ESMO Guidelines Thymic Epithelial Tumours

clinical practice guidelines Annals of Oncology 26 (Supplement 5): v40–v55, 2015

doi:10.1093/annonc/mdv277

Thymic epithelial tumours: ESMO Clinical Practice

Guidelines for diagnosis, treatment and follow-up†
N. Girard1, E. Ruffini2, A. Marx3, C. Faivre-Finn4 & S. Peters5, on behalf of the ESMO Guidelines
Committee*
1
Department of Respiratory Medicine, Expert Centre for Thymic Malignancies, Reference Centre for Orphan Pulmonary Diseases, Hôpital Louis Pradel, Hospices Civils de
Lyon, Lyon, France; 2Department of Thoracic Surgery, University of Torino, Turin, Italy; 3Institute of Pathology, University Medical Centre Mannheim, University of
Heidelberg, Mannheim, Germany; 4Institute of Cancer Sciences, The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation
Trust, Manchester, UK; 5Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
incidence and epidemiology overall, even if a slight female preponderance has been reported
for type A, AB and B1 subtypes in most studies, and a male pre-
Thymic epithelial tumours represent a heterogeneous group of dominance in carcinomas [2–7].
rare thoracic cancers, with reported annual incidence ranging No environmental or infectious factors have been demon-
from 1.3 to 3.2 per million [1]. Thymic epithelial tumours are strated to play a role in the pathogenesis of thymic epithelial
classified according to the World Health Organization (WHO) tumours. Reports on development of thymoma after radiation,
histopathological classification, which distinguishes thymomas solid-organ transplantation and immunosuppression, including
from thymic carcinomas. the context of human immunodeficiency virus infection, are
clinical practice
rare; differential diagnosis with thymic rebound hyperplasia

guidelines
thymomas
may be discussed in this setting (see below).
Thymomas are further subdivided into different types (called Genetic risk factors, such as multiple endocrine neoplasia
A, AB, B1, B2, B3 and rare others) based upon the morphology of 1 (MEN1), may influence the development of thymomas, as well
epithelial tumour cells, the relative proportion of the non-tumoural as thymic carcinoids, given their reported familial occurrence as
lymphocytic component (decreasing from type B1 to B3) and well as their association with cancer susceptibility syndromes [8].
resemblance to normal thymic architecture (Table 1) [2, 3]. The Moreover, extrathymic haematopoietic cancers (mostly diffuse
term ‘benign thymoma’ should be avoided. Thymomas are far large B-cell lymphoma and leukaemia) and a broad spectrum of
more frequent than thymic carcinomas, which have an incidence solid cancers (stomach, pancreas, colon and thyroid) have been
of 0.2 to 0.5 per million [3]. reported to occur more frequently in thymoma patients, particu-
larly subsequently [9]. This might be related to a shared unknown
thymic carcinomas
oncogenic trigger, a thymoma-associated immune deficiency or
Thymic carcinomas are similar to their extrathymic counterpart, (less likely) to adverse effects of treatments.
the most frequent subtype being squamous cell carcinoma.
Neuroendocrine tumours may occur in the thymus, and will not
be discussed in these guidelines; while localised primary thymic diagnosis
neuroendocrine tumours may benefit from surgical resection,
similar to other thymic carcinomas, the prognosis is poor given imaging and laboratory tests
frequent recurrences; for recurrent, advanced and metastatic Standard imaging for thymic tumours is i.v. contrast-enhanced
tumours, the management actually follows that of extra-thoracic computed tomography (CT) scan of the thorax, allowing a com-
neuroendocrine tumours. plete exploration of the mediastinum and the pleura from the
apex to the costodiaphragmatic recesses [IV, A]. CT is equal or
epidemiology superior to magnetic resonance imaging (MRI) for the diagnosis
Mean age at diagnosis is 50–60 years of age, but thymic tumours of mediastinal anterior masses, except in the setting of cystic
may actually be diagnosed in children as well as in elderly lesions [IV, B] [10].
patients. There is no consistent gender predilection in thymomas One-third of patients with thymoma present with autoimmune
disorders (Table 2), mainly myasthenia gravis which is particular-
ly common in type AB, B1 and B2 thymomas and almost always
*Correspondence to: ESMO Guidelines Committee, ESMO Head Office, Via L. Taddei 4, associated with anti-acetylcholine receptor antibodies (Table 1)
CH-6962 Viganello-Lugano, Switzerland. [11]. Other frequent disorders include pure red cell aplasia (5% of
E-mail: [email protected]
cases) and hypogammaglobulinaemia (Good syndrome: 5% of
†
Approved by the ESMO Guidelines Committee: July 2015. cases) [12].
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/26/suppl_5/v40/344419

by F. Hoffmann-La Roche Ltd user
on 13 November 2017
Annals of Oncology clinical practice guidelines
Table 1. Histological subtypes of thymic epithelial tumours: relative frequency, frequency of myasthenia gravis and correlation with stage
Relative frequency Myasthenia gravis Masaoka stage
I II III IVA IVB
Type A 12% (3%–26%) 15% (0%–35%) 60% 31% 8% <1% <1%

Type AB 28% (15%–43%) 20% (5%–42%) 67% 26% 6% 1% 1%
Type B1 18% (6%–53%) 40% (5%–69%) 50% 37% 9% 3% 1%
Type B2 26% (8%–41%) 50% (23%–73%) 32% 29% 28% 8% 3%
Type B3 16% (3%–35%) 50% (25%–65%) 19% 36% 27% 15% 3%
Carcinoma 18% (1%–28%) <5% 10% 10% 45% 15% 20%
Data are based on references [5–8].
In addition to recording a complete history and conducting a Table 2. Autoimmune disorders associated with thymoma [11, 12]
full clinical examination (looking especially at neurological
signs), systematic immunological check-up is recommended Neuromuscular Myasthenia gravis
when a diagnosis of thymic epithelial tumour is suspected, in- Myotonic dystrophy
cluding complete blood cells count with reticulocytes and serum Limbic encephalitis
protein electrophoresis, as well as anti-acetylcholine receptor Peripheral neuropathy
and anti-nuclear antibodies tests [V, A]. Indeed, frequent Autonomic neuropathy
Acquired neuromyotonia
immune disorders associated with thymoma may impact the
Morvan syndrome (neuromyotonia and
course of all therapeutic interventions including surgery, radio-
encephalitis)
therapy as well as chemotherapy.
Stiff person syndrome
Cerebellar degeneration
diagnosis approach Polymyositis (carcinomas)
The diagnosis of any thymic epithelial tumour relies on making Haematological disorders Red cell aplasia
the differential diagnosis with other anterior mediastinal tumours Pernicious anaemia
and non-malignant thymic lesions [13]. CT is the imaging mo- Erythrocytosis
dality of choice. The need for pretreatment biopsy depends on Pancytopoenia
the resectability of the tumour [14–16]. Haemolytic anaemia
Thymic epithelial tumours are the most frequent cause of an- Leukaemia
terior mediastinal mass, accounting for 35% of cases; the most Multiple myeloma
relevant differential diagnoses include lymphomas (Hodgkin’s Collagen and autoimmune Systemic lupus erythematosus
or non-Hodgkin’s) in ∼25% of cases and germ-cell tumours disorders Rheumatoid arthritis
(teratoma or seminoma/non-seminomatous tumours) in ∼20% Sjogren’s syndrome
of cases [13]. Thymic carcinoma must be differentiated from Scleroderma
lung carcinoma, as well as from rarer entities, such as NUT car- Interstitial pneumonitis
cinomas [17].
Immune deficiency Hypogammaglobulinaemia (Good
Clinical judgement based on a complete history and physical,
disorders syndrome)
especially neurological, examination, correlated with laboratory T-cell deficiency syndrome
tests and radiological features, helps to develop a presumptive
diagnosis. Thymoma is the most likely diagnosis when facing a Endocrine disorders Multiple endocrine neoplasia
mediastinal mass associated with one of the above autoimmune Cushing’s syndrome
diseases, while thymic carcinoma patients typically have unspe- Thyroiditis
cific local symptoms [IV, A]. Lymphoma may be considered in Dermatological disorders Pemphigus
case of rapid onset of B-signs, coexistent lymphadenopathy or Lichen planus
elevated lactate dehydrogenase. Teratoma usually shows a het- Chronic mucosal candidiasis
erogeneous morphology on imaging, with fat and cystic pattern Alopecia areata
[18]. Seminomas and non-seminomatous germ-cell tumours may
Miscellaneous Giant cell myocarditis
be large and have a fulminant onset. Elevated serum β-human
Nephrotic syndrome
chorionic gonadotropin may be observed in seminomas, along
Ulcerative colitis
with elevated alphafetoprotein in non-seminomatous germ-cells
Hypertrophic osteoarthropathy
tumours.
Differentiating thymic malignancy from hyperplasia or
non-involuted thymus may be challenging. Thymic rebound corticosteroids. Thymic lymphoid hyperplasia is most common-
hyperplasia should be considered after stress, injuries, chemo- ly observed in myasthenia gravis, but also in the setting of
therapy, radiotherapy, anti-hormonal treatment or hyperthyroidism, connective tissue or vascular disease. CT
Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

