Doubling Time of Thymic Epithelial Tumors Correlates With World Health Organization Histopathologic Classification

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1 Cardiopulmonary Imaging Original Research Jeong et al. Thymic Epithelial Tumors Cardiopulmonary Imaging Original Research JOURNAL CLUB Dong Young Jeong 1 Kyung Soo Lee 1 Myung Jin Chung 1 Jae Ill Zo 2 Young Mog Shim 2 Jung Won Moon 3 Jeong DY, Lee KS, Chung MJ, Zo JI, Shim YM, Moon JW Keywords: CT, thymoma, tumor growth DOI: /AJR Received December 18, 2016; accepted after revision February 19, Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Gu, Seoul , Korea. Address correspondence to K. S. Lee (kyungs.lee@samsung.com). 2 Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 3 Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. This article is available for credit. WEB This is a web exclusive article. AJR 2017; 209:W202 W X/17/2094 W202 American Roentgen Ray Society JOURNAL CLUB: Doubling Time of Thymic Epithelial Tumors Correlates With World Health Organization Histopathologic Classification OBJECTIVE. Awareness of volume doubling times (VDTs) of different thymic epithelial tumors (TETs), including low- and high-grade thymomas and thymic carcinomas, is important for their management. The purpose of this study was to evaluate the VDTs of incidentally found TETs using 3D volumetry (3D-VDT) and longest diameter (LD-VDT). MATERIALS AND METHODS. This retrospective study included 50 patients (30 men, 20 women) who had histologically proven TETs and who underwent at least two serial CT studies at greater than 2-month intervals. TETs were classified into World Health Organization subtypes and further divided into low-grade (group A [A B1]) and high-grade (group B [B2, B3]) thymoma and thymic carcinoma (group C). Tumor volumetry was performed by either manual segmentation (3D-VDT) or longest diameter measurement (LD-VDT). RESULTS. Groups A, B, and C accounted for 15, 26, and nine tumors. The median LD- VDT in group A was days (range, days); group B, days (range, days), and group C, days (range, days) (p < 0.01). The median 3D-VDTs were days (range, days), days (range, days), and days (range, days) (p < 0.01). In ROC analysis, both LD-VDT (AUC, 0.873; p < 0.01; optimal cutoff value, days; 90.2% sensitivity, 77.8% specificity) and 3D- VDT (AUC, 0.859; p < 0.01; optimal cutoff value, days; 92.7% sensitivity; 66.7% specificity) differentiated group C from groups A and B. CONCLUSION. VDTs differ among TETs according to tumor grade. Measurement of either LD-VDT or 3D-VDT is sensitive for differentiating carcinomas from thymomas (cutoff value, 220 days). T hymic epithelial tumor (TET) is a distinctive pathologic entity with various histologic features and heterogeneous oncologic behavior. Among the diverse classification systems, that of the World Health Organization (WHO) has been adopted because of good correlation between histologic appearance and oncologic behavior. The incidence of TETs in the United States is low at an overall 0.13 per 100,000 people [1, 2]. It is higher among Asians and Pacific Islanders in the United States, however, ranging from 0.17 to 0.30 per 100,000 people. The incidence of TET in The Netherlands is 0.32 per 100,000 people [2], but the incidence in South Korea is 0.50 per 100,000 (men, 0.60 per 100,000 people; women, 0.41 per 100,000) according to Korea Central Cancer Registry data for 2013 (proprietary data, South Korean Ministry of Health and Welfare). Lung cancer screening by CT with a lowdose technique is recommended for smokers at high risk (> 30 pack-years, < 15 years after smoking cessation) [3]. Currently, low-dose CT for lung cancer screening is covered by Medicare in the United States. In other countries, it is being performed when requested on an individual basis and is paid for by the patient [4]. Therefore, an increasing number of CT procedures are expected to be performed for screening purposes. Approximately 8 19% of low-dose CT examinations show incidental findings [5, 6], and most of these necessitate follow-up imaging studies for characterization. Of noncardiovascular abnormalities, mediastinal lesion, particularly thymic tumor, is one of the most important incidental findings [5, 7]. TETs grow slowly, although their volume doubling time (VDT) has not been studied, to our knowledge. Thymic carcinomas may grow faster than thymomas because they are associated with a lower survival rate than low-grade (WHO classification A B1) and W202 AJR:209, October 2017

