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Thymoma and thymic carcinomas – 2015

UPDATED FEBRUARY 2015

1. GENERAL INFORMATION

1.1 General data

Thymomas (Ts) and thymic carcinomas (TCs) are uncommon, primary tumours of the mediastinum, derived from the thymic epithelium (so-called thymic epithelial tumours, TETs). T is the most common primary anterior mediastinal mass, while TC is far rarer, but much more likely to spread. Thymus is the site of maturation for T cells, playing a central role in adaptive immunity; systemic autoimmune syndromes including myasthenia gravis (MG)/autoantibodies to acetylcholine receptors (AChRs), pure red cell aplasia (PRCA), parathyroid adenoma, and hypogammaglobulinemia are usually seen in patients with TETs. The natural history of the disease is usually unpredictable, including asymptomatic, incidentally-discovered disease with an indolent course or aggressive malignant tumours.
The cause of TETs remains unknown, but understanding of the aberrant pathways involved is improving. The treatment of TETs requires a multidisciplinary approach. Surgery is the mainstay of treatment in the management of thymic tumours, for patients in whom complete resection is possible. Adjuvant radiotherapy (RT) has been widely adopted in advanced stage disease, mainly when disease invades surrounding tissues or with R1-R2 residual tumour after surgery. Systemic chemotherapy currently represents the standard of care for metastatic or inoperable refractory/recurrent disease, but there remains a lack of standard treatment after first-line failure. The rarity of this tumour has precluded it from large phase II and III clinical trial investigations, and new drugs are slow in development.
For all these reasons it is recommended, with a level of type R evidence , that all patients should be managed by a multidisciplinary team with experience in the management of TETs and with specific knowledge of the ongoing clinical trials.

1.2 Epidemiology

Epithelial tumour of the thymus is extremely rare: there are on average just 800 cases per year in Europe (Siesling 2012). The frequency of rare cancers in Europe is measured by the RARECARE and RARECAREnet projects. For the period 2000-2007, the European crude incidence rate of malignant epithelial tumours of thymus was 1.7 per million per year. Most epithelial thymic cancers are malignant thymoma (rate =1.4). The incidence for thymus cancers was the same in men and in women. Incidence was highest (4.2) in the oldest age group of patients (65 years old and older), while in the 25-64 years age group, the incidence rate was 1.9 and in adolescent and young adults (<25 years of age) it was 0.4 per million per year. There are geographical difference in the occurrence of the disease, with the lowest incidence in Northern and Eastern Europe and UK and Ireland (≈ 1), and highest in Central and Southern European Countries (≈ 2). The annual age adjusted incidence rates per million ranged between 0.9 and 2.3 (Siesling 2012). Survival from malignant epithelial tumour of thymus diagnosed in Europe during the period 2000-2007 was 84% at one year and 64% at five years. There has been substantial improvement in European survival figures since the end of the nineties, especially for 5-year survival. One- and 5-year survival since diagnosis has improved from 81% to 84% and from 58% to 65% respectively (RARECAREnet). No differences in survival between men and women were revealed. Patients older than 65 years had 5-year survival of 60% compared with 78% of the youngest age group (<25 years of age). Five-year survival was higher for thymoma (69%) than squamous cell carcinoma (36%), undifferentiated carcinoma (12%) and adenocarcinoma (34%). Lymphoepithelial carcinoma has an intermediate 5-year survival (50%). Patients older than 65 years had the worst prognosis: 5-year survival was 55%, compared to 72% in the age group 25-54 years old. In Europe about 7,000 people are living with a diagnosis of an epithelial tumour of the thymus. They could be cured, be undergoing treatment or in clinical follow-up. Long-term survivors are estimated to comprise around 50% of those with the disease, that is those still alive 15 years from diagnosis (Siesling 2012).
Interestingly, thymoma incidence in the US is higher in black people and Asian/Pacific Islanders than among white or Hispanic people (Engels 2010). Furthermore, thymoma arises among blacks at much younger age than among whites. Genetic features, modulated by environmental risk factors, may be a possible explanation of the increased risk in these groups of the population. Patients with thymoma show an increased risk of developing second malignancies, with a frequency between 8% and 28% (Filosso 2013). These findings are informative with respect to the aetiology of thymoma. It has been suggested that an increased risk of specific cancers in thymoma patients could indicate that those cancers share genetic or environmental risk factors with thymoma. An elevated risk for specific cancers occurring after thymoma may also be caused by the thymoma therapy; for example, the second cancer may be related to radiotherapy (leading to cancers in the radiation field) or surgery (thymectomy leading to immunosuppression). In addition, it has been suggested that the immune dysregulation caused by the thymoma predisposes the individual to those cancers. The association between thymic cancers and lymphoma, gastrointestinal cancer, lung cancers and soft tissue sarcoma has been observed.
Okumura at al. (Okumura 2008) suggest that an autoimmune system alteration associated with thymoma might be the key to interpreting and explaining the increased risk of subsequent cancers. A T-cell development alteration within the thymus is thought to be related to the progress of autoimmune disorders in patients with thymoma. Other authors (Welsh 2000) suggest the potential role of a thymic “intrinsic factor” in the development of second tumours, supporting the theory that they are true second cancers rather than treatment-related tumours.

2. PATHOLOGY AND BIOLOGY

2.1 Histologic classification(s)

The majority of thymic tumours have non-malignant-appearing thymic epithelial cells mixed with variable proportions of lymphocytes. TETs have been the subject of much controversy over the years because of difficulties in predicting prognosis and behaviour. As a result of the complexity of these tumours, many histological classifications have been described in the literature for thymic neoplasms.
Rosai et al. in 1976 suggested that «the definition of thymoma should be restricted to neoplasms of the thymic epithelial cells, regardless of the presence or absence of a lymphoid component or the abundance of the latter» (Rosai 1976).
Bernatz et al. proposed the first widely used histological thymoma classification scheme with the following types: lymphocytic, predominantly epithelial, mixed, and spindle cell type lymphoma (Bernatz 1961); however, this classification system provided no prognostic information on the evolution of subtype-related disease.
Levine et al. in 1978 distinguished between benign (non-invasive) versus malignant (invasive) Ts. Malignant Ts were subdivided into Type I (no/minimal atypia) and Type II (moderate/marked atypia). Type II Ts were considered TCs. This classification system was clinical, as well: invasion was taken into consideration together with the degree of atypia (Levine 1978).
Marino et al. described a histogenetic classification in 1985 (Marino 1985), sub-classifying TETs into medullary and cortical types that reflected the architecture of the normal thymus. This system was of prognostic value but its use was not widespread.
The most recent classification system was proposed in 1999 by an international committee assembled by the World Health Organization (WHO) and was based on both morphology and lymphocyte/epithelial cell ratio using letters and numbers (Rosai 1999); it was updated in 2004 (Marx 2004). In the WHO system (Table 1) there are six different types of thymic tumours (A, AB, B1, B2, B3 and C).

Table 1. WHO histologic classification.

 

Type A
Tumour composed mainly of epithelial cells with spindle/
oval shape, lacking nuclear atypia, lymphocytes are rare
Spindle cell or medullary thymoma
Type AB
Tumour in which foci with features of type A thymoma are admixed with lymphocyte-rich areas: the segregation of two patterns can be sharp or indistinct Mixed thymoma
Type B1
Tumour that resembles the normal functional thymus,
combining predominant areas resembling normal thymic cortex and areas resembling thymic medulla. This is a thymoma “lymphocyte predominant” and the neoplastic epithelial cells are scant, small, with little atypia
Organoid, Lymphocyte-rich or lymphocytic or predominantly cortical thymoma
Type B2
Tumour in which the neoplastic epithelial component (plump cells with vesicular nuclei and conspicuous nucleoli) is scattered individually or in small clusters among immature lymphocytes Cortical thymoma
Type B3
Tumour composed predominantly of epithelial cells with a round or polygonal shape and exhibiting mild atypia, admixed with a minor component of immature lymphocytes Well-differentiated thymic carcinoma or epithelial thymoma or squamoid thymoma
Type C
Tumour exhibiting clear-cut cytologic atypia and lacking a significant number of immature interepithelial thymocytes.
Mature lymphocytes and plasma cells are present in the septae between tumour lobules and in the tumour periphery.
This subtype is usually indistinguishable from extrathymic carcinomas
Heterogenous thymic carcinoma

As lesions progress from A to C, there is also a progressive deterioration of the prognosis. Two types of Ts are described, based on the shape of the neoplastic cell: type A (spindle or oval, without atypia or neoplastic lymphocytes, corresponding to previously-called medullary T) and type B (dendritic or epithelioid). Type A Ts have the best prognosis and are usually low stage. Type AB tumours are similar to type A, but have foci of neoplastic lymphocytes (so-called mixed T). Type B Ts are sub-divided on the basis of the proportional increase (in relation to the number of lymphocytes) in epithelial cells (thymocytes) and cellular atypia. Type B1 tumours resemble normal thymic cortex with areas similar to the thymic medulla (corresponding to lymphocyte-rich or lymphocytic or predominantly cortical T). Type B2 have scattered neoplastic epithelial cells with vesicular nuclei (corresponding to cortical T). Type B3 are composed predominantly of epithelial cells exhibiting mild atypia, thus resembling what others have described as well differentiated thymic carcinoma (WDTC or epithelial T or squamoid T). Type B Ts may recur and are typically higher stage. TCs (Type C) clearly represent a distinct, but small (10% of TETs) group, including a variety of histopathologic subtypes according to their differentiation and aggressiveness (squamous cell, small cell/neuroendocrine, muco-epidermoid, basaloid, lymphoepithelioma-like, sarcomatoid, clear cell, papillary and undifferentiated/anaplastic carcinoma). Types A, AB, and B1 have an excellent overall survival (OS) rate of more than 90% to 95% at 10 years. Five-year survival for types B2, B3, and C are 75%, 70%, and 48%, respectively. Ts rarely metastasise, whereas TCs display a more aggressive behaviour, with distant metastases in liver, nodes, or bones and are frequently symptomatic because of the extent of local invasion.
Moran et al. proposed simplifying the WHO system to define lesions as well-differentiated tumours for the typical T (no cytological features of malignancy, so-called medullary thymoma), poorly differentiated tumours for the traditional TC (abundant mitotic figures and other cytological features of malignancy), and atypical T for lesions with intermediate features (so called WDTC, with organotypic features of Ts but areas of atypia and occasional mitoses) (Moran 2008a; Moran 2008b).

