Is a positron emission tomography computed tomography scan useful in the staging of thymic epithelial neoplasms?

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1 Interactive CardioVascular and Thoracic Surgery 19 (2014) doi: /icvts/ivu068 Advance Access publication 19 March 2014 BEST EVIDENCE TOPIC THORACIC Is a positron emission tomography computed tomography scan useful in the staging of thymic epithelial neoplasms? Andrea Viti a, *, Alberto Terzi b, Andrea Bianchi c and Luca Bertolaccini a a b c Thoracic Surgery Unit, S. Croce e Carle Hospital, Cuneo, Italy Thoracic Surgery Unit, Sacred Heart Hospital, Negrar, Verona, Italy Nuclear Medicine Service, S. Croce e Carle Hospital, Cuneo, Italy * Corresponding author. Division of Thoracic Surgery, S. Croce e Carle Hospital, Via Michele Coppino 26, Cuneo, Italy. Tel: ; fax: ; vitimassa@hotmail.it (A. Viti). Received 11 November 2013; received in revised form 12 February 2014; accepted 25 February 2014 Abstract A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed concerned the employment of 18-fluorine fluorodeoxyglucose positron emission tomography/computed tomography (PET CT) in the preoperative evaluation of thymic epithelial neoplasms (TENs). We reviewed its role as a predictor of Masaoka stage and histology (according to the WHO). In clinical practice, stage is considered the most important determinant in the therapeutic approach. A total of 265 papers were found as a result of the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All the studies are retrospective analyses. Patient numbers varied from 13 to 58. Our research showed that PET CT could clearly add information about the histology of the tumour. Thymic carcinoma constantly showed a higher standard uptake value (SUV max ) than thymomas. Furthermore, in one retrospective study of 36 patients, when using a derived PET indicator, the T/M ratio (ratio between SUV max of the tumour and SUV max of mediastinum, as conventionally measured at the level of the aortic arc), PET CT could also differentiate between low- and high-risk thymomas (low risk vs high risk P = 0.01). In another study, a cut-off value of T/M ratio of 2.75 was identified between low- and high-risk TENs. The role of PET CT in prediction of stage is harder to recognize. In one study, there was a statistically significant correlation between SUV max, T/M ratio and Masaoka stage (P = and 0.718, respectively). When analysing the data from the three larger series on this topic (58, 51 and 47 patients, the latter group selected in a multicentre study), only one study identified a correlation between SUV max and Masaoka stage (Spearman correlation coefficient 0.30, P = ), while the other two failed to identify a relationship between SUV max and stage. In three retrospective studies, PET CT identified otherwise undetected distant metastases, thereby modifying the clinical approach. Actually, when evaluating the correlation between stage and PET CT indicators (in particular SUV max ), results are controversial and would need further speculation. Keywords: Review Thymoma, positron emission tomography 18-Fluorine fluorodeoxyglucose positron emission tomography/ computed tomography, staging INTRODUCTION A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1]. THREE-PART QUESTION In patients with [thymic epithelial neoplasms], does [CT scanning alone] vs the addition of a [PET CT scan] significantly alter information on [staging or histology]? to the pericardium. The patient also had a positron emission tomography (PET-CT) scan and the lesion was found to have a standard uptake value (SUV max ) of 8.3. The patient underwent minimally invasive procedure. However, due to invasion of the pericardium, conversion to sternotomy was required. Pathological evaluation confirmed a B3 thymoma with infiltration into the pericardium (Masaoka-Koga Stage III). Afterwards, you wondered whether PET CT would be useful in the preoperative evaluation of all