2 Thymic Epithelial Tumors high-grade (B2, B3) thymomas, and histologic diagnosis of thymic carcinoma per se is an independent factor for decreased survival among patients with TETs [8]. Therefore, early characterization of TETs and discrimination of thymic carcinoma from other TETs are crucial for optimal treatment of patients with thymic carcinoma found at low-dose CT lung cancer screening. However, direct confirmation of surgical tissue and consequent surgical removal do not seem to be an appropriate management method because most incidentally found TETs are small and grow slowly. Therefore, a regular imaging followup study may be the optimal management of incidentally found small thymic tumors. In this context, awareness of the VDTs of different TETs is important for their management, because it allows distinction of thymic carcinomas from other thymomas. However, to our knowledge, VDTs for TETs have not been reported. The purpose of our study was to evaluate the VDT of incidentally found TETs using 3D volumetry (3D-VDT) and measurement of longest diameter (LD-VDT). Materials and Methods Patient Selection This retrospective study received institutional review board approval, and the requirement for patient consent for the use of clinical data was waived. By reviewing medical records of the department of thoracic surgery at Samsung Medical Center (a tertiary referral hospital in Seoul, Korea), we identified 458 patients with a surgically and histopathologically proven TET from April 2002 to May Of these 458 patients, only 75 underwent at least two serial CT studies with a follow-up interval longer than 2 months. Among the 75 patients, 21 were excluded because they underwent chemotherapy or radiotherapy during the CT follow-up period. An additional four patients were excluded because of poor quality of CT scans for analysis, mainly related to slice thickness of 7 mm or greater. Forty-two TETs were found incidentally in subjects who did not have symptoms: 36 TETs at lung cancer screening CT and six at metastasis or recurrence evaluation CT for colorectal (n = 4) and breast (n = 2) cancers. Eight TETs were seen in patients who did have symptoms (four with myasthenia gravis, three with chest pain, and one with dyspnea). Histopathologic Classification According to the WHO classification system, the TETs were subclassified into types A, AB, B1, B2, B3, and C (thymic carcinoma) and then divided into low-grade TETs (group A, which included WHO classifications A B1), high-grade TETs (group B, which included WHO classifications B2 and B3), and thymic squamous cell carcinomas (group C). If a TET was composed of diverse (two or more) histologic subtypes (n = 6), we used the higher-grade tumor subtype, irrespective of the extent of each subtype. For example, a tumor of mixed WHO classification B1 plus B2 was considered B2 (n = 5), and one of B1 plus B3 was regarded as B3 (n = 1). The histologic subtype of thymic carcinoma was squamous cell carcinoma in all nine patients. CT and Volume Doubling Time Measurements CT studies were performed with various helical CT scanners from several vendors (Appendix 1). The preoperative scanning parameters were 120 kvp and ma, and image data were reconstructed with standard soft-tissue algorithms. The data were reformatted with a section thickness of mm for transverse images. CT studies were obtained with injection of contrast medium (enhanced CT [72%]) or without injection (unenhanced CT [28%]). When initial measurements were performed on enhanced scans, followup measurements were also obtained on enhanced scans, and similarly for unenhanced scans. One radiologist (2nd-year radiologic resident) measured the longest diameter of all TETs on the transverse image in which the equator (the largest area) of the tumor was scanned (this step was performed 100 times, twice for each of 50 tumors at initial and last follow-up studies). One in-house 3D laboratory radiology technologist (who worked for the 3D laboratory for 4 years) used commercial software (AZE VirtualPlace Fujin Raijin 350 version , AZE) to perform 3D manual segmentation of each anterior mediastinal mass for volume measurement (Fig. 1). A certain threshold value was not used for tumor segmentation; by manual tracing method, each slice image was segmented. After magnification of images, tumor boundaries were determined in contrast to mediastinal fat. When mediastinal fat was absent, the imaginary borderline between the TET and mediastinal structures was presumed to be the tumor boundary. For length measurements, volumetry was similarly performed on 50 tumors at presentation and at follow-up CT examination. Before measurement, the radiologist and the 3D laboratory technician completed a 2-week training session to become familiar with the measurement technique. Actual study measurements were repeated after an interval of 2 weeks to check intraobserver variation. For 3D volumetry of TETs, an experienced radiologist (25 years of experience in chest CT interpretation) gave measurement input to confirm that all measurements were performed accurately. All segmentations and diameter measurements were performed under a mediastinal window setting at a window width of 342 HU and a window level of 56 HU. Tumor volumes were estimated with both 3D volumetry and measurement of LD. Tumor volume estimated with the longest tumor diameter was calculated with the following formula: volume (V) = (π * LD 3 ) / 6. Tumor VDTs were calculated with the modified Schwarz formula [9]: VDT = [log2 I] / [log [V l / V i ], where V l and V i are the latest (3D) and initial (LD) tumor volumes, and I is the time interval between the two serial CT scans. Statistical Methods Data were analyzed and compared in three groups (A, B, and C) by Kruskal-Wallis test. The Pearson product-moment correlation coefficient was calculated to analyze relations between demographic factors and VDT (both 3D- and LD-VDT). ROC analysis was performed to calculate cutoff value and to compare the performance of 3D-VDT and LD-VDT for discriminating group C (thymic carcinoma) from groups A and B (thymomas). Intraobserver variation for diameter and volume measurements was assessed by intraclass correlation coefficient (ICC). Statistical analyses were performed with SPSS software (SPSS Statistics Desktop version 23, IBM), and p < 0.05 was considered to indicate a significant difference. Results Demographic and Pathologic Characteristics The 50 patients (30 men, 20 women; age range, years; median, 54.5 years) underwent CT at follow-up intervals of days (median, 239 days). Fifteen (30%) of the 50 TETs were classified as group A; 26 (52%), group B; and nine (18%), group C. At the initial CT examination, the median longest tumor diameters were 25.4 mm in group A (range, mm), 27.6 mm in group B (range, mm), and 28.3 mm in group C (range, mm). The median tumor volumes measured with 3D volumetry were 8.05 cm 3 in group A (range, cm 3 ), cm 3 in group B (range, cm 3 ), and 5.93 cm 3 in group C (range, cm 3 ) (Table 1). Volume Doubling Time and Its Relation to Demographic and Pathologic Variables The median calculated LD-VDTs were days (range, days) in group A, days (range, days) in group B, and days (range, days) in group C. The LD-VDT was significantly different among the three groups (p < 0.001), and the median LD-VDT of group C was significantly shorter than that AJR:209, October 2017 W203