2.2 Molecular aberrations

Molecular aberrations underlying thymic malignancies are poorly understood and there is a lack of valid preclinical models (both cell lines and animals). Insights into the biology of thymic tumours have been made following anecdotal clinical responses to targeted therapies (Ströbel 2004a; Li 2009; Chuah 2006; Christodoulou 2008; Farina 2007; Yamaguchi 2006).

2.2.1 Epidermal growth factor receptor (EGFR)

EGFR is one of the most studied biomarkers in epithelial cancers. Several studies have investigated its expression levels in thymic tumours using immunohistochemistry (IHC) (Girard 2009; Pescarmona 1993; Gilhus 1995; Henley 2002; Suzuki 2006; Meister 2007; Yoh 2008; Aisner 2010).
EGFR was overexpressed in 70% of Ts and 53% of TCs. Higher EGFR staining was significantly associated with stage III to IV tumours. EGFR copy number status was significantly amplified in type B3 Ts. The degree of EGFR amplification as measured by fluorescence in situ hybridization (FISH) poorly correlated with EGFR overexpression whereas it was significantly associated with stage II to IV tumours (Ionescu 2005).
EGFR mutations are rare in thymic malignancies (Girard 2009; Suzuki 2006; Yoh 2008; Kurup 2005; Yamaguchi 2006). Only 3 EGFR mutants have been found between 158 tumours analysed: all of them were missense mutations in exon 21 (two cases of L858R and one case of G863D), and no mutations were detected in exons 18 and 19. There was no correlation between EGFR expression and EGFR mutational status.

2.2.2 Human epidermal growth factor receptor-2 (HER-2/c-erbB2)

Ts did not express HER-2 in a series of 63 cases, except for two type-B2 cases with focal membranous positivity (1+), and one type-A and one type-B3 case with heterogeneous positivity (2+). TCs were more likely to express the protein, exhibiting focal to strong membranous positivity in eight of 17 cases in the same report (Pan 2003). No evidence of gene amplification was detected on FISH analysis in any case.

2.2.3 Stem cell factor receptor (SCFR/KIT/CD117)

KIT is a transmembrane growth factor with tyrosine kinase activity whose ligand is the scatter cell factor (SCF). KIT is overexpressed in 2% of Ts and 79% of TCs (Pan 2004; Henley 2004; Nakagawa 2005; Tsuchida 2008). Despite protein frequent over-expression, KIT mutations were found in only 5 of 70 collectively analysed TCs (Girard 2009; Ströbel 2004a; Li 2009; Yoh 2008; Tsuchida 2008; Bisagni 2009; Giaccone 2009): they comprised a V560 deletion in two cases, a missense mutation in exon 11 (L576P substitution), a D820E mutation (in a patient responding to sorafenib), and an H697Y mutation in exon 14 (with high sensitivity to sunitinib in vitro).

2.2.4 Insulin-like growth factor-1 receptor (IGF-1R)

IGF-1R is a transmembrane receptor frequently overexpressed in squamous cell carcinomas, showing a role in multiple processes involved in oncogenesis and involved in EGFR inhibitor resistance through formation of EGFR/IGF-1R heterodimers. In a cohort of 63 thymic tumours, IGF-1R over-expression was more frequent in TCs than in Ts (86% versus 43%) and was significantly associated with EGFR over-expression; no relation with time to progression (TTP) was found (Girard 2010).
However, Zucali et al. investigated TETs and reported that among IGF-1R overexpression carries a poor prognostic value for OS, as well as for TTP among primary tumours (Zucali 2010).

2.2.5 Vascular endothelial growth factors (VEGF) and VEGF- receptors (VEGFRs)

VEGF and VEGFR are recognized as the most potent proangiogenic molecules. VEGF-A and VEGFR-1 and -2 are over-expressed in Ts and TCs (Cimpean 2008). Microvessel density and VEGF expression levels have been shown to correlate with tumour invasion and clinical stage in TETs (Tomita 2002). Patients with TCs have increased levels of VEGF in the serum, that is not observed in patients with T (Sasaki 2001).

2.2.6 Mitogen activated protein kinase (MAPK) pathway

Rat sarcoma protein (RAS) mutations were observed in 3 of 62 TETs analysed: two cases of KRAS (G12A and G12V) and one of HRAS (G13V) mutation (Ströbel 2004a; Christodoulou 2008; Kurup 2005; Chou 2005). No mutation has been identified in mitogen-activated protein kinase kinase (also known as MAP2K/MEK1) (Ströbel 2004a).

2.2.7 Phosphoinositide-3-kinase (PI3K) pathway

No alterations have been reported for PI3K-catalytic subunit (PIK3CA), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), protein kinase B (PKB or AKT1) and mammalian target of rapamycin (mTOR).

2.2.8 Other genetic aberrations

Beyond growth factor receptors and their cascades, the potential prognostic or predictive relevance of other molecular alterations are emerging in thymic malignancies.
The expression of tropomyosin receptor kinase (Trk) was evaluated in 99 patients with TET by using IHC staining (Kim 2005a).
Cyclin-dependent kinase (CDK) proteins controlling cell cycle G1-S phase transition may be altered through p16INK4 loss in Ts (Hirabayashi 1997). p16INK4, through inhibition of CDK4 and CDK6, prevents RB phosphorylation leading to G1-S block; p16 downregulation through promoter methylation has been observed in 3% to 13% of TETs (Hirabayashi 1997; Hirose 2009); no p16INK4 mutations have been described in TETs, whereas gene deletion appears related to invasive phenotypes in rat models (Tsuji 2005).
Cytogenetic studies (Herens 2003) have revealed chromosomal abnormalities in all histological subtypes, including t(15;19) translocations and 6p22-p25 deletions. The t(15;19)(q13:p13.1) translocation generates the fusion gene BRD4-NUT, which has been described in a rare subtype of undifferentiated TCs (Kuo 2004). The most frequent genetic alterations identified in Ts occur on chromosome 6p21.3 (major histocompatibility complex locus) and 6q25.2 to 25.3 (Zettl 2000; Inoue 2002; Inoue 2003). In TCs, comparative genomic hybridization (CGH) has demonstrated frequent copy number gains of 1q, 17q, and 18 and loss of 3p, 6, 16q, and 17p (Zettl 2000; Girard 2009). Similar alterations have been found in B3 T, most notably gain of 1q and loss of chromosome 6 (Zettl 2000).
Variable expression of p53 has been reported in TETs (Hayashi 1995; Pan 2003; Tateyama 1995; Chen 1996; Pich 1996; Weirich 1997; Hirabayashi 1997; Stefanaki 1997; Oyama 1998; Mineo 2005; Khoury 2009; Hino 1997; Gilhus 1995; Engel 1998; Comin 2004) with p53 being more frequently expressed in invasive Ts and TCs. p53 expression is a poor prognostic marker in TETs and inactivating mutations have been described with variable frequency.
In a series of 274 TETs, the GTF2I mutation was observed in 82% of type A and in 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes (including TP53, CYLD, CDKN2A, BAP1 and PBRM1) have been identified (Petrini 2014). Therefore, GTF2I mutation correlated with better survival.

3. DIAGNOSIS

3.1 Clinical features

Sex distribution of patients with thymic tumours is similar in the literature; the age distribution is broad, with a peak around 30-40 years in patients with MG, and 60-70 years in those without MG (primarily women) (Lewis 1987; Regnard 1996; Maggi 1991; Pan 1994; Okumura 1999; Nakahara 1988).
At presentation, approximately 40% of thymic tumours are stage I, 25% each are stage II or III, 10% stage IVa, and only 1% to 2% are stage IVb (Verley 1985; Quintanilla-Martinez 1994; Regnard 1996; Maggi 1991; Wang 1992; Elert 1988; Blumberg 1995; Pan 1994; Venuta 1997; Wilkins 1999; Okumura 1999; Nakahara 1988; Monden 1985; Myojin 2000; Kondo 2003a; Crucitti 1992). It is uncommon for patients with T to have metastatic disease at presentation (Masaoka 1994; Lewis 1987), with the pleura being the most frequent site and extra-thoracic disease accounting for <10% of cases (Chan 1991; Pescarmona 1990; Salyer 1976). TCs present with distant metastasis more frequently than Ts (Strollo 1997).
Approximately one third of patients with a thymic tumour are asymptomatic (Lewis 1987; Quintanilla-Martinez 1994; Wang 1992; Elert 1988; Blumberg 1995; Wilkins 1999; Wilkins 1991; Moore 2001; Kaiser 1989).
Of symptomatic patients, 40% present with chest pain, cough, hoarseness and dyspnoea (less frequently superior vena cava syndrome) related to the intra-thoracic mass, 30% have systemic symptoms making it difficult to differentiate from lymphoma (weight loss, rarely fever and night sweats) and the rest have neurological symptoms (Lewis 1987; Quintanilla-Martinez 1994; Wang 1992; Elert 1988; Blumberg 1995; Wilkins 1999; Wilkins 1991; Moore 2001; Kaiser 1989).
Rarely, thymic tumours can present as primary lesions outside the anterior mediastinum, such as the middle and posterior mediastinum, pleura, neck, and as intra-thyroidal lesions with histological characteristics of T (SETTLE: spindle cell epithelial tumours of thymic-like epithelium) (Verley 1985).

