Conflicting or complementary role of computed tomography (CT) and positron emission tomography (PET)/CT in the assessment of thymic cancer and thymoma: our experience and literature review

Patient population

From April 2008 to December 2012, we retrospectively reviewed a total of 90 FDG PET/CT scans that were performed on 56 patients with a known or suspected thymic disease. Moreover, in 32 subjects of the same population, we collected 38 CT scans performed within three months of the PET/CT studies. Thirty-five PET/CT scans were performed at initial staging, 28 for restaging, 17 for evaluation of response to therapy, and 10 for long term follow-up. Out of 38 CT scans, 14 were made at initial staging, eight for restaging, six for response to therapy, and 10 for follow-up. For the end points of the present study, we considered 26 patients at initial staging of thymoma or thymic cancer. There were eight male and 18 female patients (30.8 vs. 68.2%, respectively). The median age was 57.5 years (31–78 years). All patients had a PET/CT scan, while only eight subjects had an available CT in the same setting. The defined diagnosis was obtained by surgical specimens after thymectomy. The surgical specimens were reviewed by two experienced pathologists, and the tumors were divided into six subtypes on the basis of WHO classification: type A, type AB, type B1, type B2, type B3, and thymic carcinoma. All of the tumors were staged on the basis of the presence and extent of transcapsular invasion into adjacent mediastinal tissues as determined by surgical findings and confirmed by microscopic examination:³ stage I, encapsulated tumor without microscopic evidence of capsular invasion; stage II, microscopic or macroscopic invasion of the surrounding fatty tissue or the mediastinal pleura; stage III, macroscopic invasion of neighboring organs, such as the pericardium, lung or the great vessels; and stage IV, pericardial or pleural dissemination (IVa) and lymph node or distant metastases (IVb). This study was approved by the local institutional review board for retrospective analysis, and was conducted according to the Declaration of Helsinki (2000).

Computed tomography (CT) imaging

All chest CT examinations were acquired from the lung apices through the middle portions of both kidneys. Three examinations were made using a 40-row detector CT (Somatom Definition AS; Siemens Medical Systems, Erlangen, Germany) using the following parameters: section thickness 3 mm, reconstruction 2 mm, gantry rotation time 0.5 seconds, pitch 0.8, tube potential 120 kV, and mAs setting adjusted for body weight. All patients received intravenous contrast medium (2 mL/kg; flow rate 3 mL/second; Omnipaque 350; GE Healthcare, Milan, Italy). Imaging data of hard copies in five patients whose CT scans were obtained at other hospitals were scanned and uploaded to a picture archiving and communication system. All monitors showed images obtained using both mediastinal (width, 400 H; level, 20 H) and lung (width 1.500 H, level −700 H) window settings. Multiplanar reconstruction images were assessed for lesion shape and size. CT images were reviewed and interpreted by two radiologists with at least five years experience of chest CT interpretation. Both specialists were presented with the patients’ clinical history, but were unaware of histological findings. Chest CT scans were also retrieved to a commercially available stand-alone workstation loaded with commercial volume CT software (syngo.via, Siemens, Hoffman Estates, IL, USA) which automatically measured the tumor volume by calculating the space that is enclosed within the segmented tumor. Qualitative and quantitative chest CT findings were documented for each patient; in particular, the tumor shape was classified as round if the long-to-short axis ratio was less than or equal to 1.5, oval if the ratio was greater than 1.5 but less than 3.0, and plaque-shaped if the ratio was greater than 3.0. Marginal characteristics were subclassified as smooth, lobulated or irregular. Tumor necrosis and calcifications were considered. The pattern of enhancement was recorded as homogeneous or heterogeneous and the degree of enhancement was classified as low or high compared to that of the chest wall muscle. Fatty mediastinal infiltration, great vessel invasion (such as the degree of abutment), pleural and pericardial effusion, and enlarged lymph nodes were evaluated. Among quantitative variables, tumor size (two maximal axial diameters and maximal longitudinal diameter measured by multi planar reconstruction (MPR) and volume (in mL) were computed.