3 TABLE 1: Demographic and Pathologic Characteristics Jeong et al. Characteristic Low Grade (A) High Grade (B) Carcinoma (C) Total p Sex (no. of patients) a Men Women Median age (y) 57 (39 77) 53 (30 73) 54 (48 81) 54.5 (30 81) a Symptoms (no. of patients) a Asymptomatic Symptomatic Myasthenia gravis Chest pain Dyspnea 1 1 Smoking a Other malignancy a Median initial longest diameter (mm) 25.4 ( ) 27.6 (6 94.8) 28.3 ( ) 27.9 ( ) a Median initial volume (cm 3 ) b 8.05 ( ) ( ) 5.93 ( ) 9.60 ( ) a Median follow-up interval (d) 182 ( ) 317 ( ) 180 ( ) 239 ( ) a WHO pathologic subtype A 4 4 AB 9 9 B1 2 2 B B3 9 9 C 9 9 Total Note Values in parentheses are percentages. WHO = World Health Organization. a Fisher exact test. b Measured with 3D volumetry. of groups A and B (group A vs group B, p = 0.038; group B vs group C, p = 0.033; group A vs group C, p < 0.001) (Fig. 2A). The median 3D-VDTs were days (range, days) in group A, days (range, ,209.5 days) in group B, and days (range, days) in group C. The 3D-VDT was significantly different among the three groups (p = 0.001), and the median 3D-VDT in group C was significantly shorter than that of groups A and B (group A vs group B, p = 0.327; group B vs group C, p = 0.021; group A vs group C, p = 0.001) (Figs. 2B, 3, and 4). Pearson correlation analysis showed that neither LD-VDT nor 3D-VDT had a linear correlation with demographic factors, such as age, initial longest diameter and tumor volume, presence of other malignancy, or follow-up interval (Table 2). Only group classification by grade (groups A, B, and C according to WHO classification) had a linear correlation with VDT (LD-VDT, p < 0.001; 3D-VDT, p = 0.036). Intraobserver agreement was excellent for both VDT measurements, as indicated by an ICC of greater than 0.99 (LD-VDT ICC, [95% CI, ]; 3D-VDT ICC, [95% CI, ]). ROC Analysis for Differentiating the Three Groups ROC curves were plotted with LD-VDT (AUC, [95% CI, ]; p = 0.001; optimal cutoff value, days with 90.2% sensitivity and 77.8% specificity) and 3D-VDT (AUC, 0.859; 95% CI, ; p = 0.001; optimal cutoff value, days with 92.7% sensitivity and 66.7% specificity) for differentiating thymic carcinoma (group C) from thymoma (groups A and B) (Fig. 2C). Both LD-VDT and 3D-VDT could be used to differentiate thymic carcinomas, but 3D-VDT was slightly more sensitive than LD-VDT and had a shorter cutoff time (218.0 vs days) for differentiation. Discussion Surgical resection, especially complete thymectomy, is the standard treatment protocol for resectable and aggressive TETs [10]. TABLE 2: Correlations (Pearson Product-Moment Correlation Coefficient) Between Volume Doubling Time (VDT) and Demographic Factors Age Initial Diameter Initial Volume Interval Symptom Other Malignancy VDT r p r p r p r p r p r p Longest diameter D W204 AJR:209, October 2017

4 Thymic Epithelial Tumors There has been limited information, however, regarding surgical indication in terms of tumor size for small TETs (particularly tumors 2 cm or less in diameter) found incidentally at low-dose CT for lung cancer screening. Some surgeons prefer surgical management of small TETs and insist that the tumors eventually grow and necessitate surgery sometime in the future. Others may recommend followup evaluation to make sure that the tumor undergoes apparent interval growth or has a VDT in the thymic cancer range, given the presence of clear surgical risk even in videoassisted thoracoscopic surgery [11]. An additional clinical implication of our study may be the situation in which a patient happens to have an older imaging study that would allow calculation of VDT (for patients who were lost to follow-up or refused surgery). Tumor VDT is known to be a powerful prognostic factor because it can provide useful information regarding tumor aggressiveness [12]. However, tumor doubling time of TETs has rarely been reported. Ours may be the first study that provides information on tumor VDT in TETs determined with two different methods of measuring the longest tumor diameter (LD-VDT) or segmented areas and their integration (3D-VDT). Our data show significant differences in both LD-VDT and 3D-VDT among low- or high-grade TETs and thymic carcinomas. Neither LD-VDT nor 3D-VDT had a significant relation to any demographic factor. However, both VDTs had an important association with the WHO classification of TETs. Most important, we could differentiate thymic carcinomas from incidentally found thymomas by measuring VDT on serial CT studies. ROC analysis showed good performance with both LD-VDT and 3D-VDT for differentiating thymic carcinomas from thymomas. The optimal cutoff