3.1.1 Parathymic syndromes

Of unique interest, Ts are associated with several syndromes, generally autoimmune conditions (Souadjian 1974; Rosenow 1984). Abnormal regulation of lymphocytes within the thymus gland can result in autoimmunity and/or immunodeficiency. Autoimmunity may also be caused by cross-immunity of antigens in other tissues with T associated antigens. As a result, several end organs may be affected and more than one immunologic disorder may be present in any given patient diagnosed with a T.
MG is the most common, occurring in approximately 45% (range 30-65%) of patients with T (Regnard 1996; Maggi 1991; Okumura 1999; Nakahara 1988; Kondo 2003a). Conversely, approximately 10%-15% of patients with MG will have a T (Rosenow 1984; Drachman 1994). Patients with T-associated MG can produce autoantibodies to a variety of neuromuscular antigens, particularly the AChR and titin, a striated muscle antigen (Voltz 1997; Gautel 1993). MG is usually diagnosed by history: patients commonly present with ptosis or drooping eyelids, double vision, drooling, dysarthria, difficulty climbing stairs, easy fatigability, muscular weakness, hoarseness, dyspnoea or generalized fatigue, that is particularly worse late during the day. They will require neurological treatment. Neurological consultation should be considered if there is suspicion of MG particularly for any patient being evaluated for surgical intervention as severe respiratory morbidity can be minimized with appropriate peri-operative management.
PRCA and adult-onset hypogammaglobulinaemia (Lewis 1987; Blumberg 1995; Pan 1994; Wilkins 1999; Rosenow 1984; Souadjian 1974) are the next most common, each occurring in 2% to 5% of patients.
Other less commonly associated conditions include: chronic ulcerative colitis, regional enteritis, systemic lupus erythematous, sarcoidosis, scleroderma, rheumatoid arthritis, polymyositis, dermatomyositis, pericarditis, Sjögren’s syndrome, Raynaud’s disease, thyroiditis, parathyroid adenoma, T-cell deficiency syndrome, pemphigus, alopecia, chronic candidiasis, Cushing’s syndrome, hypopituitarism, Addison’s disease, hypertrophic osteoarthropathy, macrogenitosomia praecox, nephrosis, minimal change nephropathy, red cell hypoplasia, pernicious anaemia, erythrocytosis, agranulocytosis, multiple myeloma, haemolytic anaemia, acute leukaemia and T-cell lymphocytosis (Venuta 1997; Regnard 1996). Extremely rare, with only two cases reported in the literature, is ANA positive autoimmune hepatitis (Aigner 2009; Rashid 2013).
Many studies have also noted that 17-28% (higher than expected) of patients with T present with a second synchronous or metachronous primary malignancy, including lung, thyroid, gastrointestinal, prostate, lymphoma, brain, sarcoma, and leukaemia, especially non-Hodgkin’s lymphoma (Pan 2001; Patella 2011; Welsh 2004; Blumberg 1995; Wilkins 1999; Souadjian 1974; Masaoka 1994; Vessey 1979; Loehrer 1997).

3.2 Imaging

Chest computed tomography (CT) scan with intravenous contrast is recommended (type C evidence, standard treatment) for evaluation of anterior mediastinal masses, giving information on size, density characteristics (presence of calcification, haemorrhage, necrosis), and relationship (encasement, invasion) to surrounding intra-thoracic organs (great vessels, lungs, pericardium, heart) and, in addition, identifying pleural parietal deposits (so called “droplet metastases”) frequently found in the posterior basilar pleural space and diaphragm. On CT scans, T usually appears as a well-defined round or oval mass located anterior to the great vessels and heart, below the left innominate vein (Marom 2010). It has been reported that smooth contours and round shape suggest type A Ts; irregular margins and enlarged lymph nodes suggest TCs; calcifications suggest B1, B2 and B3 types; and the combination of homogenous enhancement and a high degree of enhancement suggest type A or AB Ts. However, false-negative and false-positive rates are too high to apply these correlations broadly (Yanagawa 2011).
Magnetic resonance imaging (MRI) of the chest is not a standard option, but it can be a reasonable choice for patients who cannot receive iodinated contrast media (type 3 evidence, individualized treatment) (Marom 2010).
The role of PET scan is currently being evaluated. It is not a standard option but it is suitable for individual clinical use (type 3 evidence, individualized treatment). The degree of uptake on the PET scan correlates with the WHO Type: there have been reports of higher maximum standard uptake value (SUV max) for B2 and B3 compared to A, AB, and B1, but still lower than C; that a value of 6.2 can differentiate Ts from TCs, and >7.1 completely differentiates the two (Yanagawa 2011; Demura 2003). PET can demonstrate hypermetabolic activity in pleural-based masses identified on CT scan, which would be highly suggestive of metastatic disease (Kubota 1996). PET can also be used to ascertain response to non-surgical therapy.
Combined PET-CT may play a role for determining whether distant metastases are present, and it provides the benefit of being able to correlate metabolic activity with anatomical structures as opposed to PET scan alone (Sung 2006). Therefore, combining these modalities may provide diagnostic value before considering biopsy.
Recently, octreotide scanning has been shown to be 100% accurate in 17 patients (Lastoria 1998) but it remains suitable only for individual clinical use (type R evidence, individualized treatment).

3.3 Biopsy

A definitive tissue diagnosis is not a standard option but it is needed in situations where clinical presentation and imaging are only suspect, where patients require a non-operative approach or preoperative chemotherapy or chemo-radiotherapy, where lymphoma is considered to be a strong possibility or in instances in which a metastatic lesion is suspected (type C evidence, individualized treatment).
However, the biopsy should not violate the pleural space because of the propensity for pleural dissemination in thymic neoplasia. Pathological confirmation of the diagnosis of thymic tumour can be achieved by means of open surgical biopsy or fine-needle aspiration (FNA). Although CT-guided needle biopsy is the least invasive technique, the aspirated sample is often difficult to distinguish by cytology from other subtypes (lymphoma) with a sensitivity of less than 60%. Cytokeratin staining is a useful diagnostic marker for epithelial type cells in this regard. It must be emphasized however that cytology not only lacks sensitivity, but also can be misleading with respect to differentiating Ts and lymphomas (Morrissey 1993). Moreover, a substantial tissue sample for genetic marker studies including flow cytometry is considered optimal prior to treatment for haematological malignancies.
If core needle biopsy is not possible or is non-diagnostic then two surgical options with sensitivity higher than 90% exist for further evaluation (Mehran 2002; Murakawa 2000; Rendina 1988). For larger and/or invasive masses, anterior mediastinotomy (Chamberlain procedure) is considered the best option. Video-assisted thoracic surgery (VATS) provides excellent exposure to the anterior compartment for biopsy purposes using minimally invasive technology with the risk of pleural space seeding; VATS is helpful in cases of pleural disease. For small solid masses not amenable to core needle biopsy, complete surgical excision including total thymectomy could be considered as a reasonable approach for both diagnostic and therapeutic purposes.

3.4 Differential diagnosis of anterior mediastinal mass

Recommended tests for assessing mediastinal masses include chest CT with contrast and blood chemistry studies (type C evidence, standard treatment). Thymic tumours account for approximately 50% of anterior mediastinal masses, whereas lymphomas (25%) and various other tumours comprise the remainder. Treatment options radically change. Differential diagnoses are initially guided by patient’s age, gender, associated symptoms, and CT scan appearance. Malignant non-seminomatous germ cell tumours occur primarily in young adult males and can essentially be ruled out by measuring the serum tumour marker levels of alpha fetoprotein (αFP) and the beta subunit of human chorionic gonadotropin (βHCG). Mediastinal seminomas typically look invasive on CT scan, often have low elevations of the βHCG marker and require a tissue diagnosis.
Thyroid lesions involving the anterior mediastinal compartment are readily identified on CT scan as contiguous with the thyroid gland.
The main differential diagnosis is lymphoma. Patients are younger as compared to patients presenting with TETs, usually with constitutional symptoms that differ from parathymic syndromes, such as night sweats, fever, weight loss, and malaise. Physical examination can reveal suspect adenopathies; imaging could be suggestive, however, biopsy is required to establish the definitive diagnosis. A small anterior mediastinal compartment mass in a patient with a history of an associated immune disorder has a high probability of representing a TET.

4. STAGING

A number of staging systems exists. The first one was introduced by Bergh (Table 2; Bergh 1978) and later modified by Wilkins et al. (Table 3; Wilkins 1979).

Table 2. Staging system by Bergh.

 

Stage Definition
Stage I Intact capsule or growth within the capsule
Stage II Pericapsular growth into the mediastinal fat tissue
Stage III Invasive growth into the surrounding organs, intrathoracic metastases, or both
Table 3. Staging system by Wilkins and Castleman.

 

Stage Definition
Stage I Intact capsule or growth within the capsule
Stage II Pericapsular growth into the mediastinal fat tissue or adjacent pleura or pericardium
Stage III Invasive growth into the surrounding organs, intrathoracic metastases, or both

The difference between these two systems was limited to one point: stage II Wilkins thymoma involved pleura and pericardial invasion. Major inadequacies include: actual sites of intra-thoracic metastasis, the description of invasion, stage III including too broad spectrum of disease, and not well represented haematogenous and lymphogenous metastases. The most widely accepted staging system was proposed by Masaoka (Table 4; Masaoka 1981); the TNM system closely parallels the Masaoka one but is less commonly used (Table 5; Yamakawa 1991).