on 13 November 2017
clinical practice guidelines Annals of Oncology
features include low-attenuation, symmetric and fatty pattern carcinoma component should always be mentioned first [V, C].
maintaining the bi-pyramidal shape of the thymus [18]. In In case of difficult diagnosis, it is recommended to consult a
equivocal cases at CT, chemical-shift MRI may detect microscop- second pathologist or refer the case to a thymic tumour path-
ic fatty infiltration by showing homogeneous signal decrease on ology panel.
opposed phase images relative to in-phase images, which is not
observed in thymoma [IV, B] [19]. Therapeutic intervention is
usually not required if the lesion is <30 mm, given a low risk of staging and risk assessment
progression or thymic malignancy [III, D] [20].
18-Fluorodeoxyglucose positron emission tomography (PET) staging
scan is generally not recommended to assess thymic masses [IV, C]. Thymic epithelial tumours are routinely staged according to the
Standard uptake values may be higher in type B3 thymomas Masaoka-Koga staging system (Table 3) [III, A] [25–27], which is
and thymic carcinomas; however, thymic hyperplasia may also correlated with overall survival (OS) [4, 28, 29]. Masaoka-Koga
present with hypermetabolism [21]. PET scan is optional in the staging is a surgical pathology system that is assessable only after
case of tumours with aggressive histology and an advanced stage surgical resection of the tumour. A typical feature of thymic epi-
to complete the staging work-up or further characterise lesions thelial tumours is the correlation between the WHO classification
suspicious for recurrences. and stage at diagnosis (Table 1), which may explain its reported
prognostic value [4–6] (Figures 1–3).
need for biopsy The International Association for the Study of Lung Cancer
(IASLC) Staging Prognostic Factors Committee, together with
Pretreatment biopsy is not required if the diagnosis of thymic the International Thymic Malignancy Interest Group (ITMIG),
tumour is highly probable and upfront surgical resection is recently proposed a Tumour–Node–Metastasis (TNM)-based
achievable (see below, definition of resectability) [IV, E]. Biopsy is staging system for thymic malignancies, based on OS analyses of
required in all other clinical situations [IV, A]: approaches may a retrospective international database of more than 10 000 cases
consist of percutaneous core-needle biopsy or incisional surgi- (Table 4) [30]. The TNM-based approach has the advantage of
cal biopsy through mediastinotomy or mini-thoracotomy, with being more appropriate both for thymoma and thymic carcin-
sensitivity rates ranging from 40% to 93% [22]. Biopsies that omas, which present with a higher propensity toward nodal and
are deep and multiple are preferred. Pleural spaces should be distant metastatic invasion. The IASLC/ITMIG TNM system of
respected to avoid tumour cell seeding. Fine-needle aspiration thymic tumours will be incorporated as the official thymic tumour
is generally not recommended [IV, D]. staging system into the 8th edition of the TNM staging system of
thoracic malignancies expected in 2016–2017. From our stand-
thymomas. Although designed for surgical resection specimens, point, the Masaoka-Koga staging should remain the standard for
the WHO classification may be used for small biopsies [V, A]. the routine management of patients, pending the approval of the
However, thymoma subtyping on small biopsies is usually not American Joint Committee on Cancer (AJCC) and Union for
needed for the therapeutically relevant distinction between International Cancer Control (UICC) [III, A]. Moreover, given the
lymphoma and solid tumour. In any case, diagnostic discrepancies major switch that the TNM system represents and the limited
between core-needle and resection specimen histology can be amount of fair level of evidence data to support our current treat-
anticipated, given the frequent occurrence of histological ment strategies (especially postoperative radiotherapy), the value of
tumour heterogeneity that may be missed due to sampling error the TNM system to drive the therapeutic strategy has to be assessed.
[23]. The recent proposal of major and minor morphological Correlative clinical data based on this system may be encouraged in
and immunohistochemical criteria to better individualise each a research setting.
thymic epithelial tumour entity aims at addressing those issues, The assessment of resectability is mostly based on the surgeon’s
and has been integrated in the revised WHO classification expertise; it is recommended to discuss indications for surgery in a
[3, 24]. Immunohistochemical markers may be helpful, multidisciplinary tumour board setting [V, B]. There is no recog-
including cytokeratins and p63 expression for normal and nised clinical staging system, and the treatment strategy for thymic
neoplastic epithelial cells, and terminal deoxynucleotidyl epithelial tumours is primarily based on whether the tumour may
transferase expression in immature T cells (usually observed be resected upfront or not [IV, A], as complete resection has been
in types AB, B1, B2 and B3 thymomas, and absent in identified as the most consistent and significant prognostic factor of
carcinomas and type A thymomas) [3]. disease-free survival and OS [5, 6, 29]. Correlation between clinical
and surgical pathology stage is higher in advanced stages, given the
thymic carcinomas. Immunohistochemistry with anti-CD117/ identification of vessel invasion, enlarged lymph nodes, pleural/
KIT and anti-CD5 antibodies helps to establish the thymic pericardial lesions or even systemic metastases [28]. Preoperative
origin in ∼80% of mediastinal carcinomas [V, A]. Since these CT findings reported to be associated with tumour invasiveness
markers are not absolutely specific, correlation with the clinical and/or completeness of resection include: tumour size (>5/7/8 cm,
setting is always recommended, and is mandatory in the subset depending on studies), lobulated or irregular contours, calcifica-
of 20% of thymic carcinomas without expression of CD117/KIT tions, infiltration of surrounding fat, lung infiltration, great vessel
and CD5 [3]. invasion or encirclement [31–33]. The new TNM staging may even
In thymic tumours showing more than one histological provide more help in formalising resectability: T1–3 level of inva-
pattern, each component should be listed (starting with the pre- sion refers to structures amenable to surgical resection, while T4
dominant one) and be quantified in 10% increments; a thymic level of invasion includes unresectable structures (Table 4).
v | Girard et al. Volume 26 | Supplement 5 | September 2015

on 13 November 2017
Annals of Oncology
Volume 26 | Supplement 5 | September 2015
Table 3. Staging of thymic epithelial tumours: Masaoka-Koga-based staging system [25, 26], International Thymic Malignancy Interest Group refinements [27] and overall survival and recurrence-free
survival (range)a [28]
Masaoka-Koga, 1994 International Thymic Malignancy Interest Group, 2011 10-year overall 10-year cumulative incidence
survival of recurrence
Thymoma Thymic carcinoma
Stage I Grossly and microscopically completely encapsulated tumour – Invasion into but not through the capsule 84% (81%–86%)
– In the absence of capsule, absence of invasion into
surrounding tissues
Stage IIA Microscopic transcapsular invasion – Microscopic transcapsular invasion (<3 mm) 83% (79%–87%) 8% (7%–8%) 25% (22%–29%)
Stage IIB Macroscopic invasion into thymic or surrounding fatty tissue, – Gross extension into normal thymus or perithymic fat
or grossly adherent to but not breaking through the surrounding the tumour (microscopically confirmed)
mediastinal pleura or pericardium – Adherence to pleura or pericardium, with microscopic
confirmation of perithymic invasion
Stage III Macroscopic invasion into neighbouring organ (i.e. – Microscopic invasion of the mediastinal pleura (either 70% (64%–75%) 29% (27%–31%) 59% (44%–76%)
pericardium, great vessel or lung) partial or penetrating the elastin layer)
– Microscopic invasion of the pericardium (either partial in
clinical practice guidelines

the fibrous layer or penetrating through to the serosal layer)
– Microscopically confirmed direct penetration into the outer
elastin layer of the visceral pleura or into the lung
parenchyma
– Invasion into the phrenic or vagus nerves (microscopically
confirmed)
– 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)
doi:10.1093/annonc/mdv277 | v
Stage IVA Pleural or pericardial metastasis – Microscopically confirmed separate nodules in the visceral 42% (26%–58%) 71% (34%–100%) 76% (58%–100%)
or parietal pleural, pericardial or epicardial surfaces
Stage IVB Lymphogenous or haematogenous metastasis – Lymphogenous or haematogenous metastasis 53% (32%–73%) 57% (24%–90%) 54% (37%–67%)
a
Information reprinted from [27] with permission of John Wiley & Sons, Inc.

on 13 November 2017
Figure 1. Treatment algorithm for resectable thymic tumour (Masaoka-Koga stage I–III, TNM stage I–IIIA).
risk assessment management of resectable disease

Prognostic assessment is challenging, as the impact of tumour The treatment strategy is based on the resectability of the tumour.
stage and histology on OS is superseded by the achievement of a If complete resection is deemed to be achievable upfront, as it is
complete resection in reported series [4–7, 28–30]. Moreover, the case in Masaoka-Koga stage I/II and some stage III tumours
depending on stage, up to 50%–60% of patients actually do not (classified as stage I, II, IIIA/T3 in the IASLC/ITMIG TNM pro-
die of progression of the thymic tumour [34]. Autoimmune posed system), surgery represents the first step of the treatment
disorders have been reported as the cause of death in 25% of [IV, A], possibly followed by postoperative radiotherapy and, less
thymomas, especially those with early-stage tumours. The evo- frequently, chemotherapy (Table 5).
lution of these alterations, which are related to the abnormal
intrathymomatous selection of constitutively autoreactive lym-
phocytes, does not parallel that of the tumour. This is contrary surgical principles
to what is observed in paraneoplastic syndromes that are The standard approach is median sternotomy [IV, A], which
caused by tumour cell-derived cytokines or hormones or by allows the wide opening of the mediastinum and both pleural
cross-reactive antibodies. The management of autoimmune cavities, followed by evaluation of macroscopic capsular inva-
syndromes will not be discussed in these guidelines, but should sion, infiltration of perithymic and mediastinal fat, peritumoural
be integrated in the oncological management of these patients and pleural adherences and involvement of surrounding struc-
[V, A]. tures [14, 15, 35, 36]. Generally, complete thymectomy
v | Girard et al. Volume 26 | Supplement 5 | September 2015