value was approximately 200 days with greater than 90% sensitivity and approximately 70% specificity. Therefore, when a small thymic tumor is found incidentally on a chest CT scan, a follow-up study with an interval of at least 6 months and calculation of VDT (preferably 3D-VDT) may be considered. A longer follow-up interval (for example, more than 1 year of follow-up) and resultant calculation of VDT may also help in diagnosis of thymic carcinoma. In that circumstance, however, the thymic carcinoma might have spread to the thorax or extrathoracic organs with loss of opportunity for complete resection. We calculated tumor volume using either a unidimensional (maximum diameter) or 3D method. Measurements of lung tumor size on CT scans are often inconsistent, even to the extent of incorrect interpretation of tumor response. Erasmus et al. [13] reported that unidimensional and bidimensional measurements of tumor size on CT scans were often inconsistent and that consistency can be improved if the same reader performs serial measurements. In our study, one radiologist measured the LD for LD-VDT, and one technician performed all measurements of tumor volume for 3D- VDT. Intraobserver variability was excellent for both the LD and tumor volume measurements. Kostis et al. [14] and Gou et al. [15] reported that 3D volume measurement of pulmonary nodules is more repeatable than 2D volume measurement. There were several limitations in our study. First, our study design was retrospective; therefore, there was unavoidable bias. Second, there might have been potential selection bias because not all anterior mediastinal tumors were thymic in origin and because we included only cases that were pathologically proved. This could have introduced a bias toward more aggressive or at least impressive masses. Third, because some diagnoses of thymoma or thymic carcinoma had already been made in another hospital and the patients came to our hospital for surgical management, the initial CT scans were obtained with different types of CT scanners. Fourth, we did not evaluate interobserver variability for volume measurements using the LD or tumor segmentation (3D volume measurements). Fifth, the number of patients included in our study was small because of the low incidence of TET. Further study with a larger number of patients may be needed. Finally, contrast medium was used in 72% of CT studies. This inhomogeneous use of contrast medium might have introduced differences in the measurement of VDT. Conclusion VDTs measured as both LD-VDT and 3D-VDT differ among TETs according to tumor grade. Measuring either LD-VDT or 3D-VDT is sensitive for differentiating carcinomas from thymomas (cutoff value, 220 days). Even though surgical removal is the standard treatment protocol for resectable and aggressive TETs, in small TETs found incidentally at low-dose CT for lung cancer screening and particularly those smaller than 2 cm in diameter, short-term follow-up CT may help characterize small thymic tumors. Acknowledgment We thank our radiologic technologist Sangwook Kim for participating in the measurement of 3D-VDT in all cases. References 1. Thomas PA. The need for organization and collaboration: establishing a thymoma registry. Thorac Surg Clin 2011; 21: de Jong WK, Blaauwgeers JL, Schaapveld M, Timens W, Klinkenberg TJ, Groen HJ. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008; 44: National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: Yi CA, Lee KS, Shin MH, et al. Low-dose CT screening in an Asian population with diverse risk for lung cancer: a retrospective cohort study. Eur Radiol 2015; 25: van de Wiel JC, Wang Y, Xu DM, et al. Neglectable benefit of searching for incidental findings in the Dutch-Belgian lung cancer screening trial (NELSON) using low-dose multidetector CT. Eur Radiol 2007; 17: Kucharczyk MJ, Menezes RJ, McGregor A, Paul NS, Roberts HC. Assessing the impact of incidental findings in a lung cancer screening study by using low-dose computed tomography. Can Assoc Radiol J 2011; 62: Rampinelli C, Preda L, Maniglio M, et al. Extrapulmonary malignancies detected at lung cancer