Table 4. Staging system by Masaoka.

 

Stage Definition
Stage I Macroscopically completely encapsulated and microscopically no capsular invasion
Stage II Macroscopic invasion into surrounding fatty tissue or mediastinal pleura, or
Microscopic invasion into capsule
Stage III Macroscopic invasion into neighbouring organ, i.e., pericardium, great vessels, or lung
Stage IVa Pleural or pericardial dissemination
Stage IVb Lymphogenous or haematogenous metastasis
Table 5. TNM Classification.

 

Factor Characteristics
T factor
T1 Macroscopically completely encapsulated and microscopically no capsular invasion
T2 Macroscopically adhesion or invasion into surrounding fatty tissue or mediastinal pleura, or microscopic invasion into capsule
T3 Invasion into neighbouring organs, such as pericardium, great vessels, and lung
T4 Pleural or pericardial dissemination
N factor
N0 No lymph node metastasis
N1 Metastasis to anterior mediastinal lymph nodes
N2 Metastasis to intrathoracic lymph nodes except anterior
mediastinal lymph nodes
Metastasis to extrathoracic lymph nodes
M factor
M0 No haematogenous metastasis
M1 Haematogenous metastasis

In France, multiple centres have adopted the Gruppe d’Etude des Tumeurs Thymiques system (GETTS) as described by the French Study Group on Thymic tumours (Table 6; Gamondes 1991); in this system, the predominant feature is the extent of surgical resection.

Table 6. French system.

 

Stage Definition
Stage I
Ia Encapsulated, non invasive.
Total excision.
Ib Localized invasion to mediastinal structures.
Total excision.
Stage II Invasive growth into the surrounding organs.
Total excision.
Stage III
IIIa Invasive growth into the surrounding organs.
Incomplete excision.
IIIb Invasive growth into the surrounding organs.
Biopsy of the tumour.
Stage IV
IVa Largely invading tumour cells with clavicular
lymph nodes or pleural or pulmonary grafts.
IVb Haematogenous metastasis (1 or more).

Although this may be of prognostic value, it does not lend itself to clinical staging of patients before treatment to select the optimal approach.

4.1 Masaoka-Koga-ITMIG system

This system was proposed in 1981 as a surgical and pathologic staging system based on the extent of disease, focusing on the integrity of the thymic capsule, the presence of micro- or macro-scopic invasion into adjacent mediastinal structures, and lymphogenous or haematogenous metastatic spread.
Invasion into the pleural cavity is preceded by the breaching of anatomical barriers: capsule, mediastinal pleura, visceral pleura and finally lung. This is followed by growth into the mediastinum, invasion of the capsule, mediastinal adipose tissue, pericardium (or great vessels) and finally heart.
Stage II disease involves invasion into the mediastinal pleura evident at perioperative inspection, even if histological invasion cannot be proved.
Stage IV disease is divided into two categories: IVa, consisting of serosal dissemination (i.e. involvement of the pleura and pericardium); stage IVb, with metastasis via lymphogenous and haematogenous (usually liver, lung and rib) routes. Accordingly, stage IVb includes cases with lymph node metastasis at any station.
Koga proposed a staging modification in 1994 (Table 7; Koga 1994).

Table 7. Masaoka-Koga staging system.

 

Stage Definition
Stage I Grossly and microscopically completely encapsulated tumour
Stage II
IIa Microscopic transcapsular invasion
IIb Macroscopic invasion into thymic or surrounding fatty tissue, or grossly adherent to but not breaking through mediastinal pleura or pericardium
Stage III Macroscopic invasion into neighboring organ (i.e. pericardium, great vessel or lung)
Stage IV
IVa Pleural or pericardial metastases
IVb Lymphogenous or hematogenous metastasis

The Masaoka classification with Koga modification has been adopted by the International Thymic Malignancy Interest Group (ITMIG) with further nuances added to the definitions (Table 8; Detterbeck 2011a).

Table 8. ITMIG clarification and definition of terms in Masaoka-Koga staging.

 

Stage Definition
Stage I * Grossly and microscopically completely encapsulated tumour.
* This includes tumours with invasion into but not through the capsule, or tumours in which the capsule is missing but without invasion into surrounding tissues.
Stage II
IIa * Microscopic transcapsular invasion.
* Microscopic transcapsular invasion (not grossly appreciated).
IIb * Macroscopic invasion into thymic or surrounding fatty tissue, or grossly adherent to but not breaking through mediastinal pleura or pericardium
* Gross visual tumour extension into normal thymus or perithymic fat surrounding the thymoma (microscopically confirmed), or
* Adherence to pleura or pericardium making removal of these structures necessary during resection, with microscopic confirmation of perithymic invasion (but without microscopic extension into or through the mediastinal pleura or into the fibrous layer of the pericardium).
Stage III * Macroscopic invasion into neighbouring organ (i.e. pericardium, great vessel or lung)
* This includes extension of the primary tumour to any of the following tissues:
* Microscopic involvement of mediastinal pleura (either partial or penetrating the elastin layer); or
* Microscopic involvement of the pericardium (either partial in the fibrous layer or penetrating through to the serosal layer); or
* Microscopically confirmed direct penetration into the outer elastin layer of the visceral pleura or into the lung parenchyma; or
* Invasion into the phrenic or vagus nerves (microscopically confirmed, adherence alone is not sufficient); or
* Invasion into or penetration through major vascular structures (microscopically confirmed);
* Adherence (i.e. fibrous attachment) of lung or adjacent organs only if there is mediastinal pleural or pericardial invasion (microscopically confirmed).
Stage IV
IVa * Pleural or pericardial metastases
* Microscopically confirmed nodules, separate from the primary tumour, involving the visceral or parietal pleural surfaces, or the pericardial or epicardial surfaces.
IVb * Lymphogenous or haematogenous metastasis
* Any nodal involvement (e.g. anterior mediastinal, intrathoracic, low/anterior cervical nodes, any other extrathoracic nodes)
* Distant metastases (i.e. extrathoracic and outside the cervical perithymic region) or pulmonary parenchymal nodules (not a pleural implant).

4.2 TNM-WHO system

In 1991, Yamakawa proposed a TNM classification system (see Table 5). N1 corresponds to anterior mediastinal, N2 other mediastinal, and N3 extrathoracic lymph node metastasis. M1 means haematogenous metastasis in any organ. However, the staging system was not revised. All N-positive and M-positive cases were included in stage IVb.
In 2004, the World Health Organization (WHO) proposed a new system of TNM classification and staging (Table 9; Travis 2004).

Table 9. WHO staging system.

 

Primary tumour (T)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour completely encapsulated
T2 Tumour invades pericapsular connective tissue
T3 Tumour invades into neighbouring structures, such as pericardium, mediastinal pleura, thoracic wall, great vessels, and lung
T4 Tumour with pleural or pericardial dissemination
Regional lymph nodes (N)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in anterior mediastinal lymph nodes
N2 Metastasis in other intrathoracic lymph nodes excluding anterior mediastinal lymph nodes N0
No regional lymph node metastasis
N3 Metastasis in scalene and/or supraclavicular lymph nodes
Distant metastasis (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage
Stage I T1; N0; M0
Stage II T2; N0; M0
Stage III T1; N1; M0
T2; N1; M0
T3; N0, 1; M0
Stage IV T4; Any N; M0
Any T; N2,3; M0
Any T; Any N; M1

This system is similar to the Masaoka one except for two points: histological invasion into mediastinal pleura is categorized into T3; N1allocation in stage III. The Masaoka system respects the concept of invasion by contiguity (stage III) versus discontinuous progression (stage IV). By contrast, the WHO staging system respects localization of the involved area, giving priority to the results of surgery.

5. PROGNOSIS

Tumour stage is the single most important prognostic factor; in one of the largest series, the 10-year survival of completely resected patients was 80%, 78%, 75%, and 42% for stages I, II, III, and IVa (Regnard 1996). However, a combination of stage and histological subtype should be considered in predicting survival. Types A, AB, and B1 have an excellent OS rate of more than 90% to 95% at 10 years (Chen 2002; Quintanilla-Martinez 1994). Five-year survival for types B2, B3, and C are 75%, 70%, and 48%, respectively. Aside from staging and histology, there are other important prognostic factors to consider.
First, completeness of resection is extremely important for prognosis, even for stage III and IV lesions (Nakahara 1988; Yagi 1996). Second, although MG once was associated with worse prognosis (Wilkins 1966), advances in managing MG are such that most patients are diagnosed as stage I and II, and have a better outcome (Regnard 1996; Maggi 1991; Wang 1992; Wilkins 1999; Moore 2001), whereas hypogammaglobulinemia and PRCA are associated with worse prognosis. Third, early recurrence has also been reported to be a poor prognostic indicator of OS.
Fourth, there is some suggestion that patients with smaller tumours (Blumberg 1995) and fifth, that patients younger than 30 to 40 years have a better prognosis (Lewis 1987; Venuta 1997).

6. TREATMENT

6.1 Surgical treatment of thymic tumours

Surgery is the mainstay of treatment in the management of thymic tumours, as long as they are completely resected (type C evidence, standard treatment). As a direct consequence, resection should be tailored according to the extent of the disease, which may be classified preoperatively in two different groups: either the presence of a small, clinical stage I or II tumour with radiological characteristics of thymoma, or extended tumours suggesting stage III-IV disease and/or thymic carcinoma. These two situations differ in the preoperative, intraoperative and postoperative management.