patients with mediastinal masses and, in particular, its role in predicting histology and stage of thymic epithelial neoplasms (TENs). You resolve to check the literature yourself. BEST EVIDENCE TOPIC CLINICAL SCENARIO A 57-year old patient presented with an incidental finding of an isolated thymic mass 3 cm in diameter after a computed tomography (CT) scan of the thorax. It looked like it might be adherent SEARCH STRATEGY A Medline search from 1990 to December 2013 was performed using the PubMed interface with the following terms: [Thymoma OR Thymic Neoplasms] AND [Positron Emission Tomography OR The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 130 A. Viti et al. / Interactive CardioVascular and Thoracic Surgery Table 1: Best evidence papers Author, date, journal and country Study type (level of evidence) Patient group Outcomes Key results Comments Sung et al. (2006), J Nucl Med, Korea [2] Kumar et al. (2009), Ann Nucl Med, India [3] Igai et al. (2010), Eur J Cardiothorac Surg, Japan [4] Fukumoto et al. (2012), Eur J Cardiothorac Surg, Japan [5] Shibata et al. (2009), Cancer, Japan [6] Korst et al. (2014), J Thorac Cardiovasc Surg, USA [7] of prospectively collected data 33 patients (16 thymic carcinomas included) 23 patients (including 4 carcinomas and 5 hyperplasias) 13 patients (including 5 thymic carcinomas) 58 patients (11 carcinomas and 3 carcinoids) 40 patients (Type A = 1, AB = 12, B1 = 11, B2 = 7, B3 = 6 and C = 3) 21 patients who underwent induction therapy in a phase II trial Parameters evaluated: SUV max and intralesional pattern of uptake correlation with histology Possible role in staging to characterize different thymic lesions and histological characterization Correlation between SUV max and staging not evaluated and histological characterization Correlation between SUV max and staging evaluated, 18-FDG and 11-carbon acetate (AC) for histological characterization Correlation between SUV max and staging evaluated Radiolabelled 11-carbon acetate is a marker of plasma membrane synthesis correlation with histological characterization and stage was a secondary end point of this study SUV max significantly higher in carcinomas than in thymomas (P < 0.001) Carcinomas showed a more homogeneous uptake of 18-fluorine fluorodeoxyglucose ( 18 F-FDG) than thymomas (P < 0.001) In 2 cases, otherwise undetected metastases were evidenced Significant differences between hyperplasia (mean SUV max 1.1), thymoma (mean SUV max 3) and carcinoma (mean SUV max 7; P < 0.01) No statistically significant difference was observed between low-risk and high risk TENs Mean SUV max in the thymic carcinoma group was 8.15 ± 7.88, and in the thymoma group, it was 3.43 ± 2.19 (P = 0.002) SUV max significantly higher in carcinomas (P < 0.001). No significant differences between lowand high-risk groups. SUV max in advanced stages (III and IV) was not significantly higher (P = 0.06) FDG SUV max : Type A/AB: 3.2 ± 0.7; Type B1: 4.8 ± 2.0; Type B2: 3.7 ± 1.2; Type B3: 5.0 ± 1.4 and Type C: 9.2 ± 2.4. The uptake value was higher in carcinomas than in other types (A B3: P = ). AC SUV max higher in A/AB thymomas (P < 0.01). Neither FDG SUV nor AC SUV uptake correlated with stage Patients with carcinoma had a higher SUV max than other TENs (P = 0.003). No significant differences in initial SUV max were appreciated between the tumours postoperatively determined to be Stages I and II (median SUV max 4.1) vs Stages III and IV (median SUV max 5.3; P = 0.41) Integrated PET CT can be useful for differentiating between thymoma and carcinoma PET CT useful for detecting lymph node metastases, undetected with stand-alone computed tomography PET CT can differentiate between TENs No relationship between dimension and SUV max small number of patients for each group Pretreatment SUV max may be useful for differentiating thymoma from thymic carcinoma Although neither FDG SUV nor AC SUV can predict invasiveness of thymomas assessed by tumour stage, they are useful for predicting histological types Benveniste et al. (2013), J Thorac Oncol, USA [8] 51 patients (including carcinomas and carcinoids), SUV peak, SUV mean, volumetric indicators (cm 3 ) tumour volume above 45% of SUV max SUV max, SUV peak and SUV mean higher in carcinomas and carcinoids than in other thymomas (P = , P = and P = ). Focal SUV max, SUV peak and SUV mean could be helpful in differentiating carcinomas and B3 thymomas Continued