screening. Radiology 2011; 261: Moon JW, Lee KS, Shin MH, et al. Thymic epithelial tumors: prognostic determinants among clinical, histopathologic, and computed tomography findings. Ann Thorac Surg 2015; 99: Schwartz M. A biomathematical approach to clinical tumor growth. Cancer 1961; 14: Narm KS, Lee CY, Do YW, et al. Limited thymectomy as a potential alternative treatment option for early-stage thymoma: a multi-institutional propensity-matched study. Lung Cancer 2016; 101: Langdon M, Cunningham AJ. Perioperative cardiorespiratory complications in adults with mediastinal mass: incidence and risk factors. Surv Anesthesiol 2005; 49: Usuda K, Saito Y, Sagawa M, et al. Tumor doubling time and prognostic assessment of patients with primary lung cancer. Cancer 1994; 74: AJR:209, October 2017 W205

5 Jeong et al. 13. Erasmus JJ, Gladish GW, Broemeling L, et al. Interobserver and intraobserver variability in measurement of non small-cell carcinoma lung lesions: implications for assessment of tumor response. J Clin Oncol 2003; 21: Kostis WJ, Yankelevitz DF, Reeves AP, Fluture SC, Henschke CI. Small pulmonary nodules: reproducibility of three-dimensional volumetric measurement and estimation of time to follow-up CT. Radiology 2004; 231: Guo X, Wang Y, Li D, et al. The intra-observer variability of volumetric measurement of pulmonary nodules: comparison of two-dimensional and three-dimensional method [in Chinese]. Zhongguo Fei Ai Za Zhi 2014; 17: APPENDIX 1: Devices Used for Initial CT Genesis HiSpeed RP, LightSpeed 16, LightSpeed Plus, LightSpeed Ultra, LightSpeed QX/i, LightSpeed VCT, and Discovery CT750 HD (GE Healthcare); Brilliance 40, Brilliance 64 (Philips Healthcare); Somatom Definition Flash, Sensation 16, Sensation 64, Balance, Spirit, Somatom Plus (Siemens Healthcare); Aquilion 64 (Toshiba Medical Systems). A B E Fig year-old man with type B3 thymoma. Example of 3D segmentation and volume measurement. A, Rendered 3D model shows thymic epithelial tumor and its calculated volume. B G, CT images show how 3D volume rendering is performed by integrating manually segmented areas on loaded axial images with magnification. C F D G W206 AJR:209, October 2017

6 Thymic Epithelial Tumors Median LD-VDT (Q1 Q3) Sensitivity LD-VDT (d) Group A ( ) Group B ( ) Group C ( ) LD-VDT 3D-VDT Reference Line Specificity * * A C Median 3D-VDT (Q1 Q3) 3D-VDT (d) Group A ( ) * Group B ( ) * Group C ( ) B Fig. 2 Comparisons of volume doubling times (VDTs) among three groups and ROC curves between longest diameter (LD)-VDT and 3D-VDT. A and B, Box plots show median LD-VDT (A) and 3D-VDT (B) for group A (lowgrade thymic epithelial tumor [TET]), group B (high-grade TET), and group C (thymic carcinoma). Both median LD- and 3D-VDTs were significantly shorter for group C than for two other groups. Circles represent outlier values. Three 3D-VDT outliers are not expressed owing to their exceptionally different values. Unexpressed outlier values are as follows: and in group A and in group B. Q3 Q1 represents range of both upper (75th) and lower (25th) quartiles; asterisk, p < Lower and upper limits of whiskers indicate minimum and maximum of all of data. C, ROC curve shows comparisons between LD-VDT and 3D-VDT for differentiating thymic carcinoma from other thymomas. AUC value is for LD-VDT and for 3D-VDT (p = 0.001). A B Fig year-old man with growing anterior mediastinal mass diagnosed as thymic squamous cell carcinoma. A and B, Original axial (A) and magnification (B) CT images show anterior mediastinal mass (arrow) measuring 27.9 mm. C, Three-dimensional rendering shows mass and resultant volume measurement of 2.43 cm 3. ml = cm 3. C (Fig. 3 continues on next page) AJR:209, October 2017 W207