on 13 November 2017
Figure 2. Treatment algorithm for unresectable thymic tumour (Masaoka-Koga stage III–IVA, TNM stage IIIA–IIIB–IVA).
including the tumour, the residual thymus gland and perithymic areas are also designated on the resection specimen, as dis-
fat is preferred because local recurrences have been observed cussed below. Phrenic nerve preservation does not affect OS
after partial thymectomy when part of the thymus gland is left but increases the risk of local recurrence [IV, C], and should be
behind [IV, B]. Thymomectomy—leaving residual thymic tissue balanced with the achievement of a complete resection, espe-
and perithymic fat behind—alone is an option in stage I cially in patients with severe myasthenia gravis [38, 39]. Frozen
tumours in non-myasthenic patients [IV, C] [14, 37]. If the sections to assess tumour involvement of resection margins are
tumour is widely invasive (stage III/IV), en bloc removal of all not recommended [V, D], given the high risk of false-negative
affected structures, including lung parenchyma (usually through results [36].
limited resection), pericardium, great vessels, nerves and pleural Minimally invasive surgery is an option for presumed stage I
implants, should be carried out [IV, A]. Resection of venous and possibly stage II tumours in the hands of appropriately
vascular structures (innominate vein(s) and superior vena trained thoracic surgeons [IV, C] [14, 35, 40]. This includes
cava) include partial resection with suturing or complete resec- transcervical, extended transcervical, video-assisted thoraco-
tion and vessel reconstruction using vascular prosthesis. Areas scopy (VATS) and robotic approaches (right or left, right and
of uncertain resection margins are marked with clips to allow left, right and cervical, left and cervical, subxiphoid and right
precise delivery of postoperative radiotherapy [IV, B]; those and left, cervical and subxiphoid); robotic surgery may allow a
Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

on 13 November 2017
better visualisation of the tumour when compared with VATS. jeopardise or change the principles that are deemed appropri-
The choice for minimally invasive resection should not ate for an open approach, especially the achievement of com-
plete resection that may ultimately require switching to an
open procedure [V, A]. Minimally invasive surgery is not
recommended for stage III tumours, given the absence of long-
term follow-up data [IV, D].
Lymphadenectomy has historically rarely been carried out
after resection of thymic tumours. The new IASLC/ITMIG
TNM staging system of thymic tumours, however, leads to the
recommendation that locoregional lymphoadenectomy should
be carried out during resection of all types of thymic tumours. A
proposed nodal map is available from ITMIG [41]. The pro-
posed N descriptor in the staging system includes:
• anterior region (N1), which involves the anterior mediastinal
nodes ( prevascular, para-aortic, ascending aorta, superior and
inferior phrenic and supradiaphragmatic) and the anterior
cervical nodes (low anterior cervical); and
• the deep region (N2), which includes the middle mediastinal
(internal mammary, upper and lower paratracheal, subaortic,
subcarinal and hilar) and the deep cervical (lower jugular and
supraclavicular).
Routine removal of anterior mediastinal nodes and anterior cer-

vical nodes is recommended [IV, A]. Systematic sampling of
other intrathoracic sites is encouraged (i.e. paratracheal, aorto-
pulmonary window and subcarinal areas, depending on tumour
location) in stage III/IV tumours [V, B] [36]. Systematic lym-
Figure 3. Treatment algorithm for metastatic thymic tumour (Masaoka-
Koga stage IVB, TNM stage IVB).
phadenectomy (N1 + N2) is strongly recommended in case of
Table 4. Proposed Tumour–Node–Metastasis staging (International Association for the Study of Lung Cancer Prognostic Factors
Committee- International Thymic Malignancy Interest Group) [30] and corresponding Masaoka-Koga stage
Stage Descriptors
Tumour
T1 T1a Encapsulated or unencapsulated, with or without extension into the mediastinal fat
T1b Extension into the mediastinal pleura
T2 Direct invasion of the pericardium (partial or full-thickness)
T3 Direct invasion of the lung, the brachiocephalic vein, the superior vena cava, the chest wall, the phrenic nerve
and/or hilar (extrapericardial) pulmonary vessels
T4 Direct invasion of the aorta, arch vessels, the main pulmonary artery, the myocardium, the trachea or the
oesophagus
Node
N0 N0 No nodal involvement
N1 N1 Anterior (perithymic) nodes (IASLC levels 1, 3a, 6 and/or supradiaphragmatic/inferior phrenics/
pericardial)
N2 N2 Deep intrathoracic or cervical nodes (IASLC levels 2, 4, 5, 7, 10 and/or internal mammary nodes)
Metastasis
M0 No metastatic pleural, pericardial or distant sites
M1 M1a Separate pleural or pericardial nodule(s)
M1b Pulmonary intraparenchymal nodule or distant organ metastasis
Stage grouping Corresponding Masaoka-Koga stage
I T1N0M0 I, IIA, IIB, III

II T2N0M0 III
IIIA T3N0M0 III
IIIB T4N0M0 III
IVA T any N0,1 M0,1a IVA, IVB
IVB T any N0-2 M0-1b IVB
v | Girard et al. Volume 26 | Supplement 5 | September 2015

on 13 November 2017
Table 5. Stage-matched therapeutic strategy
Masaoka-Koga Thymoma Thymic carcinoma
stage
Stage I Upfront surgery [IV, A] Upfront surgery [IV, A]

No biopsy [IV, E] No biopsy [IV, E]
If complete resection (R0): no postoperative radiotherapy [II, E] If resection complete (R0): consider postoperative radiotherapy
If incomplete resection (R1): postoperative radiotherapy (45–50 Gy) [V, C]
(50–54 Gy) [IV, B] If incomplete resection (R1): postoperative radiotherapy
(50–54 Gy) [IV, B]
Stage IIA Upfront surgery [IV, A] Upfront surgery [IV, A]

If complete resection (R0): If complete resection (R0):
– Type A–B2: no postoperative radiotherapy [IV, C] – Consider postoperative radiotherapy (45–50 Gy) [IV, B]
– Type B3: consider postoperative radiotherapy If incomplete resection (R1):
(45–50 Gy) [IV, C] – Postoperative radiotherapy (50–54 Gy) [IV, B]
If incomplete resection (R1): – Consider postoperative chemotherapy
– Postoperative radiotherapy (50–54 Gy) [IV, B]
Stage IIB Upfront surgery [IV, A] Upfront surgery [IV, A]

If complete resection (R0): If complete resection (R0):
– Type A–B1: no postoperative radiotherapy [IV, C] – Consider postoperative radiotherapy (45–50 Gy) [IV, B]
– Type B2–B3: consider postoperative radiotherapy If incomplete resection (R1):
(45–50 Gy) [IV, C] – Postoperative radiotherapy (50–54 Gy) [IV, B]
If incomplete resection (R1): – Consider postoperative chemotherapy
– Postoperative radiotherapy (50–54 Gy) [IV, B]
Stage III–IVA Resectable tumour (TNM I–IIIA, i.e. T1–3): Resectable tumour (TNM I–IIIA, i.e. T1–3):
– Upfront surgery [IV, A] – Upfront surgery [IV, A]
– Postoperative radiotherapy (45–50 Gy), with boost on areas of – Postoperative radiotherapy (40–50 Gy), with boost on areas of
concern [IV, B] concern [IV, B]
Unresectable tumour (TNM IIIA-B, i.e. T3-T4, IVA): – Consider postoperative chemotherapy
– Biopsy Unresectable tumour (TNM IIIA-B, i.e. T3-T4, IVA):
– Primary chemotherapy (prefer anthracycline-based) [III, A] – Biopsy
– If the tumour becomes resectable: – Primary chemotherapy (prefer anthracycline-based) [III, A]
– Surgery [III, A] – If the tumour becomes resectable:
– Postoperative radiotherapy (45–50 Gy), with boost on areas – Surgery [III, A]
of concern (R0, R1 resection) [IV, B] – Postoperative radiotherapy (45–50 Gy), with boost on areas
– If the tumour remains unresectable or R2: of concern (R0, R1 resection) [IV, B]
– Definitive radiotherapy (60 Gy) [IV, B] – Consider postoperative chemotherapy (R0, R1 resection)
– Option: chemoradiotherapy – If the tumour remains unresectable or R2:
– Option: concurrent chemoradiotherapy (platin and etoposide, – Definitive radiotherapy (60 Gy) [IV, B]
60 Gy) [III, B] – Option: chemoradiotherapy
– Option: concurrent chemoradiotherapy (platin and etoposide,
60 Gy)
Stage IVB Definitive chemotherapy [III, A] Definitive chemotherapy [III, A]

– If the tumour becomes resectable, consider:
– Surgery and postoperative radiotherapy
– Definitive radiotherapy
thymic carcinoma due to the high rate of lymphatic spread (20% involved structures, organs or areas of likely residual microscopic
versus 3% in thymomas) [V, B]. or macroscopic disease are the primary responsibility of the oper-
ating surgeon, and may be done using a mediastinal board [V, B].
The final pathological examination leads to a final histological
surgical pathology principles diagnosis and staging of the tumour, based on the WHO classi-
Communication between surgeons and pathologists is required to fication and the Masaoka-Koga system, respectively (Tables 1
accurately stage thymic epithelial tumours [V, A] [36]. The and 3). Staging according to the proposed IASLC/ITMIG TNM
proper orientation of the specimen and the designation of system is optional [V, C]. Given the potential heterogeneity of
Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

on 13 November 2017
thymic epithelial tumours, a sufficient number of representative to define the target volume) [IV, B]; however, the optimal
sections should be examined regardless of the tumour diameter postoperative dose/fractionation is still to be defined; and
(at least five sections up to a diameter of 5 cm, with one add- • conventional fractionation scheme consisting of daily doses of
itional block per additional centimetre of maximal diameter); if 1.8–2 Gy over a 4- to 6-week period [IV, A] [48]. The field
the margin is <1 mm, at least three additional sections through may encompass involved nodes [IV, B] and the site of a
this area should be obtained [V, B]. Completeness of resection resected pleural implant [V, C].
should be assessed, making the distinction between tissues that
have been cut or dissected, and a surface bounded by a space Prophylactic irradiation of supraclavicular nodes is not recom-
(such the mediastinal pleura, pericardium or endothelium of the mended [V, E]. Low-dose entire hemithoracic radiotherapy is
innominate veins), which should not be designated as a positive also not recommended [IV, C] [49]. Ideally, postoperative radio-
margin [V, A]. therapy should start within 3 months of the surgical procedure
[V, B].
postoperative radiotherapy thymomas. Postoperative radiotherapy is not indicated after