3 A. Viti et al. / Interactive CardioVascular and Thoracic Surgery 131 Table 1: (Continued) Author, date, journal and country Study type (level of evidence) Patient group Outcomes Key results Comments Endo et al. (2008), Lung Cancer, Japan [9] Terzi et al. (2011), Lung Cancer, Italy [11] Matsumoto et al. (2012), Ann Thorac Surg, Japan [12] 36 patients (15 low-risk thymomas, 10 high-risk thymomas and 11 thymic carcinoma) 26 consecutive patients (including carcinomas) 39 patients (Type A = 1, AB = 4, B1 = 13, B2 = 11, B3 = 7 and C = 3) and volume of tumour with SUV above 3.5 and SUV T/M ratio The authors did not evaluate the Masaoka classification in detail and SUV T/M ratio for histological classification and staging for histological classification and staging. Correlation between SUV max and Ki-67 expression uptake higher in B3 thymomas than in Type A, AB and B1 thymomas (P < 0.006) Tumour volume above 45% of SUV max and volume of tumour with SUV above 3.5 relate with more advanced stages (P = and 0.029) Mean T/M ratio: Low risk: 2.64 ± 0.78 High risk: 4.29 ± 1.41 Carcinoma: 8.90 ± 3.62 (low risk vs high risk P = 0.01; high risk vs carcinoma P = 0.01) SUV max and T/M ratio resulted: Type A: 3.4 ± 0.8; 1.0 ± 0.8 Type AB: 3.8 ± 1.3; 1.9 ± 0.4 Type B1: 4.9 ± 0.8; 2.1 ± 0.3 Type B2: 6.6 ± 1.0; 4.9 ± 0.2 Type B3: 9.4 ± 3.6; 3.4 ± 0.2 Carcinoma: 17.1 ± 8.5; 9.6 ± 5.5 Stage I: 3.7 ± 0.8; 2.1 ± 1.2 Stage II: 4.5 ± 1.7; 2.6 ± 1.1 Stage III: 12.1 ± 6.9; 3.7 ± 0.2 Stage IV: 19.7 ± 8.7; 11.5 ± 6.4 Significant correlation between T/M ratio SUV max and increasing malignancy (P = and according to Bravais Pearson linear correlation) Significant correlation between T/M ratio SUV max and increasing stage (P = and according to Bravais Pearson linear correlation) A cut-off value of T/M ratio of 2.75 between low- and high-risk groups FDG SUV max higher in carcinomas (P < 0.001) and in advanced stage (Stage IV) than in Stages I and II (P < 0.008) Advanced Masaoka stages and more malignant thymomas showed higher SUV max Focal FDG uptake, as described by SUV max, SUV peak and SUV mean, cannot predict stage Volumetric indicators depict the volume of metabolic avid tumour and better correlate with stage Integrated PET CT can differentiate between risk groups, according to Okamura Classification [10] Introduction of SUV T/M ratio as a predictor of histology Introduction of a cut-off value between low- and high-risk groups In this series, PET CT identified otherwise undetected distant metastases in 2 cases SUV max correlated positively with Ki-67 expression BEST EVIDENCE TOPIC Viti et al. (2014), Eur J Cardiothorac Surg, Italy [13] 23 patients. 17 low-risk thymomas (3 A, 9 AB and 5 B1) and 6 high-risk thymomas (5 B2 and 1 B3) Carcinomas were excluded and SUV T/M ratio for histological classification and staging Correlation between T/M ratio and Ki-67 Low-risk thymomas showed a mean SUVmax of 4.01 ± 0.72, and a mean T/M ratio of 1.91 ± High-risk thymomas showed a mean SUVmax of 7.60 ± 2.38, and a mean T/M ratio of 3.73 ± 0.76 The difference between mean SUV max and T/M ratio proved to be significant between low- and Ki-67 expression turned out to be significantly higher in high-risk thymomas (P = ) Continued

