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Citation: Alqaidy, D. Thymoma: An
Overview. Diagnostics 2023,13, 2982.
https://doi.org/10.3390/
diagnostics13182982
Academic Editor: Angelo Carretta
Received: 21 August 2023
Revised: 15 September 2023
Accepted: 16 September 2023
Published: 18 September 2023
Copyright: © 2023 by the author.
Licensee MDPI, Basel, Switzerland.
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4.0/).
diagnostics
Review
Thymoma: An Overview
Doaa Alqaidy
Department of Pathology, King Abdulaziz University, Jeddah 21589, Saudi Arabia; dyalqaidy@kau.edu.sa
Abstract:
Thymomas are considered one of the most prevalent types of mediastinal epithelial tumors,
which frequently develop in the anterior mediastinum. Due to their rarity, these tumors’ nomencla-
ture, classification, and staging are likely to be the subject of debate and argument for most expert
pathologists. Furthermore, the significance of thymoma histologic classifications have been debated
over the past twenty years. While certain advocates argue that staging at the time of diagnosis is
more significant, others believe that histologic subtyping has a significant impact on how patients
behave clinically. In this review, we will focus on some of the challenges that diagnostic surgical
pathologists may experience while evaluating the histopathology of thymomas and staging these
tumors. We will additionally glance over the clinical characteristics of these distinct tumors and the
current management strategy.
Keywords: thymus; mediastinum; thymoma; staging; classification
1. Introduction
Thymic epithelial lesions are mostly thymomas. They are a common cause of anterior
mediastinal mass in adults [
1
]. However, in general practice, thymomas account for
approximately 0.2–1.5% of all malignant neoplasms. Among the anterior mediastinal
tumors, thymoma is the most common. It accounts for 20% of all mediastinal neoplasm in
adults [
2
,
3
]. Thymomas occur in 0.13–0.26 cases per 100,000 people per year [
1
,
4
,
5
]. They
are extremely uncommon in young people and are more prevalent among individuals in
their fifth and sixth decades of life. Only 11% of thymomas were diagnosed before the age
of 35 [
1
,
6
]. It affects females slightly more commonly than males [
3
,
4
,
7
]. In a more detailed
analysis of the epidemiology of thymoma, Engels stated in his study that Asian and Pacific
Islanders had a greater prevalence of thymomas in the USA [8].
Patients are commonly presented as a single well-circumscribed mass, readily identi-
fied by the computed tomography (CT) technique. The majority of thymomas present as
round or oval lobulated lesions on magnetic resonance imaging (MRI) scans and computed
tomography (CT) [
6
,
9
,
10
]. Areas of calcification and hemorrhage (low densities on CT scan)
are rarely seen, although irregularities are often indicators of local invasion and aggressive
behavior [1,9,10].
2. Clinical Features
Thymoma can present in different ways, including asymptomatically as a mediastinal
mass on chest radiography (about one-third of cases), local compressive symptoms as chest
pain, a neck mass, or superior vena cava syndrome, or concurrently with myasthenia gravis
in one-third of cases [1,7,8].
Although thymoma patients present with a variety of symptomatologies, it is impor-
tant to emphasize the link between thymomas and paraneoplastic diseases [
11
,
12
]. The
numerous associations between thymomas and other illnesses, such as autoimmune dis-
orders, collagen vascular disorders, hematological disorders, neoplasia, and others, are
well established [
1
,
7
,
8
]. The medical condition that seems to have the strongest association
with thymoma is myasthenia gravis. It is widely believed that thymomas are present in
roughly 10–15% of myasthenia gravis (MG) patients [
13
]. Additionally, it has been shown
Diagnostics 2023,13, 2982. https://doi.org/10.3390/diagnostics13182982 https://www.mdpi.com/journal/diagnostics
Diagnostics 2023,13, 2982 2 of 13
that 20–25% of individuals with MG and 40% of those with thymoma had one or more
paraneoplastic autoimmune diseases [
2
,
7
,
14
,
15
]. In a study by Mao et al. [
14
,
16
], the au-
thors stated that out of 2206 potentially relevant studies, the incidence of thymoma in MG
patients was 21%. Additionally, thymoma appears to be much more common in male MG
patients and those who were older than 40 at the time of MG’s diagnosis [
14
]. Furthermore,
in a study by Okuma et al. [
17
], immunological abnormalities were found in 21.8% of
the thymoma group in a clinicopathological investigation of 187 thymic malignancies,
including thymomas, thymic carcinomas, and neuroendocrine carcinomas. In total, 13.3%
of these individuals had secondary malignancy [
17
]. Weissferdt et al., in one of the largest
series on thymomas ever reported [
18
], found that 807 patients out of 1470 patients with
thymomas had pertinent clinical data available to them. The authors found the following
connections in their examination of 807 patients:
•Myasthenia gravis—17%;
•Neoplasia—6.8%;
•Other autoimmune diseases—3.8%.
In terms of therapy and prognosis, the preferred course of therapy for thymomas is sur-
gical resection, which is typically successful [
7
,
15
]. The extent of the tumor ’s invasiveness
and its resectability, however, are significant factors that are considered when determining
if surgical resection is appropriate [
19
]. The degree of invasion is directly related to the
clinical prognosis for patients with thymomas. Complete surgical resection seems to be
the preferred course of treatment for individuals whose illness has only spread to the
mediastinum and the risk of recurrence is low [
20
]. On the other hand, invasive disease is
more likely to be treated with additional medical techniques, such as chemotherapy and/or
radiation therapy [
10
,
16
,
19
]. Even when a full resection is performed, thymoma often
recurred, so it is important to plan for a long period of follow-up. Recurrences of thymoma
affect between 10 and 29% of individuals. Distant metastasis commonly manifests in the
lungs, liver, and bone [
7
]. The lung is widely recognized as the most frequent location for
distant metastases.
3. Thymoma Classification
Even though many publications have noted the difficulty in classifying thymomas,
specifically due to their heterogeneity and the risk of predicting outcomes based on specific
cell types, this is likely one of the most debatable issues in the history of thymomas [
2
,
21
].
For classifying thymomas, several histological schemes have been suggested and proposed
over the years [2,11,21], Table 1.