Current practices for postoperative mediastinal radiotherapy are complete resection of Masaoka-Koga stage I thymoma [II, E]. One
highly variable and there is paucity of prospective, multicentre randomised trial including 29 patients compared postoperative
evidence. The global trend over the past years has been towards radiotherapy versus surgery alone in this setting, and failed to show
a less frequent use of postoperative radiotherapy in thymoma, any differences in patient outcome [50].
and to keep it in reserve for high-risk cases (Table 5) [14–16]. Postoperative radiotherapy is not recommended after com-
This is based on recent reports from large databases [6, 7, 42–45], plete resection of stage II thymoma [IV, C]. In the ITMIG data-
as well as pooled analyses of retrospective studies [46], indicating: base, cumulative incidence of mediastinal or extramediastinal
recurrence was only 8% at 10 years (Table 2) [28]. Postoperative
• the absence of survival benefit after radiotherapy in stage I radiotherapy may be considered in case of aggressive histology
thymoma, or after R0/1 resection of stage II–III thymoma (type B2, B3) or extensive transcapsular invasion (stage IIB) [IV,
[7, 42, 43]; C] [51–53].
• a similar rate of recurrence in patients who received post- Postoperative radiotherapy is recommended after complete
operative radiotherapy or not, after complete resection of resection of stage III/IVA thymoma, in an effort to prolong RFS
thymoma [46]; and and OS [IV, B] [54].
• a recurrence-free survival (RFS) and OS benefit with postoperative
radiotherapy after resection of thymic carcinoma [7, 44, 45].
thymic carcinoma. After complete resection of thymic carcinoma,
Stage and completeness of resection are thus the most relevant postoperative radiotherapy is optional for stage I tumours [V, C],
criteria in the decision making, followed by histology [IV, B]. should be considered for stage II tumours [IV, B] and is recom-
Those factors are the most significant predictors of RFS [4–7, mended for stage III/IVA tumours [IV, B] [7, 44, 45]. Postoperati-
28–29]; however, one must take into account that retrospective ve radiotherapy is recommended in case of microscopically
analyses are likely to be biased, since postoperative radiotherapy (R1) or macroscopically incomplete (R2) resection [IV, B], to a
is most likely administered in patients with incomplete resection total dose of 50–54 and 60 Gy, respectively, with a 10-Gy boost
or high-grade tumours. Therefore, the absence of survival differ- directed to areas of likely residual disease.
ences may then suggest that postoperative radiotherapy reduced
or overcame the risk of recurrence in those patients. Another postoperative chemotherapy
point to consider is that recurrences of thymic epithelial tumours thymomas. Postoperative chemotherapy is not recommended
occur outside the mediastinum in more than 60% of cases [47]. after R0–R1 resection of a thymoma [III, E] [6, 14–16, 55].
The development of the TNM system leads to redefinition of
subsets of patients, based especially on the T descriptors, that
thymic carcinomas. Since thymic carcinomas do present with
may help to clarify which patients benefit from postoperative
frequent and early locoregional and systemic recurrences after
radiotherapy. Meanwhile, the grouping of Masaoka-Koga stage I,
incomplete surgery [3, 7, 28, 44, 45], postoperative chemotherapy
IIA, IIB and some stage III tumours in one single T1 category
may be considered as an option in stage II/III/IV thymic
must be assessed in dedicated studies.
carcinomas, especially if not delivered as induction treatment
Current evidence for postoperative radiotherapy in thymic
(Table 5) [14–16].
epithelial tumours support the use of:
• 3D conformal radiotherapy or intensity-modulated radiation
therapy targeted to the tumour bed, keeping at-risk thoracic
management of advanced disease
organs within accepted safe constraints [IV, A];—clinical If complete resection is deemed not to be achievable upfront on
target volume includes the whole thymic space, the tumour the basis of imaging studies, as it is frequently the case in
and its extensions and the anterior, superior and middle Masaoka-Koga stage III/IVA tumours (classified as stage IIIA/
mediastinum [IV, A]. T3, IIIB/T4, /IVA in the IASLC/ITMIG TNM proposed system),
• a total dose of 45–50 Gy after complete resection, 50–54 Gy a biopsy should be carried out, followed by primary/induction
after R1 resection, with a boost to areas of likely residual chemotherapy as part of a curative-intent sequential strategy
disease (as mentioned above, surgical clips may then be useful that integrates subsequent surgery or radiotherapy [14–16].
v | Girard et al. Volume 26 | Supplement 5 | September 2015

on 13 November 2017
Table 6. Selected chemotherapy regimens for advanced thymic performance status or co-existing medical conditions—definitive
epithelial tumours assessed in phase II trials (adapted from [60] with radiotherapy is recommended as part of a sequential chemora-
permission of Informa Healthcare) diotherapy strategy [III, A] [56]. Combination with chemother-
Regimen Agents Doses apy (including cisplatin, etoposide chemotherapy and a total dose
of radiation of 60–66 Gy in 30–33 fractions) may be considered
ADOC Doxorubicin 40 mg/m2/3 weeks [V, C].
Cisplatin 50 mg/m2/3 weeks
Vincristine 0.6 mg/m2/3 weeks
Cyclophosphamide 700 mg/m2/3 weeks definitive chemotherapy
2 Chemotherapy should be offered as single modality treatment in
CAP Cisplatin 50 mg/m /3 weeks
Doxorubicin 50 mg/m2/3 weeks
advanced, non-resectable, non-irradiable or metastatic (stage
Cyclophosphamide 500 mg/m2/3 weeks IVB) thymic epithelial tumours. The aim is to relieve tumour-
related symptoms by eliciting tumour shrinkage, while pro-
PE Cisplatin 60 mg/m2/3 weeks longed survival is uncertain [III, A]. Cisplatin-based combin-
Etoposide 120 mg/m2 × 3 days/3 weeks ation regimens should be administered [III, A] (Table 6) [66–
VIP Etoposide 75 mg/m2 × 4 days/3 weeks 71]. No randomised studies have been conducted and which
Ifosfamide 1.2 g/m2 × 4 days/3 weeks regimen should be considered standard remains unknown.
Cisplatin 20 mg/m2 × 4 days/3 weeks Multiagent combination regimens and anthracycline-based regi-
mens appear to have improved response rates compared with
CODE Cisplatin 25 mg/m2/1 week
etoposide-based regimens [59, 60, 72]. Combination of cispla-
Vincristin 1 mg/m2/2 weeks
tin, doxorubicin and cyclophosphamide is preferred [III, B].
Doxorubicin 40 mg/m2/2 weeks
Combination of carboplatin and paclitaxel is an option for
Etoposide 80 mg/m2 × 3 days/2 weeks
thymic carcinoma [69, 71] [III, B]. Surgery or radiotherapy is
Carbo-Px Carboplatin AUC 5–6/3 weeks possible in rare and selected metastatic cases, without proven
Paclitaxel 200–225 mg/m2/3 weeks outcome benefit [IV, C].
Response Evaluation Criteria in Solid Tumours (RECIST)
CAP-GEM Capecitabine 650 mg/m2 b.i.d. 14 days/3 weeks
Gemcitabine 1000 mg/m2 × 2 days/3 weeks
v1.1 criteria should be used to assess response to chemotherapy
[V, A]; adapted criteria for pleural lesions include the use of the
short axis as the measurement plane and the unidimensional meas-
Patients not eligible for local treatment should receive palliative urement of two pleural tumour sites at three different levels [73].
chemotherapy only.
primary chemotherapy recurrences

Primary/induction chemotherapy is standard in non-resectable Recurrences of thymic epithelial tumours are not uncommon
advanced thymic epithelial tumours [III, A] [56–58]. Cisplatin- (∼10%–15% of all-stage resected tumours) and should be managed
based combination regimens should be administered; combinations according to the same strategy as newly diagnosed tumours [IV,
of cisplatin, doxorubicin and cyclophosphamide, and cisplatin A]. The average time-to-recurrence in completely resected thymic
and etoposide, are the recommended options (Table 6) [III, A] [59, tumours is 5 years (with a range of 3–7 years). Complete resection
60]. Primary chemoradiotherapy with platin and etoposide is an of recurrent lesions represents a major predictor of favourable
option, especially for thymic carcinomas [III, B] [33, 61]. outcome [74–76], and surgery is then recommended in the case
Usually, two to four cycles are administered before imaging is of resectable lesion. Of note, histological switch from lymphocytic
carried out to reassess resectability of the tumour [III, A]. Surgery lesions to more epithelial tumours has been reported, and may be
should be offered to patients for whom complete resection is related to tumour heterogeneity, as well as the effect of previous
deemed achievable, according to principles discussed above [III, A]; corticosteroid and chemotherapy treatment [74].
extended resection may be required [62]. Hyperthermic intra- In non-resectable recurrences, several consecutive lines of
pleural chemotherapy, as well as extra-pleural pneumonectomy, chemotherapy may be administered when the patient presents
may be discussed in case of stage IVA tumour [IV, C] [63, 64]. with tumour progression (Table 6). The re-administration of a
Postoperative radiotherapy delivery should follow. previously effective regimen should be considered [IV, B], espe-
Subtotal resection, so-called debulking resection, is an option cially in case of previous response, late occurring recurrence
in selected cases of thymoma, aiming at facilitating subsequent and, for anthracyclines, a patient in a good medical condition
definitive radiotherapy [IV, C] [65]. Debulking is not recom- who has not received cumulative doses precluding the safe deliv-
mended in thymic carcinoma [V, D]. Postoperative chemora- ery of at least three additional cycles [77]. Of note, the risk of
diotherapy (including cisplatin, etoposide chemotherapy and a cardiac toxicity is further increased in patients having received
total dose of radiation of 60 Gy in 30 fractions) may be consid- previous mediastinal radiotherapy. Participation to clinical trials
ered after debulking/R2 resection [IV, B]. is recommended.
Preferred regimens for second-line treatment include carbo-
definitive radiotherapy platin plus paclitaxel [69], and platin plus etoposide [67] [III,
If the patient is not deemed a surgical candidate—either because B]; capecitabine plus gemcitabine is an option (Table 6) [III, B].
R0 resection is not thought to be achievable, or because of poor These regimens were evaluated in dedicated phase II trials.
Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