6.1.1 Preoperative management

It is accepted that in cases of an isolated mass within the anterior mediastinal space with a radiological aspect suggesting a diagnosis of thymoma and without involvement of surrounding organs, a preoperative histological diagnosis is useless (type C evidence, standard treatment) (Ruffini 2011). When this strategy is adopted, the risk of performing thymectomy for disease other than thymic tumours (lymphoma, thymic hyperplasia, thymic cyst or other benign disease of the thymus) is in the order of 25% (Kent 2014), thymic hyperplasia being the most common diagnosis.
Preoperative diagnosis is mandatory (type C evidence, standard treatment) in cases of unresectable disease, need of neoadjuvant treatment and uncertain differential diagnosis with lymphoma (Detterbeck 2010). Policies and reporting guidelines for mediastinal mass biopsies have been developed recently by an ITMIG working group comprised of pathologists and surgeons (Marchevsky 2011).
Once the staging work-up has been completed, decisions about surgical treatment should be based mainly on two variables: the risk of incomplete resection and the surgical risk for the patient (Table 10).

Table 10. Decision about surgical treatment, by risk.

 

Surgical risk
Low Higha
Risk of incomplete resection Low Surgery Surgery
Highb Neoadjuvant Inoperable
a. High surgical risk means an expected postoperative mortality of 10-15%; an higher risk should be considered uncceptable. Every effort should be done to improve conditions which may rise this risk (i.e. MG) b. higher than 30%.

Accuracy in the evaluation of both depends on the surgeon’s experience. In cases of resectable disease, surgery is usually the first step of treatment (type C evidence, standard treatment), once that concomitant diseases such as MG have been stabilized. When the risk of incomplete surgery is greater than 30%, a neoadjuvant treatment can be considered in order to improve R0 resection rate (Venuta 2003; Macchiarini 1991) in low-risk patients (type C evidence, standard treatment). Incomplete surgery in high risk patients should be avoided, as debulking procedures are not useful (type C evidence, standard treatment).

6.1.2 Intraoperative management

The standard surgical procedure for stage I or II thymic tumour is thymectomy, the removal of the entire thymus gland en bloc with the tumour (type C evidence, standard treatment). For complete thymus removal cervical dissection above the innominate vein should be combined with mediastinal dissection, due to the fact that thymic upper poles lie in the neck. The type of thymectomy may range from complete thymectomy (complete removal of the thymic gland with surrounding fatty tissue, in patients without MG) to extended thymectomy (removal of mediastinal pleura and all the adipose tissue in mediastinal and pericardiophrenic areas), as suggested for patients with MG (type C evidence, individualized treatment) (Toker 2011). This approach has been adopted since there is frequently thymic tissue present within mediastinal fat (Masaoka 1975), which may be responsible for lack of MG remission or late MG occurrence after surgery.
The standard surgical approach for thymectomy is median sternotomy, allowing both cervical dissection and bilateral pleural exploration in case of tumours extended to the mediastinal pleura (type C evidence, standard treatment). The development of VATS (Chen 2007; Zielinski 2004) and more recently of robotic surgery (Marulli 2012; Mussi 2012) raised the question of utilizing a minimally invasive approach in order to reduce surgical risk (especially in MG patients) and postoperative stay. A minimally invasive resection of thymoma has been recently defined as «any approach as long as no sternotomy (including partial sternotomy) or thoracotomy with rib spreading is involved and in which a complete resection of the tumour is intended» (type C evidence) (Toker 2011). Some authors claimed superiority of robotic surgery as compared to VATS (Ye 2013) or sternotomy (Weksler 2012) in Masaoka stage I thymoma, but these retrospective results require further confirmation in controlled trials.
In stage III thymic tumours infiltrating surrounding structures, there is no place for minimally invasive techniques. In this setting, multidisciplinary evaluation is crucial to decide whether a neoadjuvant treatment should precede surgery.
Management of large stage III tumours requires a flexible intraoperative strategy, considering that thymectomy should be performed en bloc with infiltrated surrounding structures (type C evidence, standard treatment). Sternotomy may be inadequate for surgical exposure and surgical access should be adapted to area of anticipated difficult dissection: sterno-thoracotomy allows proper exposure of lung hilum and superior vena cava in large lateralised tumours, while a trans-manubrial approach is required when the origin of the innominate veins need to be exposed. When feasible from a functional point of view, one infiltrated phrenic nerve can be generally sacrificed and diaphragm plication may prevent postoperative eventration (Leo 2010). Infiltration of the superior vena cava may require tangential resection, patch repair or prosthetic replacement, depending of the extent of the infiltration. The extent of lung resection ranges from atypical resection (tangential infiltration or peripheral lung metastases) to upper lobectomy to pneumonectomy, when the dimensions of the tumour preclude proper hilar dissection, or transfissural infiltration is present. Pleurectomy may be required when pleural metastases are present. After such a combined procedure, postoperative morbidity is usually proportional to the extent of lung resection (maximal after pleuropneumonectomy) and to nerve damage (phrenic, recurrent), particularly when bilateral.
Suspicious lymph nodes should be dissected, considering that the risk of nodal metastases in thymoma is around 2% and exceeds 25% in thymic carcinomas and thymic carcinoids (Kondo 2003a). For this reason, ITMIG policies suggest performing a systematic anterior mediastinal node dissection and systematic sampling of appropriate intrathoracic sites (paratracheal, subcarinal, aorto-pulmonary window) in stage III thymoma, adding supraclavicular and lower cervical nodes in cases of suspected or known thymic carcinoma (type C evidence, standard treatment) (Detterbeck 2011).
Radicality of the resection and stage are the main prognostic factors after surgery for thymic tumours. Additionally, most of decisions on postoperative adjuvant treatment will be taken based on these elements. For these reasons, maximal effort should be employed to improve the precision of pathological assessment; the specimen should be properly oriented and marked intraoperatively and the operative report should include the precise state of the resection (R0 versus R2), area of adherences, surrounding resected areas, and whether the pleural and the pericardial space were inspected (Detterbeck 2011).

6.1.3 Pathological staging, adjuvant treatment and follow-up

After surgical resection, three issues should be addressed:
a. proper definition of pathological staging and WHO type;
b. the need for adjuvant treatment;
c. the type of follow-up required.
For pathological staging, several staging systems have been proposed (Masaoka 1981; Koga 1994; Yamakawa 1991; Gamondes 1991), the Masaoka-Koga system (Koga 1994) being recommended (type C evidence) (Huang 2011). Modifications from the original Masaoka classification mainly concern staging of partial capsular invasion (stage I in the Masaoka-Koga) and the definition of adherences or microscopic incomplete pleural/mediastinal infiltration as stage IIb (not mentioned in the Masaoka system) (see Table 7).
In order to define the need for adjuvant treatments, three factors are usually considered in relation to adjuvant radiotherapy: radicality of the resection, stage and histology. In cases of incomplete resection, radiotherapy is usually proposed to reduce the risk of mediastinal progression (type C evidence, standard treatment) (Curran 1988; Ciernik 1994; Urgesi 1990). More controversial is the use of radiotherapy after complete resection of stage >II thymoma – a situation in which radiotherapy has classically been proposed in the past (Masaoka 1981; Nakahara 1988; Monden 1985; Forquer 2010). This approach has been reported as being not useful (Kondo 2003b) or even detrimental (Ruffini 1997; Vassiliou 2009) by some authors. More recently, it has been proposed that radically resected thymoma stage I and II WHO types A, AB and B1 do not benefit from postoperative radiotherapy and therefore should not be treated (type C evidence, standard treatment) (Utsumi 2009; Zuang 1999). Decisions on adjuvant radiotherapy in higher stages and/or WHO type B2 B3 and C should be based on multidisciplinary evaluation (type 3 evidence, individualized treatment). Even in thymic carcinoma, which is the most aggressive thymic tumour, the role of postoperative radiotherapy remains unclear due to conflicting published data (type 3 evidence, individualized treatment) (Kondo 2003b; Hsu 2002).
Follow up should take into account that thymomas are indolent tumours that may develop recurrences many years after resection (type C evidence, standard treatment). For that reason, it is proposed that patients undergo an annual CT scan for the first 5 years after surgical resection of stage I-II thymoma. CT is alternated with chest X-ray for the next five years and an annual chest X ray thereafter. In higher stages, incomplete resection or thymic carcinoma, a CT scan every 6 months for the first 3 years is suggested (Huang 2011). An alternative strategy is to maintain annual CT scan for life, the rationale being the peculiar risk in thymoma patients of developing second tumours (15-20%) (Wilkins 1999; Welsh 2000; Filosso 2013) and very late recurrence (Uemura 2006; Awid 1998).