7 Jeong et al. D G E Fig. 3 (continued) 51-year-old man with growing anterior mediastinal mass diagnosed as thymic squamous cell carcinoma. D F, Follow-up axial (D) and magnification (E) CT images and 3D rendering (F) obtained 284 days after A C show interval growth of anterior mediastinal mass (arrow, D and E), which measures 48.3 mm. Resultant volume measurement is cm 3. ml = cm 3. G, Photograph of gross specimen shows infiltrative mass histopathologically confirmed as thymic squamous cell carcinoma. Longest diameter volume doubling time (VDT) of mass was days, and 3D-VDT of mass was 87.8 days. F A B Fig year-old man with very slowly growing anterior mediastinal mass diagnosed as type AB thymoma. A and B, Original axial (A) and magnification (B) CT images show anterior mediastinal mass (arrow) measuring 22.1 mm. C, Three-dimensional rendering shows mass and resultant volume measurement of 2.23 cm 3. ml = cm 3. C (Fig. 4 continues on next page) W208 AJR:209, October 2017

8 Thymic Epithelial Tumors D G FOR YOUR INFORMATION Fig. 4 (continued) 52-year-old man with very slowly growing anterior mediastinal mass diagnosed as type AB thymoma. D F, Follow-up axial (D) and magnification (E) CT images and 3D rendering (F) obtained after A C show interval growth of anterior mediastinal mass (arrow, D and E), which measures 23.0 mm. Resultant volume measurement is 2.44 cm 3. ml = cm 3. G, Photograph of gross specimen shows lobulated mass histopathologically confirmed as type AB thymoma. Longest-diameter volume doubling time (VDT) of mass was days; 3D-VDT was days. This article has been selected for AJR Journal Club activity. The accompanying Journal Club study guide can be found on the following page. This article is available for CME and Self-Assessment (SA-CME) credit that satisfies Part II requirements for maintenance of certification (MOC). To access the examination for this article, follow the prompts. E F AJR:209, October 2017 W209

9 Jeong et al. AJR Journal Club Study Guide Doubling Time of Thymic Epithelial Tumors Correlates With World Health Organization Histopathologic Classification Joseph J. Budovec 1, Margaret Mulligan 1, Alan Mautz 2 1 Medical College of Wisconsin, Milwaukee, WI. 2 The Aroostook Medical Center, Presque Isle, ME. jbudovec@mcw.edu, mmulliga@mcw.edu, amautz@emhs.org* Introduction 1. What is the purpose of the study? What is the rationale for the study? 2. Is this study timely? Does the study address a lack of knowledge? 3. How would you formally state the authors hypotheses? How would you state the alternative hypotheses? Methods 4. What research design was used in this study? 5. What were the inclusion criteria for the study? What were the exclusion criteria? 6. What were the limitations of this study? Were these limitations adequately acknowledged and discussed? 7. What variables were selected for analysis? 8. What statistical methods were used in the study analysis? Results 9. Was the research question answered? Were the primary and secondary hypotheses resolved? Research Methods 10. In this study, all the measurements were performed by either one radiologist or one technologist. What is the rationale that the authors give for this study design? 11. What are some methods for reducing measurement variability? What statistical tests may be performed to analyze observer variability? Discussion 12. How do the results of this study compare with those of other studies? 13. How might the study be improved? 14. The study suggests at its conclusion that short-interval follow-up CT to allow calculation of tumor volume doubling times (VDTs) for lesions smaller than 2 cm may be clinically useful. What is your current practice when anterior mediastinal lesions are discovered incidentally at CT? Will you alter your practice on the basis of the study results? 15. The study population was selected from a group of patients with histopathologically proven thymic epithelial tumors. How may this affect the study s relevance to clinical practice when anterior mediastinal masses may be found de novo and management decisions are yet to be made and histopathologic results are not yet known? Background Reading 1. Rampinelli C, Preda L, Maniglio M, et al. Extrapulmonary malignancies detected at lung cancer screening. Radiology 2011; 261: Yi CA, Lee KS, Shin MH, et al. Low-dose CT screening in an Asian population with diverse risk for lung cancer: a retrospective cohort study. Eur Radiol 2015; 25: *Please note that the authors of the Study Guide are distinct from those of the companion article. W210 AJR:209, October 2017