Table 1. Different histological classification systems.
Bernatz Muller-Hermelink Moran–Suster WHO, 6th Edition
Spindle cell thymomas
Mixed thymomas
Lymphocytes-rich thymomas
Medullary thymoma
Mixed thymoma
Predominantly cortical
Cortical thymoma
Thymoma
Thymoma
Thymoma
Thymoma
Type A
Type AB
Type B1
Type B2
Epithelial-rich thymomas
with cytologic atypia Well-differentiated thymic carcinoma Atypical thymoma Type B3
Thymic carcinoma Thymic carcinoma Thymic carcinoma
Prior to the original 1999 World Health Organization consensus publication on thy-
moma, the first attempt to classify this heterogenous group of tumors in 1961 was made by
Bernatz [
22
] et al. based on the amount of lymphocytes present in each kind of thymoma
into the following categories:
•
Lymphocyte-rich thymomas are those tumors where lymphocytes predominate over
epithelial cells;
Diagnostics 2023,13, 2982 3 of 13
•
Epithelial-rich thymomas are those where lymphocytes are present in smaller amounts
than the epithelial cells;
•
Mixed thymomas, also known as lymphoepithelial thymomas, are those tumors where
lymphocytes and epithelial cells are present in roughly equal amounts.
The “histologic-based classification”, which Marino and Muller-Hermelink suggested
in 1985 [
23
], is based on the medulla and cortex of the normal thymus compartment. The
tumors are categorized into three categories in this proposal: Tumors that are intended to
recapitulate the healthy thymic medulla are known as “medullary thymomas”. However,
thymomas that mimic the normal thymic cortex are referred to as cortical thymomas. Finally,
mixed thymomas are tumors with medullary and cortical components. Furthermore,
a more histologic classification attempt was proposed, and in 1999, because of several
differences in how thymomas are classified histologically, the World Health Organization
(WHO) proposed an “official” classification system [
4
,
6
,
21
]. The classification depends
on the concept that there are two primary histologic kinds of tumor cells in thymomas:
round/epithelioid (named type B) and spindle/oval (designated type A) [
21
], (Figure 1).
Type AB was given to tumors that included elements of these two categories. In the current
2021 WHO classification [
4
], type AB thymoma is also compassing cases of mixtures with a
lymphocyte-depleted type A component and a type B-like lymphocyte-rich component.
These elements may combine into distinct, independent lobules or may be intermingled. For
thymoma type B, three subgroups designated as B1, B2, and B3 were further subclassified
on the basis of the proportional increase (in relation to the lymphocytes) and the presence of
atypia of the neoplastic epithelial cells [
2
,
4
,
21
]. The former WHO type C thymoma, which
was designated to cases that revealed significant cytologic atypia, nuclear pleomorphism,
and notable mitotic activity, all of which are signs of malignancy, was removed from the 2004
WHO classification, and since then, these cases are considered thymic carcinoma [
2
,
4
,
21
].
The diagnosis should describe all observable histological types, starting with the main
component, and minor components should be estimated in 10% increments for thymomas
that have several histological patterns [4].
Diagnostics 2023, 13, x FOR PEER REVIEW 3 of 17
• Lymphocyte-rich thymomas are those tumors where lymphocytes predominate over
epithelial cells;
• Epithelial-rich thymomas are those where lymphocytes are present in smaller
amounts than the epithelial cells;
• Mixed thymomas, also known as lymphoepithelial thymomas, are those tumors
where lymphocytes and epithelial cells are present in roughly equal amounts.
The “histologic-based classification”, which Marino and Muller-Hermelink sug-
gested in 1985 [23], is based on the medulla and cortex of the normal thymus compart-
ment. The tumors are categorized into three categories in this proposal: Tumors that are
intended to recapitulate the healthy thymic medulla are known as “medullary thy-
momas”. However, thymomas that mimic the normal thymic cortex are referred to as cor-
tical thymomas. Finally, mixed thymomas are tumors with medullary and cortical com-
ponents. Furthermore, a more histologic classification attempt was proposed, and in 1999,
because of several differences in how thymomas are classified histologically, the World
Health Organization (WHO) proposed an “official” classification system [4,6,21]. The clas-
sification depends on the concept that there are two primary histologic kinds of tumor
cells in thymomas: round/epithelioid (named type B) and spindle/oval (designated type
A) [21], (Figure 1). Type AB was given to tumors that included elements of these two cat-
egories. In the current 2021 WHO classification [4], type AB thymoma is also compassing
cases of mixtures with a lymphocyte-depleted type A component and a type B-like lym-
phocyte-rich component. These elements may combine into distinct, independent lobules
or may be intermingled. For thymoma type B, three subgroups designated as B1, B2, and
B3 were further subclassified on the basis of the proportional increase (in relation to the
lymphocytes) and the presence of atypia of the neoplastic epithelial cells [2,4,21]. The for-
mer WHO type C thymoma, which was designated to cases that revealed significant cy-
tologic atypia, nuclear pleomorphism, and notable mitotic activity, all of which are signs
of malignancy, was removed from the 2004 WHO classification, and since then, these cases
are considered thymic carcinoma [2,4,21]. The diagnosis should describe all observable
histological types, starting with the main component, and minor components should be
estimated in 10% increments for thymomas that have several histological patterns [4].
(a) (b)
Figure 1.
The two epithelial components characteristically seen in thymoma: (
a
) the spindle/oval
cells commonly seen in type A and type AB thymoma; (
b
) round/epithelioid epithelial cells found in
type B thymoma. (a,b) (H&E, 40×).
When discussing thymoma classification, it is crucial to highlight the Suster–Moran
proposal which was first introduced in 1999 [
24
]. According to their proposal, primary
thymic epithelial neoplasms are a spectrum of lesions that range from well to poorly
differentiated tumors. This assumption served as the foundation for their histologic grading
of the tumors [
21
,
24
]. Based on the presence or absence of the distinctive organotypical
signs of differentiation in the normal thymus and the cytologic atypia, the degree of
differentiation for every specific subtype was established as follows:
Diagnostics 2023,13, 2982 4 of 13
•
Thymoma: Well-differentiated thymic epithelial neoplasms are tumors that exhibit the
majority or all the organotypical characteristics of thymic differentiation and lack of
cytologic atypia.