6.1.4 Results of surgical treatment and prognostic factors

Interpretation of the results of surgical management of thymic tumours should take into account three different elements:
a. thymic tumours are rare diseases and large series have been collected over a long period of time, during which many aspects of management have evolved (staging systems, histotype classification, preoperative work-up and surgical techniques);
b. since thymoma is an indolent disease, survival should be measured with an adequate follow-up (>10 years) (type C evidence, standard treatment) (Huang 2011);
c. overall survival may be not the best measure to assess the efficacy of surgical resection of thymoma, as less than 50% of recorded deaths are due to the tumour itself (Detterbeck 2008).
A recent analysis of published evidence on prognosis in thymic malignancies showed that only 3 prognostic factors were significant in more than 50% of published studies: stage (stage I and II versus others), radicality (R0 versus others) and histology (thymoma versus thymic carcinoma) (Detterbeck 2011b).
In stage I, 10 year survival ranges from 80% to 100%, while in stage II results are more variable (42%-100%) (Nakahara 1988; Wilkins 1999; Kondo 2004; Ogawa 2002; Pan 1994; Quintanilla-Martinez 1994; Blumberg 1995; Ströbel 2004b; Chen 2002; Verley 1985; Maggi 1991; Regnard 1996), probably due to the different rate of radical resection (100% in stage I, 88% in stage II) (Detterbeck 2010). Stage III 10 year survival is in the order of 50%,and ten year survival in stage IV is around 30% (Chen 2002; Maggi 1991; Regnard 1996).
The rate of R0 resection varies with stage, being very high in stage I and II, and significantly reduced in stage III (50%) and IV (25%) (Detterbeck 2010). In advanced stage, variability in the reported R0 resection rate is observed, probably due to different attitudes toward extended resections in different centres. Nevertheless, when a radical resection is obtained, stage III prognosis dramatically improves, approaching a stage I prognosis (Regnard 1996; Yagi 1996). A 10 year survival (50%) can be achieved even in the presence of selected cases of stage IV thymoma radically resected by pleuro-pneumonectomy (Wright 2006).
WHO histological subtypes correlate with invasiveness and complete resection. Type A, AB, B1 and B2 type have a homogeneous rate of invasiveness and of complete resection (28%-44% and 88-100% respectively) (Kim 2005b). Thymic carcinoma has a worse prognosis, with a 5 year survival of 35% (Suster 1991; Weksler 2013), due to its aggressive biological behaviour, translating into high invasiveness risk (91%) and low complete resection rate (58%). Type B3 shows the same behaviour as thymic carcinoma in terms of invasiveness and complete resection but an intermediate behaviour in long term survival. The clinical impact of WHO subtyping is limited by only moderate interobserver and intraobserver agreements and by the fact that, when properly sampled, more than 50% of the tumours shows a mixed pattern (Moran 2012).

6.1.5 Surgical treatment of recurrence

A certain proportion of patients may experience recurrence after surgical resection. In stage I thymoma, recurrence is a rare event (3%), occurring after a mean interval of 10 years. As stage increases, the risk of recurrence increases (11% in stage II and 30% in stage III) and time to recurrence shortens (3 years) (Detterbeck 2008). Most frequent sites of intrathoracic recurrence are mediastinum, pleurae and/or diaphragm and the lung. In many cases, treatment options are limited, because radiotherapy has been already administered in an adjuvant setting after the first resection. In some selected cases, these recurrences may be considered for surgery, as long as a radical resection can be anticipated (type R evidence, individualized treatment). When a radical resection is achieved (50%), good results can be obtained in terms of long-term survival (Ruffini 1997; Regnard 1997; Lucchi 2009; Lucchi 2010).

6.2 Radiotherapy

6.2.1 Overview

All data on therapies of TETs are biased by the absence of randomized controlled trials and all considerations on treatment strategy are not robust, being type C (general consensus), type R (rational inference) or level 3 evidence.
Another consideration should be survival end-points, mainly in thymoma. Five-year overall survival and disease specific survival are quite long in TETs, mostly above 90% in stage I and II disease and even for advanced stage as high as 70.5%, 56.3%, and 38.2% for stage III, IVa and IVb respectively (Kondo 2010). Moreover 5-year survival rates are up to 100%, 98.4%, 88.7%, 70.6%, and 52.8% in thymoma patients (Kondo 2003a).
Thus when analysing results from different series, the most valuable end-points should be tumour related deaths (TRD) or recurrence rates. Moreover, Huang and colleagues, in their report for International Thymic Malignancy Interest Group – ITMIG (Huang 2010), stated that «freedom-from-recurrence is the best measure for patients who have successfully undergone curative-intent treatment (R0 resection)», while «for patients in whom the disease was never eradicated, time-to-progression is the best measure». They also suggest, for overall survival, that 5 and 10-years rate are reported.
Surgery with a R0 resection is the mainstay of treatment (type C evidence, standard treatment). Adjuvant treatment radiotherapy (RT) has been widely adopted in advanced stage disease mainly when disease invades surrounding tissues (stage III) or with R1-R2 residual after surgery (type C evidence, standard treatment).
The role of radiotherapy remains controversial as adjuvant treatment in radically resected patients. Older series of patients showed surprising results (38.1% recurrence rate with surgery alone versus 0% of surgery followed by RT in (Curran 1988), while conflicting results have been reported from a meta-analysis of phase II trials (Korst 2009) or SEER database analysis (Forquer 2010; Patel 2012).
These newer series, and even more so for the SEER analysis, suffer from two major uncontrolled biases: a selection of RT for patients where the surgeon presumes a benefit for adjuvant treatment and the data have not been collected according to WHO sub-types that currently are deemed to correlate with expression of different clinical and biological behaviours.
Indeed, a recent Chinese series (Gao 2013) pointed out that adjuvant radiotherapy in stage III-IV type B3 thymoma was an independent prognostic factor in multivariate analysis for overall survival.
Therefore, present (D’Angelillo 2008) and future efforts should classify patients according to the class of risk (as in prostate patients) and adapting adjuvant treatment according to surgery extension, stage and tumour histology.
Moreover, with more advanced disease, where a R0 resection is deemed unachievable, patients should be referred to multimodality treatment to enable them to undergo radical surgery (type C evidence, standard treatment).
Induction chemoradiation with cisplatin and etoposide has been explored in two trials (Wright 2008; Korst 2014) but with few evaluable patients (total: 31 patients). According to the authors, this kind of approach was deemed feasible with 25, 5 and 1 patients undergoing R0, R1 and R2 resection (81%, 16% and 3%) respectively and a surgical complication rate of 32% (10 patients).
Another strategy in unresectable disease could include, as reported by Kim and colleagues (Kim 2004), neoadjuvant chemotherapy followed by surgery and adjuvant radiotherapy where total dose is defined according to pathological response: in case of complete or major (>80% necrotic tissue) response, total adjuvant dose was up to 50 Gy, otherwise up to 60 Gy with standard fractionation. With this strategy a 77% progression free survival and 79% overall survival has been reported.
Where surgery is not recommended a personalized approach including radiotherapy and/or chemotherapy should be discussed with the individual patient and the Multidisciplinary Disease Team where available.

6.2.2 Treatment of thymoma

Excellent long-term results are obtained with complete surgical thymectomy for a pathologic stage I and II WHO types A, AB and B1 thymoma patients, and no adjuvant therapy should be proposed following an R0 resection (type C evidence, standard treatment) (Utsumi 2009; Zuang 1999).
Adjuvant radiotherapy could be proposed as individualized therapy in patients with stage II disease with positive or closed margins as determined by both pathological and/or intraoperative findings (type 3 evidence, individualized treatment) (Masaoka 1981; Nakahara 1988; Monden 1985; Forquer 2010; Kondo 2003b; Ruffini 1997; Vassiliou 2009).
Stage III thymoma may be difficult to identify prior to surgery as invasion of adjacent structures may only be identified at the time of surgery. These patients often receive aggressive surgical resection including wide surgical margins with consideration of adjuvant radiation therapy (type 3 evidence, individualized treatment) (Masaoka 1981; Nakahara 1988; Monden 1985; Forquer 2010; Kondo 2003b; Ruffini 1997; Vassiliou 2009).
Debulking surgery should be avoided in patients with either stage III or stage IVA disease (type C evidence, standard treatment).
If invasion of local organs is apparent on pre-treatment imaging as stage III or IV disease, a multimodality approach including induction therapy followed by surgery may be proposed (Type R evidence, individualized treatment). Induction chemoradiation with cisplatin and etoposide (Wright 2008; Korst 2014) or induction CAPP followed by surgery and individualized radiotherapy (Kim 2004) could be of value.
Finally, in recurrent disease treatment options should be defined according to the likelihood of being able to achieve radical surgery, the previous oncological options adopted, site of recurrence, and time from initial treatment to failure (type R evidence, individualized treatment).

6.2.3 Thymic carcinoma

In comparison with thymoma, thymic carcinoma (TC) has more aggressive behaviour. In the Japanese analysis (Kondo 2003b) patients with thymic carcinoma present with more advanced disease at diagnosis (46.5% stage IV in TC versus 10% of stage IV thymoma at diagnosis), with around half of the patients deemed inoperable or only suitable fora sub-total resection. Among those who received a total resection 51% experienced a recurrence. Additionally, 5-year survival rate was significantly different between TC (50.5%) and thymoma patients (94.4%, p<0.0001).
According to these data TC should be considered as aggressive as a carcinoma arising from other primary sites, and treatment should be individualized for every patient, mostly employing a multimodality approach (D’Angelillo 2008) (type C evidence, individualized treatment).
Adjuvant radiotherapy should be considered in stage II and stage III disease with R0 resection (type 3 evidence, individualized treatment), and applied as adjuvant treatment in patients with stage II and stage III disease with R1 resection (type C evidence, standard treatment) (Komaki 2014; Kondo 2003b; Hsu 2002; Curran 1988; Ciernik 1994; Urgesi 1990), while stage IV disease should be managed in a multimodality setting (type C evidence, individualized treatment).
The observations about advanced disease and a multimodality approach already discussed for thymoma, should be applied in thymic carcinoma too.