Positron emission tomography (PET)/CT protocol

Whole body FDG PET/CT was performed using a dedicated PET/CT scanner (Biograph 16 HT, Siemens Medical Solutions, Hoffman Estates, IL, USA). The PET component is a high-resolution scanner with a spatial resolution of 4.7 mm and has no septa, thus allowing only 3-dimensional (3D) acquisitions. The CT portion of the scanner is the Somatom Sensation 16-slice CT. Together with the PET system, the CT scanner is used both for attenuation correction of PET data and for localization of FDG-uptake in PET images. All patients were advised to fast for at least six hours before the integrated PET/CT examination. After injection of 3.0 MBq of FDG per kg/bw, patients rested for a period of approximately 60 minutes in a comfortable chair. A low dose CT was performed for the attenuation correction. Emission images ranging from the proximal femur and the base of the skull were acquired for three minutes per bed position. Acquired images were reconstructed using the attenuation weighted-ordered subset expectation maximization iterative reconstruction, with two iterations and eight subsets. Fourier rebinning was used to reduce the 3D dataset to a 2D equivalent dataset, and a 4-mm full width at half maximum Gaussian filter was applied to the image after reconstruction along the axial and transaxial directions. The data were reconstructed over a 128 × 128 matrix with 2 mm pixel size and slice thickness. Processed images were displayed in coronal, transverse, and sagittal planes. Two experienced nuclear medicine physicians interpreted the PET/CT images, unaware of previous findings. At visual analysis, increased FDG uptakes not corresponding to physiological uptake patterns or in any foci of increased uptake corresponding to a CT abnormality were recorded as positive. The absence of an uptake was used to define a negative PET/CT finding.

The metabolic tumor volume (MTV), maximum, minimum, and average standardized uptake value (SUVmax, SUVmin and SUVavg, respectively) were determined by drawing iso-volumetric regions of interest (VOI) on the attenuation corrected PET/CT images around suspected thymic lesions. Moreover, the SUVmax of the aortic arch was taken as a reference region for background mediastinal activity (or blood-pool activity). Therefore, the tumor/mediastinum ratio was calculated by the ratio of thymic lesion SUVmax (T) and blood pool SUVmax (M). Finally, the total lesion glycolysis (TLG) of thymic lesions was computed according to the formula: TLG = MTVxSUVavg.

Follow-up

Data was collected via scripted telephone interviews by a researcher blinded to the patient's test result and then confirmed by the revision of medical archives or by contacting the patient's general practitioner. To determine follow-up time, the date of the last examination or consultation was used. Defined events included local or distant recurrence confirmed by biopsy or conventional imaging modalities.

Literature research strategy

A computer literature analysis on studies in human subjects was performed to identify articles that evaluated the role of PET or PET/CT, CT, and MRI in thymic disease.

Pubmed and Web of Knowledge were used to compile data from 2004 to January 2014, with the following key words: “THYMOMA or Thymic carcinoma” AND” CT” AND “MRI”, “THYMOMA” AND “CT” NOT “PET” and “THYMOMA AND PET.”

Reviews, clinical reports, and editor comments were excluded. Moreover, articles that did not evaluate the role of CT or MRI or FDG PET or PET/CT in adult thymic lesions were also excluded. We found 91 articles for thymoma and CT and MRI without any filters; when we added HUMANS/JOURNALS ARTICLE/ENGLISH LANGUAGE as filters, a total of 24 articles were obtained. Considering the words thymoma AND CT NOT PET, 419 articles were found, for a total of 91 after filters. Of all of the research compiled, eight articles on thymoma and radiologic examinations for initial assessment were recovered. Similarly, 77 reports evaluated the role of FDG PET or PET/CT in thymic disease, but only 12 met the inclusion criteria.

Statistical analysis

A non-parametric statistical analysis was used, such as the chi-square, U-Mann Whitney or Wilcoxon test, as appropriate. A P-value <0.05 was defined as significant. Survival curves were constructed using the Kaplan-Meier method to account for censored survival times and were compared with the log rank test. Progression-free survival was defined as the length of time from the date of PET/CT to any relapse (local or distance recurrence). Statistical analysis was performed with SPSS software (SPSS Inc. Chicago, IL, USA).