•
Atypical thymoma: Tumors that exhibit mild to moderate cytologic atypia and only
certain organotypical characteristics of thymic differentiation are categorized as mod-
erately differentiated thymic epithelial neoplasms.
•
Thymic carcinoma: These tumors are poorly differentiated thymic epithelial neoplasms
and are defined by the complete lack of the organotypical characteristics of the thymus
and overt cytological signs of malignancy.
It is also vital to note that thymomas are tumors with a complex heterogeneity and
many growth patterns, making it challenging to propose a single and simple classification
scheme [
25
,
26
]. Because of this heterogeneity, any histological schema is rather unrealistic,
and the staging of the tumor at the time of diagnosis is more important than ever for
determining the best course of treatment [27,28].
3.1. Pathological Features
Thymomas can have a wide range of macroscopic characteristics, such as solid, cystic,
and areas of infarction/necrosis [
27
]. The majority of thymomas are well-defined tumors,
however, a subset can be ill-defined [
1
,
7
,
27
] with ill-defined capsules. In thymoma cases
with prominent cystic or hemorrhagic changes, special attention should be given to proper
sampling of the solid areas which usually illustrate the classic thymoma features. Failure to
do so will delay the diagnosis and the proper management [
1
]. Size wise, tumors can range
from as tiny as 1 cm to ones with a maximum diameter of far over 10 cm [29].
Microscopically, as was already mentioned, there is a broad variety of histological
growth patterns that can be observed in thymomas and they can be diagnostic pitfalls.
In this section, we are going to summarize the microscopic features of the conventional
thymoma. In addition, we will highlight the thymomas’ unusual histological subtype and
illustrate how these tumors might be mistaken for other neoplasms and cause diagnostic
dilemmas.
3.1.1. Conventional Thymoma with Lymphocytes
Included in this category are the tumors that have been classified as mixed
thymoma—lymphoepithelial, cortical, and WHO type B2, as well as those that have been
identified as lymphocyte-rich, cortical, and WHO type B1 in other nomenclatures [
1
,
21
].
Microscopically, this thymoma is lymphocytic rich with minimal epithelial components. It
usually has the characteristic perivascular space [
7
,
11
] and three distinct growth patterns
may be visible in the low-power image of these tumors:
1.
A lobulated growth pattern with considerable hyalinization or bands of connective
tissue between the lobules (Figure 2a).
2.
The tumor lacks well-formed lobules, but there is the presence of collagenous material
mixed with the biphasic populations of lymphocytes and epithelial cells (Figure 2b).
3.
A diffuse growth pattern in which the tumor exhibits sheets of lymphocytes mixed
with epithelial cells in various ratios (Figure 2c,d).
Statistically, these tumors represented 31.1% of the total and 51.9% of the invasive
thymoma in that category in a study of 1470 patients that was conducted by Weissferdt
et al. [
18
]. The authors concluded that half of all cases of these types of thymomas may be
invasive at the time of diagnosis from the total number of cases of these tumors.
3.1.2. Spindle Cell Thymoma
Spindle cell thymoma has a high degree of morphologic diversity. The tumor cells may
be arranged in ways that may resemble other epithelial or mesenchymal neoplasms, but
their fundamental morphology is that of a spindle cellular proliferation made up of fusiform
cells with sparse cytoplasm, elongated nuclei, dispersed chromatin, and inconspicuous
nucleoli [19,25] (Figure 3).
Diagnostics 2023,13, 2982 5 of 13
Diagnostics 2023, 13, x FOR PEER REVIEW 5 of 17
illustrate how these tumors might be mistaken for other neoplasms and cause diagnostic
dilemmas.
3.1.1. Conventional Thymoma with Lymphocytes
Included in this category are the tumors that have been classified as mixed thy-
moma—lymphoepithelial, cortical, and WHO type B2, as well as those that have been
identified as lymphocyte-rich, cortical, and WHO type B1 in other nomenclatures [1,21].
Microscopically, this thymoma is lymphocytic rich with minimal epithelial components.
It usually has the characteristic perivascular space [7,11] and three distinct growth pat-
terns may be visible in the low-power image of these tumors:
1. A lobulated growth pattern with considerable hyalinization or bands of connective
tissue between the lobules (Figure 2a).
2. The tumor lacks well-formed lobules, but there is the presence of collagenous mate-
rial mixed with the biphasic populations of lymphocytes and epithelial cells (Figure
2b).
3. A diffuse growth pattern in which the tumor exhibits sheets of lymphocytes mixed
with epithelial cells in various ratios (Figure 2c,d).
(a) (b)
(c) (d)
Figure 2.
The different growth patterns of conventional thymoma: (
a
) type B1 thymoma showing
lobulation by thick fibrous bands; (
b
) thymoma in areas of fibrocollagenous stroma with no well-
defined lobulation; (
c
) thymoma with an even distribution of lymphocytes and epithelial cells and
a diffuse development pattern; and (
d
) higher magnification displaying the mixed population of
lymphocytes and polygonal epithelial cells. (a,b) (H&E, 4×); (c) (H&E, 10×); (d) (H&E, 20×).
Diagnostics 2023, 13, x FOR PEER REVIEW 7 of 17
(a) (b)
(a) (b)
Figure 3. Spindle cell thymoma histologic feature: (a)
low power of thymoma type A/spindle cell
thymoma; (b) high power view showing the characteristic spindle cell cytology. (a) (H&E, 10×); (b)
(H&E, 20×)
3.1.3. Atypical Thymoma, WHO Type B3 Thymoma
This entity has histological characteristics and clinical behavior that are more similar
to thymomas than to carcinomas, and as a result, the term “atypical thymoma” is best
used to describe an entity with characteristics that fall somewhere between thymomas
and thymic carcinomas [2,24,33]. Morphologically, the epithelial proliferation in this spe-
cific type of thymoma is characterized by round to polygonal cells with an abundance of
eosinophilic cytoplasm, vesicular nuclei, several cells with conspicuous nucleoli, and oc-
casionally mitotic figures [27,34]. More significantly, these tumors have a sparse popula-
tion of T-immature lymphocytes, which is essential (Figure 4).