6.2.4 Dose-Volumes definition

At the present time, no different dose/volumes have been adopted in patients with thymoma or thymic carcinoma. Differences are usually made according to the treatment setting (adjuvant, neoadjuvant, definitive treatment).
The adjuvant or post-operative setting is defined by ITMIG (Gomez 2011) as no residual disease in post-operative imaging. Tumour bed with adequate margin is defined as CTV treated up to 45-50 Gy after R0 resection with standard fractionation (Zhu 2004; Chen 2010; Harnath 2012) (type C evidence, standard treatment). No elective nodal irradiation should be given (Komaki 2014; Zhu 2004; Chen 2010). With standard 3D technique grade 3-4 toxicity is uncommon (Kim 2008; Chang 2011; Berman 2011).
For patients with microscopic positive margins after surgery, doses below 40 Gy and above 64 Gy with standard fractionation are not considered adequate (Gomez 2011), even though a total dose between 50 and 54 Gy could be of value (Type R evidence, individualized treatment).
In patients where definitive radiotherapy is recommended (macroscopic residual after surgery, tumour recurrence or who did not undergo surgery), CTV encompass the gross tumour disease plus adequate margin for microscopic regions at risk. Elective nodal coverage is not routinely recommended. Radiotherapy should be applied with standard fractionation up to a total dose of 60-66Gy for radiotherapy alone or 54 Gy if chemotherapy is administered concurrently (type C evidence, standard treatment) (Komaki 2014).

6.3 Medical therapy

6.3.1 Chemotherapy

Adjuvant chemotherapy is not recommended for radically resected (R0) stage I-II TETs (type C evidence, standard treatment). Induction therapy followed by surgery may be useful for thymic malignancies initially considered unresectable (type C evidence, individualized treatment) (Kim 2004). Patients with advanced disease are candidate for chemotherapy with or without RT (type C evidence, individualized treatment). Platinum-based combinations remain the standard of care (type 3 evidence, standard treatment).

6.3.1.1 Single-agent therapy

Because of the rarity of TETs, published experience of chemotherapy is limited to case reports, retrospective analyses and small prospective trials; they document that Ts are chemotherapy-sensitive, with an objective response (ORR) seen in an average of two thirds and a complete response (CR) in one third, producing durable remissions in those patients with advanced or metastatic Ts. However, the median duration of response varies dramatically among studies, ranging from 1 to more than 7 years. No validated biomarkers exist that predict response to chemotherapy (Liu 2007; Sasaki 2003).
Historically, a variety of drugs with demonstrated activity in case reports or small retrospective series have been used as single agents in T. Only a few small phase II trials of pretreated patients have looked at single-agent (cisplatin, ifosfamide and pemetrexed) therapy for advanced T (Table 11).

Table 11. Single agent chemotherapy.

 

Reference Study population Study treatment Main outcomes Comment(s)
Bonomi 1993 (ECOG) 21 patients Cisplatin
50 mg/m2/3 wks
ORR 10% (2 pts with PR)
OS 76 wks
2-year survival 39%
phase 2 trial
Highley 1999 15 patients (13 assessable) Ifosfamide 1.5 g/m2 x 5 dd/3 wks ORR 46.2% (5 patients with CR and 1 PR)
5-year survival 57%
Retrospective series
Loehrer 2006 27 patients (16 T and 11 TC) Pemetrexed 500 mg/m2/3 wks ORR 17%
T-group ORR 25% (2 CR and 2 PR)
TC-group ORR 9% (1 PR)
OS 29 mts

One of the first reports described a CR in a patient with renal metastases from T who was treated with cisplatin (Needles 1981). This was followed shortly thereafter by the earliest published prospective phase II trial in T, which was conducted by the Eastern Cooperative Oncology Group (ECOG) and evaluated cisplatin (50 mg/m2 every 3 weeks) in patients with advanced/metastatic T. In this study, 21 patients were eligible for assessment and two (10%) demonstrated a partial remission (PR). No CR was noted. Median OS was reported as 76 weeks for all patients on the study with a 2-year survival estimated at 39% (Bonomi 1993).
British investigators looked retrospectively at ifosfamide as single-agent therapy in invasive T. The most common toxicities were nausea, vomiting and leucopoenia. Five CRs and one PR were noted in the 13 (ORR 46.2%) assessable patients. Two of the patients had TC and had stable disease (SD) as the best response to therapy. The median duration of CR was 66 months, and the estimated survival rate 5 years after ifosfamide therapy was 57% (Highley 1999).
A phase II study evaluated pemetrexed 500 mg/m2 every 3 weeks for a maximum of six cycles in 27 patients with previously treated, unresectable, stage IVA (T) or stage IVB (TC) recurrent thymic malignancies (Loehrer 2006). In 23 fully evaluable patients, two CRs and two PRs were noted. All four responding patients had stage IVA T. Median TTP for all patients was 45 weeks (Ts, 45.4 weeks versus TC, 5.1 weeks), and the OS was 29 months for all patients. Toxicity was mild with no patient experiencing grade IV events. Overall, single-agent pemetrexed is an active agent in a heavily pretreated population of patients with recurrent Ts, but it has limited activity in TCs.

6.3.1.2 Polychemotherapy

Platinum-based combinations remain the standard of care (type 3 evidence, standard treatment). A retrospective series with ADOC regimen (cisplatin 50 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, vincristine 0,6 mg/m2 day 3 and cyclophosphamide 700 mg/m2 day 4 every 3 weeks) experienced an ORR of 92% and a OS of 15 months in first-line therapy (Fornasiero 1991).
An intergroup trial from ECOG, Southwest Oncology Group and South-eastern Cancer Study Group investigated the CAP regimen (cisplatin 50 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 administered every 3 weeks) in 30 patients experiencing an ORR of 50% (3 CRs and 12 PRs) and a SD in 10 patients; the median duration of response was 11.8 months, the time to treatment failure (TTF) 18.4 months and OS 37.7 months (Loehrer 1994). Kim et al. used a similar regimen (cisplatin 30 mg/m2 on days 1-3, doxorubicin 20 mg/m2 via continuous infusion on days 1–3 and cyclophosphamide 500 mg/m2 on day 1) with prednisone (100 mg per day) on days 1–5 (so-called CAPP schedule) in 22 patients with locally advanced T, achieving a 77% ORR (17 patients, 3 with CR); responding patients underwent surgical resection followed by radiation therapy. OS was not reported (Kim 2004).
Several regimens have evaluated combinations without anthracycline. The first prospective trial was led by the European Organization for Research and Treatment of Cancer (EORTC), in 16 previously untreated patients with advanced T receiving PE (cisplatin 60 mg/m2 on day 1 and etoposide 120 mg/m2 on days 1-3 every 3 weeks). Five CRs and four PRs were obtained for an ORR of 56%, with median response duration of 3.4 years. The median progression free survival (PFS) and OS were 2.2 years and 4.3 years, respectively (Giaccone 1996).
The ECOG conducted a prospective trial using the VIP schedule (cisplatin 20 mg/m2 plus etoposide 75 mg/m2 with the addition of ifosfamide 1.2 g/m2 on days 1-4 every 3 weeks) in 28 patients; only nine (32%) had an ORR with an OS of 31.6 months (Loehrer 2001).
Carboplatin (area under the curve -AUC- 6) plus paclitaxel (225 mg/m2) every 3 weeks demonstrated a modest clinical benefit with an ORR of 21.7% for patients with TC and a 42.9% for those with T; PFS was 16.7 and 5.0 months for thymoma and TC cohorts, respectively. Median OS was 20.0 months for patients with TC (not reached for patients with T) (Lemma 2011) (Table 12).

Table 12. Prospective chemotherapy trials in TETs.

 

Reference Study population Study treatment Main outcomes Comment(s)
Fornasiero 1991 37 patients ADOC ORR 92%
OS 15 mts
Retrospective series
Loehrer 1994 (Phase II) 30 patients CAP ORR 50%
OS 38 mts
Kim 2004 (Phase II) 22 patients CAP-P ORR 77% OS not reported
Giaccone 1996 (Phase II) 16 patients PE ORR 56%
OS 4.3 ys
Loehrer 2001 (Phase II) 28 patients VIP ORR 32%
OS 31.6 mts
Lemma 2011 (Phase II) 46 patients CBDCA-Paclitaxel ORR 42.9 (T)
ORR 21.7% (TC)
PFS 16.7 mts (T)
PFS 5 mts (TC)
OS 20 mts (TC)
OS not reached for T
6.3.1.3 Second-line therapy

Second-line chemotherapy is not a standard of care and it should be preferably offered to patients within a clinical trial. In clinical practice, second-line chemotherapy includes etoposide, ifosfamide, pemetrexed, 5-FU or analogues, gemcitabine and paclitaxel (type R evidence, individualized treatment). Preliminary results from a phase 2 trial of capecitabine (1,300 mg/m2 days 1–14) and gemcitabine (1,000 mg/m2 on days 1 and 8) every 3 weeks in 15 pretreated patients show an ORR of 40% with acceptable toxicity; 1- and 2-year survival rates were 80% and 67%, respectively (Palmieri 2010).

6.3.2 Other medical approaches
6.3.2.1 Immunotherapy

A phase II trial investigated the role of interleukin (IL)-2 (12 x 106 IU/m2/day for 5 days, 4 weeks on/2 weeks off) in 14 previously treated patients with thymoma; no objective responses were reported (Gordon 1995).

6.3.2.2 Targeted therapies
6.3.2.2.1 EGFR inhibitors

The low frequency of EGFR activating mutations in thymic tumours explains rarely observed responses to EGFR inhibitors.
In a phase II trial with gefitinib (250 mg orally daily) on 26 pretreated patients with stage IV TETs, PR and SD were observed in 1 and 14 patients, respectively. No CR was reported. Median TTP was 4 months. None of the patients analysed had evidence of EGFR or KRAS mutations (Kurup 2005).
Another phase II trial studied the combination of erlotinib (150 mg PO daily) and bevacizumab (15 mg/kg intravenously every 3 weeks) in 18 chemorefractory patients with limited clinical benefit: no response was reported, whereas eleven patients achieved SD (Bedano 2008).
Cetuximab showed activity in two case reports of heavily pretreated recurrent T (Farina 2007; Palmieri 2007). A phase II trial is ongoing in order to evaluate cetuximab in combination with CAP regimen in unresectable thymomas (Huang J).