on 13 November 2017
Table 7. Summary of recommendations
Diagnosis
– Thymic epithelial tumours are classified according to the WHO histopathological classification.
– Although designed for surgical resection specimen, the WHO classification may be used for small biopsies [V, A].
– Immunohistochemistry with anti-CD117/KIT and anti-CD5 antibodies is useful to establish the thymic primary nature of a mediastinal carcinoma [V, A].
– Each component of heterogeneous tumours may be quantified by 10% increments [V, C].
– Consultation with a second pathologist or referral of the case to a thymic tumour pathology panel is recommended whenever there is any diagnostic difficulty.
– Oncogenetic assessment should be carried out in case of familial thymic epithelial tumour, looking especially at MEN1.
Imaging and diagnostic tests
– Thymoma is the first diagnosis to consider when facing a mediastinal mass associated with autoimmune disease [IV, A].
– The diagnosis of any thymic epithelial tumour relies on making the differential diagnosis with other anterior mediastinal tumours and non-malignant
thymic lesions.
– Standard imaging for thymic tumours is i.v. contrast-enhanced (CT) scan of the thorax [IV, A].
– MRI is recommended to differentiate thymic tumour from hyperplasia whenever CT scan is doubtful, or in case of cystic lesion [IV, B].
– PET scan is generally not recommended to assess thymic masses [IV, C].
– Therapeutic intervention is usually not required if the lesion is <30 mm, given a low risk of progression or thymic malignancy [III, D].
– Systematic immunological check-up is recommended, including complete blood cells count with reticulocytes and serum protein electrophoresis, as well as
anti-acetylcholine receptor and anti-nuclear antibodies tests [V, A].
Need for a biopsy
– Pretreatment biopsy is not required if the diagnosis of thymic epithelial tumour is highly suspected and upfront surgical resection is achievable [IV, E].
– Biopsy is required in all other clinical situations [IV, A]; approaches may consist of percutaneous core-needle biopsy or incisional surgical biopsy through
mediastinotomy or mini-thoracotomy. Fine-needle aspiration is not recommended [IV, D].
Staging
– Thymic epithelial tumours are routinely staged according to the Masaoka-Koga staging system [III, A]. Masaoka-Koga staging is a surgical pathology
system that is assessable only after surgical resection of the tumour.
– Staging according to proposed IASLC/ITMIG TNM system is optional [V, C].
– The Masaoka-Koga staging system should remain the standard for the routine management of patients, pending the approval of the AJCC and UICC [III, A].
Risk assessment
– The management of autoimmune syndromes should be integrated in the oncological management of these patients [V, A].
Management of resectable disease
– The treatment strategy for thymic epithelial tumour is primarily based on whether the tumour may be resected upfront or not [IV, A].
– The assessment of resectability is mostly based on the surgeon’s expertise; it is recommended to discuss indications for surgery in a multidisciplinary
tumour board setting [V, B].
– If complete resection is deemed to be achievable upfront, surgery represents the first step of the treatment [IV, A].
Surgery principles
– Standard approach is median sternotomy [IV, A].

– Complete thymectomy including the tumour, the residual thymus gland and perithymic fat, is preferred [IV, B].
– Thymomectomy alone—leaving residual thymic tissue and perithymic fat behind—is an option in stage I tumours in non-myasthenic patients [IV, C].
– If the tumour is widely extensive invasive (stage III/IV), en bloc removal of all affected structures, including lung parenchyma (usually through limited
resection), pericardium, venous great vessels, nerves and pleural implants, should be carried out [IV, A].
– Areas of uncertain margins are marked with clips to allow precise delivery of postoperative radiotherapy [IV, B]: those areas are also designated on the
resection specimen.
– Phrenic nerve preservation does not affect OS but increases the risk of local recurrence [IV, C].
– Frozen sections to assess tumour involvement of resection margins are not recommended [V, D].
– Minimally invasive surgery is an option for presumed stage I–II tumours in the hands of appropriately trained thoracic surgeons [IV, C].
– The choice for minimally invasive resection should not jeopardise or change the principles that are deemed appropriate for an open approach, especially
the achievement of complete resection that may ultimately require switching to an open procedure [V, A].
– Minimally invasive surgery is not recommended for stage III tumours, given the absence of long-term follow-up data [IV, D].
– Routine removal of anterior mediastinal and anterior cervical nodes is recommended [IV, A].
– Systematic sampling of intrathoracic sites is encouraged in stage III/IV tumours [V, B].
– Systematic lymphadenectomy (N1 + N2) is strongly recommended in case of thymic carcinoma due to the high rate of lymphatic spread [V, B].
Continued
v | Girard et al. Volume 26 | Supplement 5 | September 2015

on 13 November 2017
Table 7. Continued
Surgical pathology principles
– Communication between surgeons and pathologists is required to accurately stage thymic epithelial tumours [V, A].
– The proper orientation of the specimen and the designation of involved structures, organs or areas of likely residual microscopic or macroscopic disease are
the primary responsibility of the operating surgeon and may be done using a mediastinal board [V, B].
– A sufficient number of representative sections should be examined regardless of the tumour diameter; if the margin is <1 mm, at least three additional
sections through this area should be obtained [V, B].
– Completeness of resection should be assessed, making the distinction between tissues that have been cut or dissected, and a surface bounded by a space,
which should not be designated as a positive margin [V, A].
Postoperative radiotherapy
– Postoperative radiotherapy should start within 3 months of the surgical procedure [V, B].
– The use of 3D conformal radiotherapy or intensity-modulated radiation therapy targeted to the tumour bed is recommended [IV, A].
– Clinical target volume includes the whole thymic space, the tumour and its extensions and the anterior, superior and middle mediastinum [IV, A].
– Standard dose constraints for thoracic radiotherapy should be used.
– Total dose of 45–50 Gy after complete resection, 50–54 Gy after R1 resection, with a boost to areas of likely residual disease are recommended (surgical
clips may then be useful to define the target volume) [IV, B].
– The use of a conventional fractionation scheme is recommended in daily doses from 1.8 to 2 Gy over a 4- to 6-week period [IV, A].
– The field may encompass involved nodes [IV, B], and the site of a resected pleural implant [V, C].
– Prophylactic irradiation of supraclavicular nodes is not recommended [V, E].
– Low-dose entire hemithoracic radiotherapy is not recommended [IV, C].
– After complete resection of thymoma:
• Postoperative radiotherapy is not indicated after complete resection of Masaoka-Koga stage I thymoma [II, E].
• Postoperative radiotherapy is not recommended after complete resection of stage II thymoma [IV, C], but may be considered in case of aggressive
histology (type B2, B3) or transcapsular invasion (stage IIB) [IV, C].
• Postoperative radiotherapy is recommended after complete resection of stage III/IVA thymoma [IV, B].
– After complete resection of thymic carcinoma:
• postoperative radiotherapy is optional for stage I tumours [V, C],
• it should be considered for stage II tumours [IV, B] and
• it is recommended for stage III/IVA tumours [IV, B].
– Postoperative radiotherapy is recommended in case of microscopically (R1) or macroscopically incomplete (R2) resection [IV, B], to a total dose of 50–54
and 60 Gy, respectively, with a 10-Gy boost to areas of likely residual disease.
Postoperative chemotherapy
– Postoperative chemotherapy is not recommended after R0–R1 resection of a thymoma [III, E].
– Postoperative chemotherapy may be considered as an option in stage II/III/IV thymic carcinomas, especially if not delivered as induction treatment.
Management of advanced disease
– If complete resection is deemed not to be achievable upfront, primary/induction chemotherapy is administered, part of curative-intent sequential strategy
integrating subsequent surgery or radiotherapy. Cases not eligible for local treatment receive palliative chemotherapy only.
Primary/induction chemotherapy
– Primary/induction chemotherapy is the standard in non-resectable locally advanced thymic epithelial tumours [III, A].
– Cisplatin-based combination regimens should be administered; combinations of cisplatin, doxorubicin and cyclophosphamide, and cisplatin and etoposide
are recommended options [III, A].
– Primary chemoradiotherapy with platin and etoposide chemotherapy is an option for thymic carcinomas [III, B].
– Usually, two to four cycles are administered before imaging is carried out to reassess resectability of the tumour [III, A].
– Surgery should be offered to patients for whom complete resection is deemed achievable after primary chemotherapy, according to principles discussed in
the text [III, A].
– Hyperthermic intrapleural chemotherapy, as well as extra-pleural pneumonectomy, may be discussed in case of stage IVA tumour [IV, C].
– Postoperative radiotherapy is recommended.
– Subtotal resection, so-called debulking resection, is an option in selected cases of thymoma, aiming at facilitating subsequent definitive radiotherapy [IV, C].
– Debulking is not recommended in thymic carcinoma [V, D].
– Postoperative chemoradiotherapy (including cisplatin, etoposide chemotherapy and a total dose of radiation of 60 Gy) may be considered after debulking/
R2 resection [IV, B].
Definitive radiotherapy
– When the patient is not deemed to be a surgical candidate, definitive radiotherapy is recommended as part of a sequential chemoradiotherapy strategy [III, A].
– Combination with chemotherapy (including cisplatin, etoposide chemotherapy and a total dose of radiation of 60–66 Gy) may be considered [V, C].
Continued
Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