Figure 3.
Spindle cell thymoma histologic feature: (
a
) low power of thymoma type A/spindle cell
thymoma; (
b
) high power view showing the characteristic spindle cell cytology. (
a
) (H&E, 10
×
);
(b) (H&E, 20×).
These tumors can exhibit three distinct growth patterns at low power magnification:
lobulated, diffuse, and vascular or HPC growth pattern [
30
,
31
]. Additionally, regions
of hyalinization, which can range from focal to widespread, may be seen in spindle cell
thymomas. The lymphocyte component can vary in this thymoma from none or few
lymphocytes to prominent lymphocytes intermixed with the spindle cells. In the WHO
Diagnostics 2023,13, 2982 6 of 13
classification, this thymoma is classified as type A or type AB. From a statistical perspective,
spindle cell thymomas make up around 13% of all thymomas [31,32].
3.1.3. Atypical Thymoma, WHO Type B3 Thymoma
This entity has histological characteristics and clinical behavior that are more similar to
thymomas than to carcinomas, and as a result, the term “atypical thymoma” is best used to
describe an entity with characteristics that fall somewhere between thymomas and thymic
carcinomas [
2
,
24
,
33
]. Morphologically, the epithelial proliferation in this specific type of
thymoma is characterized by round to polygonal cells with an abundance of eosinophilic
cytoplasm, vesicular nuclei, several cells with conspicuous nucleoli, and occasionally
mitotic figures [
27
,
34
]. More significantly, these tumors have a sparse population of T-
immature lymphocytes, which is essential (Figure 4).
Diagnostics 2023, 13, x FOR PEER REVIEW 8 of 17
(a) (b)
(a) (b)
Figure 4. Atypical thymoma/WHO type B3: (a) atypical thymoma case showing nested pattern and
rosette-like formation; (b) higher magnification showing atypia and focal comedo necrosis. (a)
(H&E, 4×); (b) (H&E, 10×).
Atypical thymoma (WHO category B3) appears to be more frequently attributed to
invasion, more rapid recurrence, and a higher risk of tumor-related fatalities than the bet-
ter-differentiated forms of the disease [2,21,35]. In a large cohort study by Weissferdt et
al. [18], they examined 1470 thymomas, of which 186 were atypical thymomas, accounting
for around 12.7% of the total. In total, 139 of the 186 atypical thymomas in this cohort were
invasive tumors at various clinical stages, roughly 75% of the cases. As a result, the dis-
tinction between thymomas and atypical thymomas became statistically significant when
a survival curve was analyzed.
3.2. Unusual Histologic Subtypes
3.2.1. Micronodular Thymoma with B-Cell Lymphoid Hyperplasia
The first description of this specific type of thymoma was by Suster and Moran in
1999 [36], which is characterized by the presence of lymphoid nodules that have signifi-
cant germinal centers and spindle cell nodules. The oval cells that make up the spindle
cell nodules lack nuclear atypia and mitotic activity (Figure 5).
Figure 4.
Atypical thymoma/WHO type B3: (
a
) atypical thymoma case showing nested pattern and
rosette-like formation; (
b
) higher magnification showing atypia and focal comedo necrosis. (
a
) (H&E, 4
×
);
(b) (H&E, 10×).
Atypical thymoma (WHO category B3) appears to be more frequently attributed to
invasion, more rapid recurrence, and a higher risk of tumor-related fatalities than the better-
differentiated forms of the disease [
2
,
21
,
35
]. In a large cohort study by Weissferdt et al. [
18
],
they examined 1470 thymomas, of which 186 were atypical thymomas, accounting for
around 12.7% of the total. In total, 139 of the 186 atypical thymomas in this cohort were
invasive tumors at various clinical stages, roughly 75% of the cases. As a result, the
distinction between thymomas and atypical thymomas became statistically significant
when a survival curve was analyzed.
3.2. Unusual Histologic Subtypes
3.2.1. Micronodular Thymoma with B-Cell Lymphoid Hyperplasia
The first description of this specific type of thymoma was by Suster and Moran in
1999 [
36
], which is characterized by the presence of lymphoid nodules that have significant
germinal centers and spindle cell nodules. The oval cells that make up the spindle cell
nodules lack nuclear atypia and mitotic activity (Figure 5).
Cystic changes can be prominent in this type of thymoma. Oramas et al. reported
the clinopathological features of 25 cases of micronodular thymomas with prominent
cystic changes. In this case series, four cases were invasive tumors with invasion into the
perithymic adipose tissue through the fibrous capsule. However, the majority of them
(21 tumors) were encapsulated [
37
]. By immunohistochemistry, the epithelial spindle cells
are positive for cytokeratin, while the lymphoid component was shown to be mainly B-
lymphocytes [
1
,
37
]. In the clinical follow-up provided in this initial publication [
36
], as
Diagnostics 2023,13, 2982 7 of 13
well as in the subsequent studies, the patients were free of recurrence in around half of the
cases. This clinical behavior was like that seen in conventional thymomas.
Diagnostics 2023, 13, x FOR PEER REVIEW 9 of 17
(a) (b)
(a) (b)
Figure 5. Micronodular thymoma with B-cell lymphoid hyperplasia: (a) islets of nodular epithelium
embedded within a lymphocytic stroma; (b) many germinal centers are easily identifiable. (a) (H&E,
2×); (b) (H&E, 10×).
Cystic changes can be prominent in this type of thymoma. Oramas et al. reported the
clinopathological features of 25 cases of micronodular thymomas with prominent cystic
changes. In this case series, four cases were invasive tumors with invasion into the peri-
thymic adipose tissue through the fibrous capsule. However, the majority of them (21 tu-
mors) were encapsulated [37]. By immunohistochemistry, the epithelial spindle cells are
positive for cytokeratin, while the lymphoid component was shown to be mainly B-lym-
phocytes [1,37]. In the clinical follow-up provided in this initial publication [36], as well
as in the subsequent studies, the patients were free of recurrence in around half of the
cases. This clinical behavior was like that seen in conventional thymomas.
