic epithelial tumor. In cases of induction therapy, the treatment regimen is dependent on the pathological result. A CT-guided biopsy (CTGB) is a standard maneuver for a preoperative biopsy to make a pathological diagnosis. However, a CTGB may induce complications, such as mediastinal hemorrhage. 9 To decrease the rate of such complications, a preoperative CTGB is sometimes avoided in mediastinal tumors of a small size or which are attached to the great vessels. In such cases, PET-CT might help identify candidates for a CTGB for the precise preoperative diagnosis.
Surgical treatment for thymic epithelial tumor includes the trans-sternal approach and minimally invasive approaches, such as video assisted thoracoscopic surgery (VATS) and robot assisted thoracoscopic surgery (RATS). 10 The choice of approach is important in order to acquire an appropriate surgical view for complete tumor resection. 11 In cases of thymoma, especially those ≤5 cm in size, our institution selects the VATS/RATS approach. 12 In contrast, median sternotomy is selected for resection of thymic carcinoma to obtain an appropriate surgical view for mediastinal lymph node dissection. Preoperative PET-CT provides valuable information for the differentiation of those two scenarios.
Regarding the surgical position, the supine position is selected in most cases of thymic epithelial tumor resection in our institution. However, the lateral position is sometimes preferred in cases with the tumor located in the right-or left-sided mediastinum. Based on the findings from the current study, for tumors with SUV max of >5 or SUV max /TS of >1.0, the supine position seems more appropriate than the lateral position due to the possibility of thymic carcinoma. From this perspective, PET-CT provides ample information to support the accurate selection of not only the surgical approach but also the surgical position.
Several studies have shown that PET-CT is useful for differentiating thymoma and thymic carcinoma based on their SUV max scores. Park et al. reported that the cutoff value of SUV max for this purpose with the maximum sensitivity was 5, 13 with the same score found by the ROC curve analysis. However, we sometimes encounter cases of thymic carcinoma with a moderate SUV max of ≤5, and the SUV max /TS index is investigated in those patients. Lococo et al. revealed that the mean SUV max /TS value in thymoma was 0.92, and that in thymic carcinoma was 1.93. In our entire cohort, the cutoff value of the SUV max /TS for the differentiation of thymoma and thymic carcinoma was 1.0. Furthermore, in tumors showing an SUV max of ≤5, the cutoff value of the SUV max /TS as 1.0 also showed high sensitivity and specificity. Our findings suggest that the SUV max /TS value indicates the metabolic activity of the tumor and might reflect the malignant potential of the tumor. For this reason, we aggressively conduct PET-CT as a preoperative examination, even in cases with small tumors.
Thymic carcinoma is a rare disease, and previous studies regarding SUV max /TS have involved small sample sizes, especially for thymic carcinoma. 4,5 Two previous studies both involved just seven cases of thymic carcinoma each. As far as we examined, our study included the largest case number of thymic carcinoma (31 cases) as a single institution study compared with previous reports. We hope that the current results will enhance the clinical significance of the SUV max /TS in the radiological diagnosis.
We were also curious about the influence of the SUV max /TS on the prognosis of thymic epithelial tumor. Several reports have described the impact of the SUV max on the prognosis of thymoma and thymic carcinoma. Seki et al. reported that a higher SUV max reflected a lower recurrencefree survival. 14 Furthermore, Hamaji et al. revealed that the metabolic tumor volume and total lesion glycolysis were related to the risk of postoperative recurrence of thymic carcinoma. 15 In our study, the observational period was short, so it was difficult to conclude the relationship between the SUV max /TS index and the prognosis after radical resection. A further analysis will be required to investigate the influence of the SUV max /TS on the postoperative prognosis.
Several limitations associated with the present study warrant mention. First, our cohort was small, and this study was a single-institution and retrospective observational one. To validate the concept and strengthen our findings, a different cohort collected separately and prospectively will be required. Second, our cohort was limited to patients who underwent surgical treatment. Whether or not our concept can be applied to more advanced diseases with multiple pleural dissemination remains unclear.
In conclusion, the current study demonstrated the role of the SUV max and SUV max /TS as predictive features of the pathological diagnosis of thymic epithelial tumors. We expect these findings to aid surgeons in selecting the most appropriate surgical approach and treatment strategy.

ACKNOWLEDGMENTS
We thank Dr Brian Quinn for the English language editing.

CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.