Clinical and histopathological data

Table 1 reports the clinical and histopathological characteristics of the study population. Seventeen (65.4%) patients had a histologically proven thymoma, while nine (34.6%) had a thymic cancer. WHO classification was type A/B in three (11.5%) patients, type B1 in three (11.5%), type B1/B2 in one (3.8%), type B2 in three (11.5%), and type B3 in seven (26.9%) patients. The Masaoka-Koga system was stage I in three (11.5%) patients, stage IIa in six (23%), stage IIb in one (3.8%), stage III in six (23%), stage IVa in four (15.7%), and stage IVb in six (23%) patients. Among nine patients with thymic cancer, one (11.1%) was stage IIB, two (22.2%) were stage III, two (22.2%) were stage IVA, and four (44.5%) were stage IVB.

PET/CT and CT findings

Of the 17 patients with thymoma, 15 (88.2%) showed a positive PET/CT scan, whereas two had a false-negative finding. On the other hand, 100% of patients with thymic cancer had a positive scan. CT was available in 5/9 (56%) patients with thymic cancer and in 3/17 (17.6%) with thymoma. In all cases, CT clearly identified the primary tumor.

Tumor necrosis, calcifications, fat infiltration, and pleural effusion were more frequent in thymic cancer compared to thymoma. Conversely, infiltration of vessels was reported both in thymic cancer and in thymoma, as illustrated in Table 2. All quantitative CT parameters were significantly higher in patients with thymic cancer than thymoma (median maximum axial diameter: 45 vs. 20 mm, median maximum longitudinal diameter: 69 vs. 21 mm, and median volume: 77.91 vs. 4.52 mL; all P < 0.05). Conversely, among semiquantitative PET/CT features, only MTV and TLG were significantly different in patients with thymic cancer than thymoma (Table 3), while SUVmax, SUVavg, and T/B ratio was similar, although with a trend to increase in thymic cancer. Figure 1 illustrates two examples of CT and PET/CT images in patients with thymic and thymoma cancer, respectively. According to Masaoka clinical staging, 10 (38.5%) patients were at stage I-II and 16 (61.5%) were at stage III-IV. Table 4 demonstrates that maximum longitudinal diameter, volume at CT, MTV, and TLG at PET were significantly higher in patients at stage III-IV than those at stage I-II.

Analysis of literature research

From the collection of published papers on FDG PET/CT, it emerged that four studies have compared mean SUVmax among low and high-risk thymoma, and thymic cancer patients.^4–7 The median SUVmax in 175 patients were 4.48, 6.75, and 10.80 for low and high-risk thymoma, and thymic cancer, respectively. As shown in Figure 2a, a slight overlap was found between the three categories. Conversely, the median SUVmax of thymoma and thymic cancer, obtained from 95 patients enrolled in another four studies,^8–11 were 3.37 and 8.68, showing a large gap (Fig 2b). Moreover, considering studies that evaluated the relationship between CT measures and thymic disease, we found that in non-invasive thymoma, morphological characteristics were substantially similar to the results of Priola et al.¹² and Tomiyama et al.¹³ In particular, smooth contour, homogeneous enhancement, and partial mediastinal fat infiltration were detected in >50% of patients. Conversely, only the presence of lobulated contours was equally distributed in both patient populations, while the residual CT data (such as necrotic or cystic component and calcifications) were different. Studies by Sadohara et al.,¹⁴ Jeong et al.,¹⁵ and Liu et al.¹⁶ focused on the differentiation among low and high-risk thymoma, and thymic cancer. According to their results, a similar distribution was found for homogeneous contours in low-risk thymoma, for lobulated contours in high-risk thymoma, and for the presence of necrotic or cystic components and heterogeneous enhancement in thymic cancer.

Outcome

After a median follow-up of 17.45 months (range: 1–50 months), four patients experienced a recurrence of disease: three in patients with thymic cancer and one with a type B2 thymoma. Follow-up data were lost in three subjects. The median CT volume in two patients with recurrent disease was 102.19 mL versus 62.50 mL in six disease-free patients (P = 0.865). MTV and TLG were higher in the recurrent than in the disease-free patient subset (143.3 vs. 81.13 and 756.8 cm³ vs. 322.31, respectively); however, these results were not statistically significant (P = 0.075 and 0.118). In Kaplan-Meier analysis, a MTV and a TLG higher than 83.5 cm³ and 371.3, respectively, was associated with a poor prognosis (Fig 3).