3.2.2. Other Histologic Variants
Thymoma with significant plasma cells, also known as plasma cell-rich thymoma, is
one of the rare histologic types that appears to frequently be associated with an underly-
ing autoimmune illness, particularly myasthenia gravis, [27,38]. It shows a mixture of both
epithelial and plasma cells. It is also important to note that plasma cells are one of the
normal cellular components of the normal thymus, and they may be present in the normal
Figure 5.
Micronodular thymoma with B-cell lymphoid hyperplasia: (
a
) islets of nodular epithelium
embedded within a lymphocytic stroma; (
b
) many germinal centers are easily identifiable. (
a
) (H&E, 2
×
);
(b) (H&E, 10×).
3.2.2. Other Histologic Variants
Thymoma with significant plasma cells, also known as plasma cell-rich thymoma, is
one of the rare histologic types that appears to frequently be associated with an under-
lying autoimmune illness, particularly myasthenia gravis, [
27
,
38
]. It shows a mixture of
both epithelial and plasma cells. It is also important to note that plasma cells are one of
the normal cellular components of the normal thymus, and they may be present in the
normal thymus, although not in the same proportion as lymphocytes [
3
,
7
,
39
]. Metaplastic
thymoma is another unusual histological type of thymoma. It is characterized by a spindle
cell component mimicking sarcoma with minimal lymphoid component. This specific
variant has been described in 1997 under the term of thymoma with pseudosarcomatous
component [
40
]. Other rare variants of thymomas can have myoid cells, showing papil-
lary/pseudopapillary, adenomatoid-like, alveolar, glandular, signet ring cell, and clear cell
features. It is important to bring attention to the difficulty that these thymoma variations
may present in tiny mediastinoscopic biopsies, potentially leading to an incorrect diagnosis.
Those tumors, nonetheless, need to be treated appropriately under the term “thymoma”,
and more crucially, they do belong to certain categories rather than a specific position in
any classification scheme [27].
4. Immunohistochemical and Molecular Characteristics
Although thymoma is often diagnosed morphologically, various investigations have
provided some insight into the immunohistochemical characteristics of these tumors. There
is currently no established unique immunohistochemical marker for malignancies orig-
inating from thymic epithelial cells [
41
]. Generally, the epithelial component is usually
positive for broad-spectrum cytokeratin, cytokeratin 5/6, while CD45 and TDT usually
highlight the T-cell component. Occasionally, the epithelial cells can express polyclonal
PAX8, calretinin, TTF-1, CD5, CD117, synaptophysin, CD56, and PD-L1 [
41
,
42
], and they
are generally negative for monoclonal PAX8 and EMA.
Several studies have investigated the role of high expression of programmed cell death
1 ligand (PD-L1) in thymic epithelial neoplasm, including thymoma [
42
,
43
]. Wei et al.,
in their cohort, examined the PDL1 expression in 100 surgically treated thymomas and
they stated that high PD-L1 expression was associated with advanced Masaoka staging
and with high-grade histology [
43
]. In a similar study by Weissferdt et al. [
42
], expression
of PD-1 was detected in 46/74 thymomas (62%). In their cohort, neither PD-1 nor PD-L1
Diagnostics 2023,13, 2982 8 of 13
expression appeared to be related to patient outcomes, which raises questions about the
usefulness of these markers as prognostic indicators. However, neoadjuvant treatment
was linked to PD-L1+ cases in thymoma. Also, this study illustrated that up to 82% of
thymic epithelial neoplasms express PD-1 and/or PD-L1. These findings support the need
for PD-1/PD-L1 targeted treatment for these malignancies, but their prognostic predictive
value is yet unknown.
In the past decade, many investigations have been conducted in an effort to character-
ize the molecular profile of thymic epithelial neoplasms, including thymoma. Thymomas
typically have low mutational burdens and a variety of copy number abnormalities [
44
,
45
]
(summarized in Table 2). The observed low mutation burden in thymomas has been associated
with the smaller number of somatic mutations present in the DNA of neoplastic cells [46].
Table 2. Common mutations in different histologic subtypes of thymoma.
Molecular Alteration Thymoma Histologic Subtypes
Loss of heterozygosity across chromosome 6
(FOXC1 6q25.2-p25.3) Common in thymoma type A, type AB, type B2, and type B3
Missense mutations in in GTF2I p.L424H Mainly in thymomas type A and type AB (38% of cases)
HRAS gene mutation Restricted to type A and AB thymomas
NRAS and TP53 gene mutations Common in type B2 and B3 thymomas and thymic carcinomas
GTF2I and BCOR mutations Mutually exclusive in thymomas from individuals with Myasthenia Gravis
The most common molecular alteration in thymoma type A, type AB, type B2, and
type B3 is the loss of heterozygosity across chromosome 6 (the 6q25.2-p25.3 region contains
the FOXC1 tumor suppressor gene) [
45
,
47
]. This particular alteration was not detected
in thymoma type B1. In addition, missense mutations in GTF2I p.L424H are the most
frequent recurring genetic change, mainly in thymomas type A and type AB (occurring
in up to 38% of cases). It is linked to a lower prevalence of myasthenia gravis and a
better prognosis. Researchers observed a pattern of GTF2I and BCOR mutations that are
mutually exclusive in thymomas from individuals with myasthenia gravis [
46
]. While
NRAS and TP53 mutations are substantially more prevalent in type B2 and B3 thymomas
and thymic carcinomas, mutations in the HRAS gene are primarily restricted to type A
and AB thymomas [
48
,
49
]. Finally, thymomas have not been found to have any targetable
mutations, such as those in the EGFR or KIT genes [
45
,
50
]. For patients with invasive
diseases that cannot be treated by surgery alone, more research is required in order to shed
some light and provide information regarding helpful targeted therapies [44,47].
5. Thymoma Staging
In thymoma, staging is the most critical step in patient management as it has been
linked to prognosis. Many staging system schemes have been published in the literature
throughout the years. In this section, we will give a historical summary of how these
tumors have been staged, with a focus on current developments in this area (summarized
in Table 3).