4 132 A. Viti et al. / Interactive CardioVascular and Thoracic Surgery Table 1: (Continued) Author, date, journal and country Study type (level of evidence) Patient group Outcomes Key results Comments Toba et al. (2013), Eur J Cardiothorac Surg, Japan [14] Lococo et al. (2013), Lung Cancer, Italy [15], multicentre study Otsuka (2010), J Med Invest, Japan [16] Review of literature and retrospective 33 patients (15 low-risk thymomas, 10 high-risk thymomas and 8 carcinomas) 47 patients (Type A = 2, AB = 11, B1 = 9, B2 = 9, B3 = 9 and C = 7) 35 patients (Low risk = 11, high risk = 13 and carcinomas = 11) (Stages I II = 15 and Stages III IV = 20) for histological classification and staging and SUV max /T index (the ratio tumour SUV max to tumour size) for histological classification and staging SUV max and histology high-risk tumours (P = and 0.001, respectively) No correlation between T/M ratio and Masaoka-Koga Stage (P = 0.3 according to Spearman Rank non-linear correlation) SUV max Low-risk TENs: 3.7 ± 2.0 High-risk TENs: 3.5 ± 2.1 Carcinomas: 5.9 ± 1.9 Stage I: 2.4 ± 1.3 Stage II: 3.7 ± 1.8 Stage III: 5.1 ± 1.9 Stage IV: 5.3 ± 2.2 Higher SUV max in thymic carcinomas vs thymomas (P = 0.008). No significant difference between lowand high-risk thymomas Mean SUV max value higher in Stages III and IV than in Stage I (both P = 0.002) SUV max and SUVmax/T index were found to be higher in carcinomas than in other forms (P = and ) SUV max correlated with Masaoka stage (Spearman correlation coefficient: 0.30; P = 0.04), while SUV max /T index did not SUV max Low risk (LR) TENs: 3.7 ± 1.8 High risk (HR) TENs: 4.0 ± 2.8 Carcinomas: 7.6 ± 3.7 The difference of SUV max between carcinomas and the other forms was statistically significant (P = ). Differences between LR and HR not significant 6/11 (55%) carcinomas showed distant metastases PET CT scan may indicate metastases, which are sometimes difficult to detect using other modalities PET/CT OR PET-CT]. All the results were screened for adherence to the topic. Case reports were excluded. SEARCH OUTCOME Two hundred and sixty-five papers were found as a result of the reported search. From these, 14 papers provided the best evidence to answer the question. These are presented in Table 1. RESULTS Many factors have been studied in the evaluation of prognosis for TENs. Large series identified as independent prognostic factors histology and Masaoka-Koga stage [17, 18]. In clinical practice, however, stage is considered the most important determinant of the therapeutic approach. Locally advanced stages (III and IV) would benefit from preoperative, platinum-based chemotherapy. Stage is mainly predicted based on indirect radiological signs

5 A. Viti et al. / Interactive CardioVascular and Thoracic Surgery 133 (i.e. phrenic nerve palsy to indicate infiltration into the mediastinal pleura and the phrenic nerve). Okamura grouped together A, AB and B1 types as low-risk thymomas (low invasiveness and better prognosis), and B2 and B3 as high-risk thymomas (more aggressive) [10]. A CT scan of the thorax is ineffective in differentiating between those two groups [19]. Therefore, a more precise indication about histology and stage in the pretreatment work-up should be useful. A growing group of retrospective studies of small groups of patients evaluated the role of PET CT in preoperative evaluation (mainly correlation with histology and staging) of TENs. PET CT in prediction of histology Sung et al.[2] identified a significant difference in SUV max between thymoma and thymic carcinomas. The author concluded that PET CT can be employed in the preoperative work-up of thymomas, and SUV max can be a good predictor of histology and stage. SUV max turned out to be significantly higher in carcinomas in the groups studied by Kumar et al.[3], Igai et al.[4], Fukumoto et al.[5], Shibata et al.[6] and more recently, Korst et al.