on 13 November 2017
Table 7. Continued
Definitive chemotherapy
– Chemotherapy should be offered as the single modality treatment in advanced, non-resectable, non-irradiable or metastatic (stage IVB) thymic epithelial
tumour [III, A].
– Cisplatin-based multiagent combination regimens should be administered [III, A].
– Combination of cisplatin, doxorubicin and cyclophosphamide is preferred [III, B].
– Combination of carboplatin and paclitaxel is an option for thymic carcinoma [III, B].
– Surgery or radiotherapy is possible in rare and selected metastatic cases without proven outcome benefit [IV, C].
– RECIST v1.1 criteria should be used to assess response to chemotherapy [V, A].
Recurrences
– Recurrences of thymic epithelial tumours should be managed according to the same strategy as newly diagnosed tumours [IV, A].
– Complete resection of recurrent lesions, when achievable, is recommended.
– Several consecutive lines of chemotherapy may be administered when the patient presents with tumour progression. The re-administration of a previously
effective regimen should be considered [IV, B].
– Preferred regimens for second-line treatment include carboplatin plus paclitaxel, and platin plus etoposide [III, B]; capecitabine plus gemcitabine is an
option [III, B].
– Options for subsequent lines include pemetrexed [III, B] and oral etoposide.
– In patients with octreoscan-positive thymoma not eligible to receive additional chemotherapy, octreotide alone or with prednisone may represent a
valuable option [III, B].
Targeted agents
– KIT sequencing (exons 9–17) is an option for refractory thymic carcinomas in the setting of potential access to specific inhibitors, particularly in the
context of clinical trials [IV, B].
– It is not recommended to administer imatinib in the absence of a KIT-sensitising mutation [III, E].
– Sunitinib is an option as second-line treatment of thymic carcinomas independently from KIT status [III, A].
– Everolimus may represent an option for refractory tumours [III, B].
Follow-up
– Baseline thoracic CT scan should be carried out 3–4 months after surgery [V, C].
– For completely resected stage I/II thymomas: CT scan should be done every year for 5 years, then every 2 years [V, C].
– For stage III/IV thymomas, thymic carcinoma or after R1–2 resection: CT scan should be done every 6 months for 2 years, then annually [V, C].
– Follow-up may be continued for 10–15 years [V, C].
– Patients with clinical myasthenia gravis, or even isolated positive anti-acetyl choline receptor antibodies, should be informed and educated about the risks
of myasthenic crisis in specific situations such as stress or the administration of certain drugs [V, A].
WHO, World Health Organization; MEN1, multiple endocrine neoplasia 1; CT, computed tomography; MRI, magnetic resonance imaging; PET scan,
positron emission tomography scan; AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; OS, overall survival;
RECIST, Response Evaluation Criteria in Solid Tumours; IASLC, International Association for the Study of Lung Cancer; ITMIG, International Thymic
Malignancy Interest Group; TNM, tumour node metastasis.
Options for subsequent lines include pemetrexed [78] [III, B] or predictive value. However, the recent identification of mo-
and oral etoposide. In patients with octreoscan-positive thymoma lecular alterations occurring in the KIT, vascular endothelial
not eligible to receive additional chemotherapy, octreotide alone or growth factor receptors (VEGFRs) and mammalian target of
with prednisone may represent a valuable option [III, B] [79, 80]. rapamycin (mTOR) signalling pathways, may lead to consider-
ation—in an off-label setting—of the use of targeted agents for
the treatment of refractory thymic malignancies.
personalised medicine
Molecular characterisation of thymic epithelial tumours indi- targeting of KIT
cates the occurrence of chromosomal aberrations, altered DNA While KIT is overexpressed in 80% of thymic carcinomas, KIT
methylation and deregulated expression of cancer-related genes, gene mutations are found only in 9% of cases, consisting of
such as CDKN2, MGMT, FOXC1, IGF-1R [81]; some of those mutations observed in gastrointestinal stromal tumours or mela-
alterations and gene expression signatures were reported to asso- nomas (V560del, L576P), or restricted to thymic carcinomas
ciate preclinically with the efficacy of some targeted agents, or to (H697Y, D820E) [81]. Responses were reported with the use of
predict recurrence or survival of patients [81, 82]. KIT tyrosine kinase inhibitors (TKIs) imatinib, sunitinib or sor-
Personalised medicine approaches in thymic malignancies are afenib, mostly in single-case observations [59]. KIT-mutant
ultimately hampered by the limited amount of available research tumours are not uniformly sensitive to imatinib, based on the
to identify reliable, validated molecular markers with prognostic clinical and/or the preclinical evidence in thymic carcinoma
v | Girard et al. Volume 26 | Supplement 5 | September 2015

on 13 November 2017
and/or other KIT-mutant malignancies. KIT sequencing (exons [87]. Everolimus was evaluated in thymic epithelial tumours in
9–17) is an option for refractory thymic carcinomas in the a recently reported phase II trial reporting on a 22% response
setting of potential access to such inhibitors, particularly in the rate, as well as a 93% DCR [88]. Everolimus may, therefore, re-
context of clinical trials [IV, B]. present an off-label option for refractory tumours [III, B].
It is not recommended to administer imatinib in the absence
of a KIT-sensitising mutation, following the report showing the
absence of activity in two phase II trials conducted in this follow-up and long-term implications
setting [III, E] [83, 84]. No prospective data are available to build recommendations
The use of KIT inhibitors is off-label in thymic malignancies. about post-treatment oncological follow-up of patients. While a
relapse might still be treatable in a curative-intent, patients should
targeting of angiogenesis benefit from a regular radiological assessment. Based on expert
Available KIT TKIs also potently inhibit other kinases, including consensus, and data of cumulative incidence of recurrences over
VEGFRs and platelet-derived growth factor receptors activated in time [28], the proposals are the following [V, C]:
thymic malignancies [85, 86]. A phase II trial recently demon- • baseline thoracic CT scan 3–4 months after surgery
strated the efficacy of sunitinib in terms of response and disease • for completely resected stage I/II thymomas: CT scan every
control rate (DCR) in thymic epithelial tumours, including thymic year for 5 years, then every 2 years
carcinomas [objective response rate (ORR) 26%; DCR: 91%] and, • for stage III/IV thymomas, thymic carcinoma or after R1–2
to a lesser extent, thymomas (ORR: 6%; DCR: 81%) [82]. resection: CT scan every 6 months for 2 years, then annually
Sunitinib may then represent an off-label option as second-line • continuation of follow-up for 10–15 years
treatment of thymic carcinomas, independently from KIT status
[III, A]. There is no reliable clinical data reporting on anti-tumour Secondary tumours may occur. Besides oncological follow-up,
efficacy of other anti-angiogenic drugs, including aflibercept and clinicians should be aware of the possible late onset of new auto-
bevacizumab. immune disorders. Patients with clinical myasthenia gravis, or
even isolated positive anti-acetyl choline receptor antibodies,
targeting mammalian target of rapamycin should be informed and educated about the risks of myasthenic
mTOR is emerging as a potential target in thymic epithelial crisis in specific situations such as stress or the administration of
tumours, following tumour responses observed in phase I trials certain drugs [V, A].
Participation in collaborative research initiatives, including
Table 8. Levels of evidence and grades of recommendation regional and international databases, and clinical trials when
(adapted from the Infectious Diseases Society of America-United available, is recommended.
States Public Health Service Grading Systema)
Levels of evidence methodology
I Evidence from at least one large randomised, controlled trial These clinical practice guidelines were developed in accordance
of good methodological quality (low potential for bias) or with the ESMO standard operating procedures for clinical prac-
meta-analyses of well-conducted randomised trials without tice guidelines development. The relevant literature has been
heterogeneity selected by the expert authors, using the Medline database, as
II Small randomised trials or large randomised trials with a well as abstracts lists from major surgery, medical oncology and
suspicion of bias (lower methodological quality) or meta- thoracic oncology meetings, over the past 20 years. A summary
analyses of such trials or of trials with demonstrated of recommendations is presented in Table 7. Levels of evidence
heterogeneity and grades of recommendation have been applied using the
III Prospective cohort studies
system shown in Table 8 [89]. Statements without grading were
IV Retrospective cohort studies or case–control studies
considered justified standard clinical practice by the experts and
V Studies without control group, case reports, experts opinions
the ESMO faculty. This manuscript has been subjected to an an-
Grades of recommendation onymous peer review process.
A Strong evidence for efficacy with a substantial clinical benefit,
strongly recommended acknowledgements
B Strong or moderate evidence for efficacy but with a limited
clinical benefit, generally recommended The authors thank Benjamin Besse (Gustave Roussy, Villejuif,
C Insufficient evidence for efficacy or benefit does not outweigh France) for reviewing the manuscript. NG thanks all investiga-
the risk or the disadvantages (adverse events, costs, …), tors of the RYTHMIC network for their input on the French
optional recommendations, which was valuable for the subsequent devel-
D Moderate evidence against efficacy or for adverse outcome, opment of the present clinical practice guidelines.
generally not recommended
E Strong evidence against efficacy or for adverse outcome, never
conflict of interest
recommended
NG has reported consultancy from Amgen, Astra-Zeneca, Bristol-
a
By permission of the Infectious Diseases Society of America [89]. Myers Squibb, Boehringer Ingelheim, Eli-Lilly, Hoffmann-La
Roche, Novartis, Pfizer, Teva. SP has provided consultancy, attended
Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