One of the earlier staging systems was presented in 1981 by a Japanese team led by
Masaoka [
51
]. This system put a strong emphasis on the severity of the disease, and it
became the cornerstone for the subsequent schemes. The thymoma was divided into the
following four stages based on macroscopic and microscopic evaluation:
•Stage I: macroscopically fully encapsulated with no capsular invasion.
•
Stage II: macroscopic invasion into surrounding fatty tissue or mediastinal pleura or
microscopic invasion into the capsule.
•
Stage III: macroscopic invasion into the surrounding organs, such as the pericardium,
great vessels, or lung.
•
Stage IV: (a) pleural or pericardial dissemination or (b) lymphoid or hematogenous
metastasis.
Diagnostics 2023,13, 2982 9 of 13
Table 3. Different staging systems for thymoma.
TNM Definition Mazaoka/Koga Moran
TX Primary tumor cannot be assessed NA NA
T0 No evidence of primary tumor Encapsulated tumor NA Encapsulated thymoma
T1
Encapsulated tumor
T1a- No mediastinal pleural involvement
T1b- Direct invasion of mediastinal pleura
Stage I
NA
Stag II
Minimally invasive thymoma
without involvement of any
adjacent structure
T2 Direct invasion of pericardium Stage III Stage IIA (innominate vein,
mediastinal pleura, lung)
Stage IIB (pericardium)
T3
Invasion into lungs, brachiocephalic vein, superior
vena cava, phrenic nerve, chest wall, extrapericardial
pulmonary artery or veins
Stage III
T4 Invasion into aorta, arch vessels, pulmonary artery,
myocardium, trachea, esophagus Stage III Stage IIC (great vessels
and heart)
M1a, b
M1a: The tumor has spread to the lining of the lung,
called the pleura, or the lining of the heart, called the
pericardium
M1b: The tumor may have spread to the lining of
the lung or the heart
Stage IVa: pleural, pericardial
dissemination
Stage IVb: lymphogenous
Hematogenous
Stage III—metastatic disease
IIIA—intrathoracic structure
Diaphragm (drop metastasis)
Lymph nodes
IIIB—extrathoracic
NA: not applicable.
In the subsequent generation of Masaoka staging systems, updated by Koga, the Koga-
modified Masaoka staging system has been the most frequently adopted to stage thymic
epithelial neoplasms [
52
]. It is noted accurately in this amended staging system that a
tumor cannot be categorized as invasive if it does not penetrate through the capsule [
53
–
55
].
The modified Masaoka stage II tumors have either microscopic trans-capsular invasion or
macroscopic invasion into the perithymic fatty tissue. Cases adhering to the pericardium
or mediastinal pleura but not rupturing them are also considered stage II.
More recent and pathologically user-friendly schemas for staging thymoma and thymic
carcinoma have been presented, taking into account the fact that the mode of spread for
these tumors is frequently divergent [
53
,
56
,
57
]. Moran et al.’s subsequent staging system,
based on over 200 cases of thymoma, was designed with the goal of informing the clinical
team of the precise anatomical regions that the tumor cells had penetrated. This is helpful
in distinguishing thymomas that are localized to the mediastinum from those that are
infiltrating nearby anatomical tissues [
34
]. This could spare patients who would benefit
from full surgical resection alone from receiving extra therapy. It is also vital to note that a
more tailored approach to treatment may be used if particular information regarding the
anatomy that is involved is provided [
54
]. This staging system, as illustrated in Table 2,
gives a precise description of encapsulated versus invasive thymomas, as well as definitions
of the phrases “pleural” and “pericardial involvement”, respectively. The term “drop metas-
tasis” is also discussed and is defined as discontinuous tumor extension to the diaphragm
or other intrathoracic structures (stage IIIa) as opposed to direct tumor infiltration into
intrathoracic structures (stage II) or lymph node metastasis or hematogenous extrathoracic
spread (stage IIIb). Additionally, the idea of stage 0 is presented to highlight how similar
these tumors are to in situ tumors at other organ locations, where total removal of the lesion
would probably lead to a complete cure.
Lately, the American Joint Committee on Cancer (AJCC) [
58
] has updated its guidelines
to include the new TNM proposal [
59
,
60
], which T is not based on the tumor size. However,
it is related to the tumor capsule integrity and tumor invasion into the adjacent structure
(Table 2). The concept of adopting a TNM staging system for thymoma started a long
time ago when Yamakawa et al. [
61
] presented a series of 207 cases of thymomas, in one
of the early attempts to develop a TNM staging system for thymomas, and noted that
“only a few cases had lymph node metastases”, adding that the TNM system has a minor
advantage over the traditional staging systems. Additionally, it can be more suitable for
thymic carcinoma than thymoma.
Diagnostics 2023,13, 2982 10 of 13
It is clear how significant appropriate staging plays in predicting the clinical course of
thymomas. Regardless of whether Masaoka and Moran’s proposals or the TNM staging is
used, the staging must be reliable and useful for clinical use.
6. Management and Treatment Strategies
Surgical excision has been widely accepted as the preferred and most effective treat-
ment modality for thymomas, regardless of their specific histological classification. This
is evidenced by the high overall and disease-free survival rates it achieves in patients
with stage I and stage II disease [
7
,
20
]. The conventional procedure involves performing a
median sternotomy, followed by a complete thymectomy and excision of the tumor. The
5-year survival rates following surgical removal of stage I thymoma vary between 80% and
100%, with an average rate of 91%. In cases of more invasive lesions, particularly those
classified as Masaoka stage III, where the tumor has invaded the surrounding tissues, the
preferred therapy remains definitive surgical removal.
It is important to acknowledge that a more extensive surgical procedure may be
necessary (including possible resection of part of the pericardium and a portion of the
lung) [
35
,
62
]. In cases when the hemidiaphragm is involved, it may also be subject to
resection and subsequent reconstruction with a prosthetic patch, often composed of polyte-
trafluoroethylene (PTFE). The primary objective in managing these lesions is to achieve a
complete resection, preferably with clear margins. Thymoma resection can be performed
using a variety of methods. The most common method is a median sternotomy. Several
minimally invasive techniques have been documented in the literature, such as transcer-
vical, extended transcervical or video-assisted thoracoscopic, and robotic surgery. These
techniques involve various approaches, including right, left, cervical, and sub-xiphoid
approaches [63].