[7]. Benveniste et al. [8] identified a SUV max cut-off value of 6 between thymomas and carcinomas. In other studies, a significant difference in SUV max was observed also between low- and high-risk thymomas. Those studies introduced another metabolic descriptor, besides SUV max, that is the ratio between SUV max and mean SUV of the mediastinum conventionally measured at the level of the aortic arch (SUV T/M ratio). This derived descriptor could avoid some of the bias of simple SUV max such as biological factors (difference of tracer uptake among the patients) and inter-scanner variability. In a cohort of 36 patients, Endo et al. [9] identified a significant relationship between T/M ratio and histological subtype in TENs when a three-group classification was employed (low-risk, highrisk and carcinomas). Terzi et al. [11] identified in a cohort of 26 consecutive patients a strong correlation between SUV T/M ratio and risk groups. A cut-off value between the two classes was identified at an SUV T/M ratio of Matsumoto et al. [12] and Viti et al. [13] identified a correlation between, respectively, SUV max and T/M ratio of TEN and the expression of Ki-67, a marker of proliferation and biological aggressiveness, thereby providing a correlation between biological behaviour of TENs and imaging observation. We may conclude that PET CT may have a possible role in definition ( prediction) of histology. PET CT and prediction on stage As far as correlation between PET CT indicators and stage is concerned, the results are more ambiguous. Previously mentioned studies failed to find a correlation between SUV max and T/M ratio with stage [9, 13]. In another study [11], there was a statistically significant correlation between SUV max, T/M ratio and disease stage (P = and 0.718, respectively, according to Bravais Pearson linear correlation). Matsumoto et al. [12] found a higher SUV max in Stage IV than in Stages I and II (P < and <0.001), while the difference between Stages III and IV was not statistically significant. Consequently, the authors underline that it is impossible to specify each Masaoka stage with the absolute value of SUV max. Toba et al. [14] drew similar results in a cohort of 33 patients. Stage III and IV TENs showed higher SUV max than Stage I (P = and 0.002). The MD Anderson experience [8] underlines the need for PET indicators other than SUV max as possible predictors of stage. In particular, the volume of the metabolic avid tumour, depicted by volume of tumour above 45 of SUV max and volume of tumour above SUV max 3.5 proved to be more related to advanced stage than SUV max (P = 0.002, and 0.27, respectively). On the other hand, the first multicentre performed on a cohort of 47 patients [15] employed another derived indicator that is the ratio of tumour SUV max /tumour size (SUV max /T index). Again, SUV max /T index failed to provide information about stage, although correlating with WHO classification. However, in this study, simple SUV max related to Masaoka stage (Spearman correlation coefficient 0.30, P = ). Three studies [2, 11, 16] reported the possible usefulness of PET CT in identifying otherwise unsuspected distant metastases, modifying the therapeutic approach. Therefore, besides the possibility of localization of otherwise unknown distant metastases, the role of PET CT in preoperative staging is limited and needs further speculation. In particular, volumetric indicators and new tracers should be evaluated. CLINICAL BOTTOM LINE The results, as emerged from the selected literature, are not univocal to define the role of PET CT indicators (SUV max, T/M ratio and volumetric indicators such as tumour volume above 45% of SUV max ) as possible predictors of stage, and further studies are needed. PET CT could be a useful tool in localizing distant metastases and in predicting histological type or risk group of TENs. The parameters employed should include SUV T/M ratio, besides standard SUV max, in order to avoid biological and technical bias. Conflict of interest: none declared. REFERENCES [1] Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2: [2] Sung YM, Lee KS, Kim BT, Choi JY, Shim YM, Yi CA. 18F-FDG PET/CT of thymic epithelial tumors: usefulness for distinguishing and staging tumor subgroups. 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