6.3.2.2.2 KIT inhibitors

Despite the high frequency of KIT IHC overexpression in TCs (80%), the rate of KIT mutations appears low.
Phase II trials with imatinib in B3 Ts and TCs based on KIT staining by IHC and not on genotyping were negative. Between known mutations, V560 deletions and L576P substitution are sensitive to imatinib (Ströbel 2004a). A small phase II trial evaluated imatinib (600 mg PO daily) in seven patients with TETs. Two patients had SD and five progressed. Median OS was 4 months, and median TTP was 2 months. KIT expression was found in one of four samples by IHC. No mutations were detected in the KIT or PDGFRA genes in three samples analysed. Authors concluded that imatinib has no major activity in this tumour; however, the small number of patients and no selection criteria might have affected the result (Giaccone 2009). A second trial investigated imatinib in eleven patients with pretreated, advanced, unresectable TC. IHC expression was confirmed for KIT in nine patients and PDGFR in two patients; no objective response was reported (Salter 2008).
Other known KIT mutations were: a L576P substitution; a D820E mutation, responding to sorafenib; an H697Y mutation in exon 14, with higher sensitivity to sunitinib than to imatinib in vitro; a P577-D579 deletion, responding to sorafenib; an Y553N mutation, responding to imatinib (Yoh 2008; Bisagni 2009; Girard 2009; Dişel 2011; Buti 2011).

6.3.2.2.3 IGFR inhibitors

IGF-1R overexpression in TETs has a poor prognostic value for OS and, in primary tumours, for TTP (Girard 2010; Zucali 2010). In a phase I, dose escalation study in patients with refractory solid tumours, the anti-IGF1-R monoclonal antibody figitumumab demonstrated clinical activity in a refreactory thymoma lasting more than 1 year (Haluska 2007).
A phase II trial is ongoing evaluating cixutumumab (IMC-A12), another anti-IGF-1R antibody, in advanced and refractory Ts and TCs following at least one platinum-containing chemotherapy treatment (Rajan). Preliminary data show that cixutumumab 20 mg/kg every 3 weeks is well tolerated (Rajan 2010). At present, no major signs of activity have been observed in TC, in which accrual has been halted, whereas major responses have been seen in patients with T, in which accrual is still ongoing.

6.3.2.2.4 Angiogenesis inhibitors

Despite VEGF and VEGFRs overexpression in TETs, limited data exist regarding the efficacy of angiogenesis inhibitors in these tumours.
A phase I trial (Isambert 2008) reports a PR to the combination of aflibercept, a soluble receptor that binds VEGF-A (also called VEGF trap) and docetaxel in a patient with T.
Multikinase inhibitors may also be of interest to target angiogenesis. Case reports have described evidence of the activity of sorafenib in patients with KIT gene mutation or IHC expressing tumour for KIT and p53 (Bisagni 2009; Li 2009).
In a recent phase II trial, 41 patients with chemo-refractory TETs were treated with sunitinib and have achieved 6 PR and 15 SD among 23 patients with TCs and, 1 PR and 12 SD among 16 Ts (Thomas 2015). A previously report had shown activity and efficacy in 4 patients treated with sunitinib with 3 PR (2 to 18 months) and one had prolonged SD (22 months), with OS ranging from 4 to 40 months (Ströbel 2010).
In a phase I trial of SU14813, a multitargeted tyrosine kinase inhibitor (VEGFRs, PDGFRs, KIT and FLT-3), four patients with T were treated and two had PRs with PFS of 15.3 and 9.0 months, respectively (Fiedler 2011).
As sunitinib and sorafenib, motesanib diphosphonate (AMG-706) a VEGFR-1/2/3 inhibitor, was reported to control the growth of an advanced T refractory to chemotherapy for 12 months (Azad 2009).
In a phase II trial, bevacizumab was tested in combination with erlotinib in 11 Ts and 7 TCs with no tumour response (Bedano 2008).
Interestingly, despite the large tumour burden of thymic tumours and the frequent abutment to mediastinal vascular structures, no haemorrhagic side effect has been reported with the use of these drugs.

6.3.2.2.5 Somatostatin (SST) receptors inhibitors

Octreotide, an octapeptide SST analogue with high affinity for SST2 subtype receptor, demonstrated inhibitory effect in thymic epithelial cells in vitro (Ferone 1999).
A case report showed a CR with resolution of PRCA in a patient treated with high-dosage octreotide (1.5 mg SC daily) plus prednisone (0.6 mg/kg/d) (Palmieri 1997). The report was followed by a phase II trial conducted through ECOG (Loehrer 2004) evaluating octreotide alone for two cycles and (if no objective response) in association with prednisone in patients with advanced, unresectable, octreotide scan-positive TETs. Thirty-eight patients (32 Ts, five TCs and one thymic carcinoid) received octreotide 0.5 mg subcutaneously three times daily for up to 1 year. Of 38 patients treated with octreotide alone, four (10.5%) had a PR. For the 21 patients in whom prednisone was added to octreotide, there were two CRs and six PRs noted. The ORR for all patients was 30.3%. 1- and 2-year survival rates were 86.6% and 75.7%, respectively. Eight patients had grade 4 or 5 toxicity including one death secondary to grade 5 infection without neutropenia.
An ongoing phase II trial is currently evaluating the effect of pasireotide (SOM230 LAR) in a dosage of 60 mg IM every 4 weeks in adult patients with inoperable or metastatic T (Schalke).

6.3.2.2.6 Histone deacetylase (HDAC) inhibitors

In a phase I study of belinostat (PXD101), a pan-HDAC inhibitor, a patient with thymoma had tumour reduction that lasted for 17 months on treatment. In phase II trial, belinostat (1 g/m2 on days 1 through 5 every 3 weeks) was administered to 41 patients (25 Ts and 16 TCs); two PRs (in 2 thymoma patients) were registered, wit 25 SD and 13 PD. TTP and OS were 174 days and 575 days, respectively. Treatment was well tolerated, with nausea, vomiting and fatigue as the major adverse effects (Steele 2008). An ongoing phase I/II trial is investigating belinostat in combination with CAP as first-line therapy of advanced or recurrent thymic malignancies (National Cancer Institute).

6.3.2.2.7 Trk A and CDK inhibitors

Oral milciclib maleate (PHA-848125-AC), an oral, potent inhibitor of the CDK2/cyclin. A complex and TrkA, demonstrated PRs in two of three patients with thymic malignancies (type B3 and type C) in phase I trial. Two phase II studies (Nerviano Medical Sciences(a) Nerviano Medical Sciences(b)) in advanced TETs are currently investigating the molecule in pretreated patients.

6.3.2.2.8 Src inhibitors

A phase II trial investigated saracatinib (AZD0530), a small-molecule inhibitor of Src, in patients with previously treated advanced thymic malignancies. A total of 21 patients (14 thymomas and seven TCs) received 175 mg of saracatinib daily. The trial was terminated because of lack of clinical activity (Wakelee 2010).

7. LATE SEQUELAE

Few studies have addressed recurrence rate as an outcome for thymic malignancies. OS has been the most commonly used end point; however, is not an ideal end point, because many patients die of unrelated causes, and patients may survive for many years with recurrent disease. Relapse rates for stages I, II and III are 3%, 16% and 26% respectively. Variable results are noted for stage IV. Ten-year OS and disease free survival (DFS) rates are of 90% and 94% for stage I; 70% and 88% for stage II; 55% and 56% for stage III; and 35% and 33% for stage IV, respectively (Venuta 1997). Local recurrence is more common. It usually presents as a pleural or pericardial nodule. Distant metastasis is usually found in lung, liver and bone. As previously said, factors associated with a lower rate of recurrence are Masaoka stages I and II, histological type (especially T versus TC), a complete resection and smaller tumours.

8. FOLLOW-UP

The duration of follow-up and time-table of visits has not been established; international guidelines recommend surveillance for recurrence with CT scan every 6 months for the first 2 years, then annually for 5 or 10 years in case of TC and T, respectively (type C evidence, standard treatment).

INDEX

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Dr. Rolando D’Angelillo (Author)
Radiation Oncology, Campus Bio-medico University, Rome (Italy)
mail: r.dangelillo@unicampus.it

Dr. Marina Chiara Garassino (Editor)
Struttura Semplice Oncologia Medica Toraco-Polmonare, Dipartimento Oncologia Medica,
Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan (Italy)
mail: marina.garassino@istitutotumori.mi.it

Dr. Gemma Gatta (Consultant)
Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan (Italy)
mail: gemma.gatta@istitutotumori.mi.it

Dr. Francesco Leo (Author)
Thoracic Surgery Service, Périgueux Hospital, Périgueux (France)
mail: francesco.leo@ch-perigueux.fr

Dr. Marta Scorsetti (Author)
Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center,
Rozzano (Milan, Italy)
mail: marta.scorsetti@humanitas.it

Dr. Danila Serpico (Associate Editor)
Struttura Semplice Oncologia Medica Toraco-Polmonare, Dipartimento Oncologia Medica,
Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan (Italy)
mail: danila.serpico@istitutotumori.mi.it

Dr. Paolo Zucali (Reviewer)
Humanitas Clinical and Research Center, Rozzano (Milan, Italy)
mail: paolo.zucali@cancercenter.humanitas.it