Thymic neoplasms have a notable sensitivity to chemotherapy, resulting in a response
rate that varies between 30% and 60% in patients with locally advanced diseases [
20
,
63
].
Chemotherapy may, thus, have a significant impact as a neoadjuvant intervention for those
who are not eligible for surgery, as well as serving as an adjuvant therapy to enhance the
long-term, disease-free survival rate for patients who have already had surgical procedures.
In general, cisplatin-based chemotherapy regimens are safe and effective [7,64].
Furthermore, invasive thymomas respond to radiation therapy, making it a potential
adjuvant therapy for improving local tumor control and survival. Although its efficacy in
stage II patients is still up for debate, postoperative radiation has been found to reduce the
recurrence rate of thymomas by 50–20% in stages III and IV [
65
]. Radiation therapy, both
before and after surgery, has not been shown effective for treating advanced illness [66].
Finally, it has been generally accepted that the best treatment for thymoma recur-
rences and advanced thymomas is multimodal treatments that combine radiation and
chemotherapy with surgery, where feasible. Some studies have found that an extra surgical
excision of pleural implants improves oncological outcomes. Pleuropneumonectomy has
been replaced by partial or total pleurectomy/decortication due to its high morbidity
and mortality rate. Intracavitary perfusion of chemotherapeutic agents, hyperthermic
intrathoracic chemotherapy (HITHOC), after surgical local excision of recurrences is one
of the modalities used for recurrence pleural implants. This approach has been shown to
be safe, feasible, and effective, as evidenced by the favorable survival rate and enhanced
management of local disease. In a retrospective research conducted by Aprile et al. [
67
],
the authors assess the oncological efficacy of hyperthermic intraperitoneal chemotherapy
(HITHOC), specifically focusing on its ability to control local disease. The study compares
a group of 27 patients who had HITHOC with a group of patients who did not receive this
treatment. They concluded that this therapy method may be regarded as a valuable tool for
achieving local disease management and demonstrates both safety and technical feasibility
when administered to carefully selected patients with a longer local disease-free interval
compared to surgery alone [67].
Diagnostics 2023,13, 2982 11 of 13
7. Conclusions
It is critical to emphasize that most general pathologists still struggle with the diagnosis
and categorization of thymomas. A detailed clinical and radiological evaluation is necessary
for the diagnosis. The most crucial issue is to be aware of the many patterns of growth that
thymomas might exhibit in order to prevent misdiagnosis. Even though the TNM staging
system is a useful method for thymoma staging, many studies view the modified Masaoka
system as the gold standard. Proper anatomical staging continues to be of significant
assistance to the clinical team in directing their therapy.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The author declares no conflict of interest.
References
1. Kalhor, N.; Moran, C. Mediastinal Pathology; Springer: Berlin/Heidelberg, Germany, 2019.
2.
Suster, S.; Moran, C.A. Thymoma classification: Current status and future trends. Am. J. Clin. Pathol.
2006
,125, 542–554.
[CrossRef]
3. Anastasiadis, K.; Ratnatunga, C. The Thymus Gland; Springer: Berlin/Heidelberg, Germany, 2007.
4.
Tsao, M.-S.; Nicholson, A.G.; Maleszewski, J.J.; Marx, A.; Travis, W.D. Reprint of “Introduction to 2021 WHO Classification of
Thoracic Tumors”. J. Thorac. Oncol. 2022,17, 337–340. [CrossRef] [PubMed]
5. Rich, A.L. Epidemiology of thymoma. J. Thorac. Dis. 2020,12, 7531. [CrossRef]
6.
Detterbeck, F.C.; Stratton, K.; Giroux, D.; Asamura, H.; Crowley, J.; Falkson, C.; Filosso, P.L.; Frazier, A.A.; Giaccone, G.; Huang, J.
The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: Proposal for an evidence-based stage classification system for the
forthcoming (8th) edition of the TNM classification of malignant tumors. J. Thorac. Oncol. 2014,9, S65–S72. [CrossRef]
7.
Lavini, C.; Moran, C.A.; Morandi, U.; Schoenhuber, R. Thymus Gland Pathology: Clinical, Diagnostic and Therapeutic Features;
Springer Science & Business Media: Berlin/Heidelberg, Germany, 2009.
8. Engels, E.A. Epidemiology of thymoma and associated malignancies. J. Thorac. Oncol. 2010,5, S260–S265. [CrossRef]
9.
Harris, K.; Elsayegh, D.; Azab, B.; Alkaied, H.; Chalhoub, M. Thymoma calcification: Is it clinically meaningful? World J. Surg.
Oncol. 2011,9, 95. [CrossRef]
10.
Benveniste, M.F.; Rosado-de-Christenson, M.L.; Sabloff, B.S.; Moran, C.A.; Swisher, S.G.; Marom, E.M. Role of imaging in the
diagnosis, staging, and treatment of thymoma. Radiographics 2011,31, 1847–1861. [CrossRef]
11. Kalhor, N.; Moran, C.A. Thymoma: Current concepts. Oncology 2012,26, 975.
12.
Tian, D.; Shiiya, H.; Sato, M.; Sun, C.B.; Anraku, M.; Nakajima, J. Tumor location may affect the clinicopathological features and
prognosis of thymomas. Thorac. Cancer 2019,10, 2096–2105. [CrossRef] [PubMed]
13.
Bernard, C.; Frih, H.; Pasquet, F.; Kerever, S.; Jamilloux, Y.; Tronc, F.; Guibert, B.; Isaac, S.; Devouassoux, M.; Chalabreysse, L.
Thymoma associated with autoimmune diseases: 85 cases and literature review. Autoimmun. Rev. 2016,15, 82–92. [CrossRef]
14.
Mao, Z.-F.; Mo, X.-A.; Qin, C.; Lai, Y.-R.; Hackett, M.L. Incidence of thymoma in myasthenia gravis: A systematic review. J. Clin.
Neurol. 2012,8, 161–169. [CrossRef]
15.