on 13 November 2017
advisory boards and/or provided lectures for: F. Hoffmann-La 21. Kaira K, Endo M, Abe M et al. Biologic correlation of 2-[18F]-fluoro-2-deoxy-D-
Roche, Ltd, Eli-Lilly and Company Oncology, Astra-Zeneca, glucose uptake on positron emission tomography in thymic epithelial tumors. J
Clin Oncol 2010; 28: 3746–3753.
Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-
22. Marchevsky A, Marx A, Ströbel P et al. Policies and reporting guidelines for small
Sankyo, Morphotek, Merrimack, Merck Serono, MSD, Amgen,
biopsy specimens of mediastinal masses. J Thorac Oncol 2011; 6(Suppl 3):
Clovis, Astellas and Tesaro. The other authors have declared no S1724–S1729.
potential conflicts of interest. 23. Wang H, Sima CS, Beasley MB et al. Classification of thymic epithelial neoplasms
is still a challenge to thoracic pathologists: a reproducibility study using digital
microscopy. Arch Pathol Lab Med 2014; 138: 658–663.
24. den Bakker MA, Roden AC, Marx A, Marino M. Histologic classification of thymoma:
references a practical guide for routine cases. J Thorac Oncol 2014; 9(Suppl 2): S125–S130.
1. de Jong WK, Blaauwgeers JL, Schaapveld M et al. Thymic epithelial tumours: a 25. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with
population-based study of the incidence, diagnostic procedures and therapy. Eur J special reference to their clinical stages. Cancer 1981; 48: 2485–2492.
Cancer 2008; 44: 123–130. 26. Koga K, Matsuno Y, Noguchi M et al. A review of 79 thymomas: modification of
2. Travis WB, Brambilla A, Muller-Hermelinck HK, Marx A. Pathology and genetics of staging system and reappraisal of conventional division into invasive and non-
tumours of the lung, pleura, thymus and heart. In: Travis WB (ed), World Health invasive thymoma. Pathol Int 1994; 44: 359–367.
Organization Classification of Tumours. Lyon: IARC Press 2004; p. 146. 27. Detterbeck FC, Nicholson AG, Kondo K et al. The Masaoka-Koga stage
3. Marx A, Ströbel P, Badve SS et al. ITMIG consensus statement on the use of the classification for thymic malignancies: clarification and definition of terms. J
WHO histological classification of thymoma and thymic carcinoma: refined Thorac Oncol 2011; 6(Suppl 3): S1710–S1716.
definitions, histological criteria, and reporting. J Thorac Oncol 2014; 9: 596–611. 28. Detterbeck F. Towards a TNM based prognostic classification for thymic tumours.
4. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 J Thorac Oncol 2013; 8(Suppl 2): S68 (abst. MS16.2).
patients from Japan. Ann Thorac Surg 2003; 76: 878–884. 29. Detterbeck F, Youssef S, Ruffini E, Okumura M. A review of prognostic factors in
5. Weis CA, Yao X, Deng Y et al. The impact of thymoma histotype on prognosis in a thymic malignancies. J Thorac Oncol 2011; 6(Suppl 3): S1698–S1704.
worldwide database. J Thorac Oncol 2015; 10: 367–372. 30. Detterbeck FC, Stratton K, Giroux D et al. The IASLC/ITMIG Thymic Epithelial
6. Ruffini E, Detterbeck F, Van Raemdonck D et al. Tumours of the thymus: a cohort Tumors Staging Project: proposal for an evidence-based stage classification
study of prognostic factors from the European Society of Thoracic Surgeons system for the forthcoming (8th) edition of the TNM classification of malignant
database. Eur J Cardiothorac Surg 2014; 46: 361–368. tumors. J Thorac Oncol 2014; 9(Suppl 2): S65–S72.
7. Omasa M, Date H, Sozu T et al. Postoperative radiotherapy is effective for thymic 31. Marom EM, Milito MA, Moran CA et al. Computed tomography findings predicting
carcinoma but not for thymoma in stage II and III thymic epithelial tumors: The Japanese invasiveness of thymoma. J Thorac Oncol 2011; 6: 1274–1281.
Association for Research on the Thymus Database Study. Cancer 2015; 121: 32. Zhao Y, Chen H, Shi J et al. The correlation of morphological features of chest
1008–1016. computed tomographic scans with clinical characteristics of thymoma. Eur J
8. Kojima Y, Ito H, Hasegawa S et al. Resected invasive thymoma with multiple Cardiothorac Surg 2014 [Epub ahead of print].
endocrine neoplasia type 1. Jpn J Thorac Cardiovasc Surg 2006; 54: 171–173. 33. Korst RJ, Bezjak A, Blackmon S et al. Neoadjuvant chemoradiotherapy for locally
9. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac
patterns in incidence and associations with subsequent malignancies. Int J Cancer Cardiovasc Surg 2014; 147: 36–44.
2003; 105: 546–551. 34. Huang J, Detterbeck FC, Wang Z, Loehrer PJ, Sr. Standard outcome measures for
10. Seki S, Koyama H, Ohno Y et al. Diffusion-weighted MR imaging vs. multi-detector thymic malignancies. J Thorac Oncol 2011; 6(Suppl 3): S1691–S1697.
row CT: direct comparison of capability for assessment of management needs for 35. Davenport E, Malthaner RA. The role of surgery in the management of thymoma: a
anterior mediastinal solitary tumors. Eur J Radiol 2014; 83: 835–842. systematic review. Ann Thorac Surg 2008; 86: 673–684.
11. Evoli A, Lancaster E. Paraneoplastic disorders in thymoma patients. J Thorac 36. Detterbeck FC, Moran C, Huang J et al. Which way is up? Policies and procedures
Oncol 2014; 9(Suppl 2): S143–S147. for surgeons and pathologists regarding resection specimens of thymic
12. Marx A, Hohenberger P, Hoffmann H et al. The autoimmune regulator AIRE in malignancy. J Thoracic Oncol 2011; 6(Suppl 3): S1730–S1738.
thymoma biology: autoimmunity and beyond. J Thorac Oncol 2010; 5(Suppl 4): 37. Nakagawa K, Asamura H, Sakurai H et al. Does the mode of surgical resection
S266–S272. affect the prognosis/recurrence in patients with thymoma? J Surg Oncol 2014;
13. Carter BW, Marom EM, Detterbeck FC. Approaching the patient with an anterior 109: 179–183.
mediastinal mass: a guide for clinicians. J Thorac Oncol 2014; 9(Suppl 2): 38. Yano M, Sasaki H, Moriyama S et al. Preservation of phrenic nerve involved by
S102–S109. stage III thymoma. Ann Thorac Surg 2010; 89: 1612–1619.
14. Falkson CB, Bezjak A, Darling G et al. The management of thymoma: a systematic 39. Hamdi S, Mercier O, Fadel E et al. Is sacrifying the phrenic nerve during thymoma
review and practice guideline. J Thorac Oncol 2009; 4: 911–919. resection worthwhile? Eur J Cardiothorac Surg 2014; 45: e151–e155.
15. Girard N, Mornex F, Van Houtte P et al. Thymoma: a focus on current therapeutic 40. Toker A, Sonett J, Zielinski M et al. Standard terms, definitions, and policies for
management. J Thorac Oncol 2009; 4: 119–126. minimally invasive resection of thymoma. J Thorac Oncol 2011; 6(Suppl 3):
16. NCCN Clinical Practice Guidelines in Oncology. Thymic malignancies. V.1.2015. S1739–S1742.
www.nccn.org (7 July 2015, date last accessed). 41. Bhora FY, Chen DJ, Detterbeck FC et al. The ITMIG/IASLC Thymic Epithelial
17. Evans AG, French CA, Cameron MJ et al. Pathologic characteristics of NUT Tumors Staging Project: a Proposed Lymph Node Map for Thymic Epithelial
midline carcinoma arising in the mediastinum. Am J Surg Pathol 2012; 36: Tumors in the Forthcoming 8th Edition of the TNM Classification of Malignant
1222–1227. Tumors. J Thorac Oncol 2014; 9(Suppl 2): S88–S96.
18. Ackman JB, Verzosa S, Kovach AE et al. High rate of unnecessary thymectomy 42. Forquer JA, Rong N, Fakiris AJ et al. Postoperative radiotherapy after surgical
and its cause. Can computed tomography distinguish thymoma, lymphoma, resection of thymoma: differing roles in localized and regional disease. Int J Radiat
thymic hyperplasia, and thymic cysts? Eur J Radiol 2015; 84: 524–533. Oncol Biol Phys 2010; 76: 440–445.
19. Priola AM, Priola SM, Ciccone G et al. Differentiation of rebound and lymphoid 43. Patel S, Macdonald OK, Nagda S et al. Evaluation of the role of radiation therapy in
thymic hyperplasia from anterior mediastinal tumors with dual-echo chemical-shift the management of malignant thymoma. Int J Radiat Oncol Biol Phys 2012; 82:
MR imaging in adulthood: reliability of the chemical-shift ratio and signal intensity 1797–1801.
index. Radiology 2015; 274: 238–249. 44. Ahmad U, Yao X, Detterbeck F et al. Thymic carcinoma outcomes and prognosis:
20. Henschke CI, Lee IJ, Wu N et al. CT screening for lung cancer: prevalence and results of an international analysis. J Thorac Cardiovasc Surg 2015; 149:
incidence of mediastinal masses. Radiology 2006; 239: 586–590. 95–100.
v | Girard et al. Volume 26 | Supplement 5 | September 2015

