Screening, symptoms, diagnosis and prognosis

2.6.1 Screening

In patients with paraneoplastic syndromes, particularly MG, screening for thymomas is recommended by chest CT (followed by FDG-PET) or integrated FDG-PET/CT (Titulaer, Soffietti et al. 2011).

2.6.2 Symptoms

TETS can present as an incidental finding in asymptomatic people undergoing screening investigations or during radiological workup (Chest X-ray (CXR) or computed tomogra-phy (CT)) for unrelated symptoms or disorders. TETs can present symptoms due to local compression of (thoracic) organs or systemic symptoms from TET associated parane-oplastic diseases.

Local symptoms arising from TETs that are typically located in the bed of the thymus from compression and/or invasion of adjacent thoracic organs (e.g. cough, dyspnea, chest pain). Rare symptoms are superior vena cava syndrome from direct mediastinal mass compression of the superior caval vein or diaphragmatic paralysis due to phrenic nerve invasion/compression.

Thymomas may manifest with a characteristic growth pattern along the serous mem-branes in the chest cavity, the pleura and the pericardium. Pleural and pericardial effu-sions cause local symptoms and are a sign of more advanced disease.

2.6.3 Diagnosis

A preoperative biopsy is obtained in cases of suspicion of lymphoma, germ cell tumors, mediastinal metastasis and patients with suspicion of advanced TETs with infiltration on potentially resectable structures for planning of neoadjuvant therapy. In MG patients with a high suspicion for thymomas surgery is planned without the need for a biopsy.

2.6.4 Imaging

Chest X-rays (CXR)

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Forty-five to 80% of thymomas were reported to be visible on CXR (Marom 2010) ( See Figure 3). Any anterior mediastinal mass identified on CXR has to be further character-ized by CT. Patients with clinical suspicion for thymoma and normal CXR will have a CT scan because of higher sensitivity (Marom 2010).

Figure 3: Chest X-ray of ADC of the thymus. Adopted from (Moser, Schiefer et al. 2015).

Computed tomography (CT)

CT is the preferred imaging modality for diagnosis and assessment of resectability for patients with TETs (See Figure 4). Intravenous contrast agents are essential for preoper-ative staging and assessment of resectability of invasive tumors (e.g. vessel infiltration) (Marom 2010). Standard report terms for chest CT findings of anterior mediastinal masses suspicious for thymomas were defined by ITMIG (Marom, Rosado-de-Christenson et al. 2011).

Figure 4: Computed tomography of ADC of the thymus. Adapted from (Moser, Schiefer et al. 2015).

In a retrospective study of 133 patients with thymoma who underwent surgical resection (1997-2010) 23 patients (17%) had an incomplete surgical resection. Several preoperative CT imaging characteristics predicting respectability were identified: lobulated tumor con-tour, ≥50% abutment of vessel circumference, thoracic lymphadenopathy, lung changes, pleural nodularity, larger tumor size (mean 9.7 cm). On multivariable analysis only de-gree of vessel abutment and pleural nodularity remained independent prognosticators of

A B

A B

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incomplete resection. The authors concluded that CT can predict the probability of com-plete surgical resection and might help identify patients benefiting from neoadjuvant treatments (Hayes, Huang et al. 2014).

In a retrospective study on 84 patients with thymoma (1986-2007) associations between computed tomography features of thymomas and their pathological classification (Masaoka-Koga) were reported (Ozawa, Hara et al. 2016). Stage III-IV thymomas were of larger size, displayed a more irregular shape or contour, and necrosis and calcification were more prevalent than in stages I-II. WHO B2 an B3 type thymomas showed irregular contour and shape, invasion of: mediastinal fat, great vessel, pericardium or lung more often than WHO type A, AB or B1 thymomas.

Magnetic resonance imaging (MRI)

MRI has no radiation toxicity but is not recommended for mediastinal masses with un-known etiology because it provides poor resolution of pulmonary parenchyma. It may be employed to assess vessel invasion with or without intravenous contrast agents (Marom 2010).

18Fluorine-fluorodeoxyglucose–positron emission tomography (FDG-PET)

In a retrospective study on 94 patients with anterior mediastinal nodules or masses PET/CT maximum standard uptake value (SUVmax) was found to discriminate thymomas from TC, diffuse large cell B cell lymphoma and Hodgkin lymphoma. The authors sug-gested that a tumor tissue biopsy should be obtained in cases of SUVmax ≥ 7.5 to possibly select patients with TC for neoadjuvant therapy and to avoid futile resections in patients with lymphomas (see Figure 5; (Watanabe, Shimomura et al. 2019)).

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Figure 5 SUVmax of anterior mediastinal tumors. Distribution of SUVmax (FDG-PET CT) of patients with anterior mediastinal tumors. From (Watanabe, Shimomura et al. 2019). *p < 0.05, ***p < 0.005,

****p < 0.001

Conflicting data regarding the use of SUVmax to distinguish thymoma WHO types were reported (Shibata, Nomori et al. 2009, Otsuka 2012, Watanabe, Shimomura et al. 2019).

FDG-PET CT SUVmax may aide in detecting local invasiveness of thymomas but SUVmax

cut-offs for Masaoka-Koga or TNM stage could not be defined (Luzzi, Campione et al.

2009, Otsuka 2012, Watanabe, Shimomura et al. 2019). In an ITMIG prospective data-base with FDG-PET data of 154 patients SUVmax was reported to predict histologic type and pathologic Masaoka-Koga stage; ROC analysis: area under curve: 0.79; p < 0.001 and 0.81; p < 0.001, respectively (Korst, Fernando et al. 2017).

In a study of 27 patients with advanced or recurrent TETs response to chemotherapy was assessed by 18F-FDG PET-CT according to RECIST criteria (Response Evaluation Cri-teria in Solid Tumor). Percent change of SUVmax in before and after treatment 18F-FDG PET-CT correlated with morphovolumetric response (r = 0.64, p = 0.001). Percent change of SUVmax of -25% was reported to discriminate responders from non-responders (sen-sitivity of 88% and a specificity of 80%) (Segreto, Fonti et al. 2017).

Of additional value are ⁶⁸Gallium labeled somatostatin (SST) analogues and so-matostatin receptor scintigraphies to evaluate further therapeutic modalities in patients not responding to therapy (Imbimbo, Ottaviano et al. 2018). ⁶⁸Ga-SST-analogues PET/CT and 18F-FDG-PET/CT showed concordance in 43% of 39 patients with metastasized TETs. In only 5% of patients there was additional information when ⁶⁸Ga-SST-analogues PET/CT was positive and 18F-FDG-PET/CT was negative (Sollini, Erba et al. 2014).