on 13 November 2017
45. Ruffini E, Detterbeck F, Van Raemdonck D et al. Thymic carcinoma: a cohort study European Organization for Research and Treatment of Cancer Lung Cancer
of patients from the European Society of Thoracic Surgeons Database. J Thorac Cooperative Group. J Clin Oncol 1996; 14: 814–820.
Oncol 2014; 9: 541–548. 68. Loehrer PJ, Sr, Jiroutek M, Aisner S et al. Combined etoposide, ifosfamide, and
46. Korst RJ, Kansler AL, Christos PJ, Mandal S. Adjuvant radiotherapy for thymic cisplatin in the treatment of patients with advanced thymoma and thymic
epithelial tumors: a systematic review and meta-analysis. Ann Thorac Surg 2009; carcinoma: an intergroup trial. Cancer 2001; 91: 2010–2015.
87: 1641–1647. 69. Lemma GL, Lee JW, Aisner SC et al. Phase II study of carboplatin and paclitaxel in
47. Rimner A, Gomez DR, Wu AJ et al. Failure patterns relative to radiation treatment advanced thymoma and thymic carcinoma. J Clin Oncol 2011; 29: 2060–2065.
fields for stage II-IV thymoma. J Thorac Oncol 2014; 9: 403–409. 70. Palmieri G, Merola G, Federico P et al. Preliminary results of phase II study of
48. Gomez D, Komaki R, Yu J et al. Radiation therapy definitions and reporting capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated
guidelines for thymic malignancies. J Thorac Oncol 2011; 6(Suppl 3): S1743–8. thymic epithelial tumors (TETs). Ann Oncol 2010; 21: 1168–1172.
49. Sugie C, Shibamoto Y, Ikeya-Hashizume C et al. Invasive thymoma: postoperative 71. Hirai F, Yamanaka T, Taguchi K et al. A multicenter phase II study of carboplatin
mediastinal irradiation, and low-dose entire hemithorax irradiation in patients with and paclitaxel for advanced thymic carcinoma: WJOG4207L. Ann Oncol 2015;
pleural dissemination. J Thorac Oncol 2008; 3: 75–81. 26: 363–368.
50. Zhang H, Lu N, Wang M et al. Postoperative radiotherapy for stage I thymoma: a 72. Okuma Y, Saito M, Hosomi Y et al. Key components of chemotherapy for
prospective randomized trial in 29 cases. Chin Med J (Engl) 1999; 112: 136–138. thymic malignancies: a systematic review and pooled analysis for anthracycline-,
51. Gao L, Wang C, Fang W et al. Outcome of multimodality treatment for 188 cases carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015;
of type B3 thymoma. J Thorac Oncol 2013; 8: 1329–1334. 141: 323–331.
52. Utsumi T, Shiono H, Kadota Y et al. Postoperative radiation therapy after complete 73. Benveniste MF, Korst RJ, Rajan A et al. A practical guide from the International
resection of thymoma has little impact on survival. Cancer 2009; 115: 5413–5420. Thymic Malignancy Interest Group (ITMIG) regarding the radiographic assessment
53. Chen YD, Feng QF, Lu HZ et al. Role of adjuvant radiotherapy for stage II thymoma of treatment response of thymic epithelial tumors using modified RECIST criteria.
after complete tumor resection. Int J Radiat Oncol Biol Phys 2010; 78: J Thorac Oncol 2014; 9: S119–S124.
1400–1406. 74. Sandri A, Cusumano G, Lococo F et al. Long-term results after treatment for
54. Weksler B, Shende M, Nason KS et al. The role of adjuvant radiation therapy for recurrent thymoma: a multicenter analysis. J Thorac Oncol 2014; 9: 1796–1804.
resected stage III thymoma: a population-based study. Ann Thorac Surg 2012; 93: 75. Hamaji M, Allen MS, Cassivi SD et al. The role of surgical management in
1822–1828. recurrent thymic tumors. Ann Thorac Surg 2012; 94: 247–254.
55. Attaran S, McCormack D, Pilling J, Harrison-Phipps K. Which stages of thymoma 76. Mizuno T, Okumura M, Asamura H et al. Surgical management of recurrent thymic
benefit from adjuvant chemotherapy post-thymectomy? Interact Cardiovasc Thorac epithelial tumors: a retrospective analysis based on the Japanese nationwide
Surg 2012; 15: 273–275. database. J Thorac Oncol 2015; 10: 199–205.
56. Loehrer PJ, Sr, Chen M, Kim K et al. Cisplatin, doxorubicin, and cyclophosphamide 77. Lara PN, Jr, Bonomi PD, Faber LP. Retreatment of recurrent invasive thymoma with
plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup platinum, doxorubicin, and cyclophosphamide. Chest 1996; 110: 1115–1117.
trial. J Clin Oncol 1997; 15: 3093–3099. 78. Loehrer PJ, Yiannoutsos CT, Dropcho S et al. A phase II trial of pemetrexed in
57. Kim ES, Putnam JB, Komaki R et al. Phase II study of a multidisciplinary approach patients with recurrent thymoma or thymic carcinoma. J Clin Oncol 2006;
with induction chemotherapy, followed by surgical resection, radiation therapy, and 24(Suppl 18): abstr 7079.
consolidation chemotherapy for unresectable malignant thymomas: final report. 79. Loehrer PJ, Sr, Wang W, Johnson DH et al. Octreotide alone or with prednisone in
Lung Cancer 2004; 44: 369–379. patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative
58. Berruti A, Borasio P, Gerbino A et al. Primary chemotherapy with adriamycin, Oncology Group Phase II Trial. J Clin Oncol 2004; 22: 293–299.
cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a 80. Palmieri G, Montella L, Martignetti A et al. Somatostatin analogs and prednisone in
single institution experience. Br J Cancer 1999; 81: 841–845. advanced refractory thymic tumors. Cancer 2002; 94: 1414–1420.
59. Girard M, Lal R, Wakelee H et al. Chemotherapy definitions and policies for thymic 81. Rajan A, Girard N, Marx A. State of the art of genetic alterations in thymic
malignancies. J Thorac Oncol 2011; 6(7 Suppl 3): S1749–S1755. epithelial tumors. J Thorac Oncol 2014; 9(Suppl 2): S131–S136.
60. Girard N. Chemotherapy and targeted agents for thymic malignancies. Expert Rev 82. Thomas A, Rajan A, Berman A et al. Sunitinib in patients with chemotherapy-
Anticancer Ther 2012; 12: 685–695. refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet
61. Wright CD, Choi NC, Wain JC et al. Induction chemoradiotherapy followed by Oncol 2015; 16: 177–186.
resection for locally advanced Masaoka stage III and IVA thymic tumors. Ann 83. Giaccone G, Rajan A, Ruijter R et al. Imatinib mesylate in patients with WHO B3
Thorac Surg 2008; 85: 385–389. thymomas and thymic carcinomas. J Thorac Oncol 2009; 4: 1270–1273.
62. Wright CD. Extended resections for thymic malignancies. J Thorac Oncol 2010; 84. Salter JT, Lewis D, Yiannoutsos C et al. Imatinib for the treatment of thymic
5(10 Suppl 3): S344–S347. carcinoma. J Clin Oncol 2008; 26(15s suppl): abstr 8116.
63. Yellin A, Simansky DA, Ben-Avi R et al. Resection and heated pleural chemoperfusion 85. Ströbel P, Bargou R, Wolff A et al. Sunitinib in metastatic thymic carcinomas:
in patients with thymic epithelial malignant disease and pleural spread: a single- laboratory findings and initial clinical experience. Br J Cancer 2010; 103: 196–200.
institution experience. J Thorac Cardiovasc Surg 2013; 145: 83–87. 86. Lattanzio R, La Sorda R, Facciolo F et al. Thymic epithelial tumors express vascular
64. Wright CD. Pleuropneumonectomy for the treatment of Masaoka stage IVA endothelial growth factors and their receptors as potential targets of antiangiogenic
thymoma. Ann Thorac Surg 2006; 82: 1234–1239. therapy: a tissue micro array-based multicenter study. Lung Cancer 2014; 85:
65. Hamaji M, Kojima F, Omasa M et al. A meta-analysis of debulking surgery versus 191–196.
surgical biopsy for unresectable thymoma. Eur J Cardiothorac Surg 2015; 47: 87. Wheler J, Hong D, Swisher SG et al. Thymoma patients treated in a phase I clinic
602–607. at MD Anderson Cancer Center: responses to mTOR inhibitors and molecular
66. Loehrer PJ, Sr, Kim K, Aisner SC et al. Cisplatin plus doxorubicin plus analyses. Oncotarget 2013; 4: 890–898.
cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup 88. Zucali PA, De Pas TM, Palmieri G et al. Phase II study of everolimus in patients
trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and with thymoma and thymic carcinoma previously treated with cisplatin-based
Southeastern Cancer Study Group. J Clin Oncol 1994; 12: 1164–1168. chemotherapy. J Clin Oncol 2014; 32 (5s suppl): abstr 7527.
67. Giaccone G, Ardizzoni A, Kirkpatrick A et al. Cisplatin and etoposide combination 89. Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among
chemotherapy for locally advanced or metastatic thymoma. A phase II study of the hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–144.
Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

on 13 November 2017

ESMO Guidelines Thymic Epithelial Tumours

Uploaded by

Copyright:

Available Formats

ESMO Guidelines Thymic Epithelial Tumours

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

ESMO Guidelines Thymic Epithelial Tumours

Uploaded by

Copyright:

Available Formats

clinical practice guidelines Annals of Oncology 26 (Supplement 5): v40–v55, 2015

Thymic epithelial tumours: ESMO Clinical Practice

rare; differential diagnosis with thymic rebound hyperplasia

Downloaded from https://academic.oup.com/annonc/article-abstract/26/suppl_5/v40/344419

Type A 12% (3%–26%) 15% (0%–35%) 60% 31% 8% <1% <1%

Data are based on references [5–8].

Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

v | Girard et al. Volume 26 | Supplement 5 | September 2015

clinical practice guidelines

Downloaded from https://academic.oup.com/annonc/article-abstract/26/suppl_5/v40/344419

risk assessment management of resectable disease

v | Girard et al. Volume 26 | Supplement 5 | September 2015

Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

Routine removal of anterior mediastinal nodes and anterior cer-

Stage grouping Corresponding Masaoka-Koga stage

I T1N0M0 I, IIA, IIB, III

v | Girard et al. Volume 26 | Supplement 5 | September 2015

Stage I Upfront surgery [IV, A] Upfront surgery [IV, A]

Stage IIA Upfront surgery [IV, A] Upfront surgery [IV, A]

Stage IIB Upfront surgery [IV, A] Upfront surgery [IV, A]

Stage IVB Definitive chemotherapy [III, A] Definitive chemotherapy [III, A]

Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

postoperative radiotherapy thymomas. Postoperative radiotherapy is not indicated after

v | Girard et al. Volume 26 | Supplement 5 | September 2015

primary chemotherapy recurrences

Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

Table 7. Summary of recommendations

– Standard approach is median sternotomy [IV, A].

v | Girard et al. Volume 26 | Supplement 5 | September 2015

Surgical pathology principles

Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

v | Girard et al. Volume 26 | Supplement 5 | September 2015

Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

v | Girard et al. Volume 26 | Supplement 5 | September 2015

Volume 26 | Supplement 5 | September 2015 doi:10.1093/annonc/mdv277 | v

You might also like