López-Cano, M.; Ponseti-Bosch, J.M.; Espin-Basany, E.; Sánchez-García, J.L.; Armengol-Carrasco, M. Clinical and pathologic
predictors of outcome in thymoma-associated myasthenia gravis. Ann. Thorac. Surg. 2003,76, 1643–1649. [CrossRef]
16.
Gupta, R.; Marchevsky, A.M.; McKenna, R.J.; Wick, M.; Moran, C.; Zakowski, M.F.; Suster, S. Evidence-based pathology and the
pathologic evaluation of thymomas: Transcapsular invasion is not a significant prognostic feature. Arch. Pathol. Lab. Med.
2008
,
132, 926–930. [CrossRef]
17.
Okuma, Y.; Hosomi, Y.; Watanabe, K.; Yamada, Y.; Horio, H.; Maeda, Y.; Okamura, T.; Hishima, T. Clinicopathological analysis of
thymic malignancies with a consistent retrospective database in a single institution: From Tokyo Metropolitan Cancer Center.
BMC Cancer 2014,14, 349. [CrossRef] [PubMed]
18.
Weissferdt, A.; Kalhor, N.; Bishop, J.A.; Jang, S.J.; Ro, J.; Petersson, F.; Wu, B.; Langman, G.; Bancroft, H.; Bi, Y. Thymoma: A
clinicopathological correlation of 1470 cases. Hum. Pathol. 2018,73, 7–15. [CrossRef] [PubMed]
19.
Weis, C.-A.; Yao, X.; Deng, Y.; Detterbeck, F.C.; Marino, M.; Nicholson, A.G.; Huang, J.; Ströbel, P.; Antonicelli, A.; Marx, A. The
impact of thymoma histotype on prognosis in a worldwide database. J. Thorac. Oncol. 2015,10, 367–372. [CrossRef]
20.
Luo, T.; Zhao, H.; Zhou, X. The clinical features, diagnosis and management of recurrent thymoma. J. Cardiothorac. Surg.
2016
,
11, 140. [CrossRef]
21.
Suster, S.; Moran, C.A. Histologic classification of thymoma: The World Health Organization and beyond. Hematol./Oncol. Clin.
N. Am. 2008,22, 381–392. [CrossRef]
Diagnostics 2023,13, 2982 12 of 13
22. Pe, B. Thymoma: A clinicopathologic study. J. Thorac. Cardiovasc. Surg. 1961,42, 424–444.
23.
Marino, M.; Müller-Hermelink, H.K. Thymoma and thymic carcinoma: Relation of thymoma epithelial cells to the cortical and
medullary differentiation of thymus. Virchows Arch. A 1985,407, 119–149. [CrossRef]
24.
Suster, S.; Moran, C.A. Thymoma, atypical thymoma, and thymic carcinoma: A novel conceptual approach to the classification of
thymic epithelial neoplasms. Am. J. Clin. Pathol. 1999,111, 826–833. [CrossRef] [PubMed]
25. Ruangchira-urai, R.; Treetipsatit, J. Update in Thymoma for Surgical Pathologists. Asian Arch. Pathol. 2015,11, 114–132.
26.
Johnson, S.B.; Eng, T.Y.; Giaccone, G.; Thomas, C.R., Jr. Thymoma: Update for the new millenium. Oncologist
2001
,6, 239–246.
[CrossRef]
27.
Oramas, D.M.; Moran, C.A. Thymoma: Histologically a heterogenous group of tumors. Semin. Diagn. Pathol.
2022
,39, 99–104.
[CrossRef]
28.
Tian, W.; Sun, Y.; Wu, Q.; Jiao, P.; Ma, C.; Yu, H.; Huang, C.; Tong, H. Surgical outcomes of 215 patients with thymic epithelial
tumors: A single-center experience. Thorac. Cancer 2020,11, 1840–1847. [CrossRef]
29.
Okumura, M.; Yoshino, I.; Yano, M.; Watanabe, S.-I.; Tsuboi, M.; Yoshida, K.; Date, H.; Yokoi, K.; Nakajima, J.; Toyooka, S.-I.
Tumour size determines both recurrence-free survival and disease-specific survival after surgical treatment for thymoma. Eur. J.
Cardio-Thorac. Surg. 2019,56, 174–181. [CrossRef]
30.
Weissferdt, A.; Hernandez, J.C.; Kalhor, N.; Moran, C.A. Spindle cell thymomas: An immunohistochemical study of 30 cases.
Appl. Immunohistochem. Mol. Morphol. 2011,19, 329–335. [CrossRef]
31.
Weissferdt, A.; Moran, C.A. The histomorphologic spectrum of spindle cell thymoma. Hum. Pathol.
2014
,45, 437–445. [CrossRef]
[PubMed]
32.
Moran, C.A.; Kalhor, N.; Suster, S. Invasive spindle cell thymomas (WHO type a) a Clinicopathologic correlation of 41 cases. Am.
J. Clin. Pathol. 2010,134, 793–798. [CrossRef]
33.
Kelly, R.J. Thymoma versus thymic carcinoma: Differences in biology impacting treatment. J. Natl. Compr. Cancer Netw.
2013
,11,
577–583. [CrossRef] [PubMed]
34.
Moran, C.A.; Walsh, G.; Suster, S.; Kaiser, L. Thymomas II: A clinicopathologic correlation of 250 cases with a proposed staging
system with emphasis on pathologic assessment. Am. J. Clin. Pathol. 2012,137, 451–461. [CrossRef] [PubMed]
35. Frank, C.D.; Ahmad, Z. Thymoma: Current diagnosis and treatment. Chin. Med. J. 2013,126, 2186–2191.
36.
Suster, S.; Moran, C.A. Micronodular thymoma with lymphoid B-cell hyperplasia: Clinicopathologic and immunohistochemical
study of eighteen cases of a distinctive morphologic variant of thymic epithelial neoplasm. Am. J. Surg. Pathol.
1999
,23, 955.
[CrossRef]
37.
Oramas, D.M.; Moran, C.A. Micronodular thymomas with prominent cystic changes: A clinicopathological and immunohisto-
chemical study of 25 cases. Int. J. Surg. Pathol. 2021,29, 352–357. [CrossRef] [PubMed]
38. Moran, C.A.; Suster, S.; Koss, M.N. Plasma cell–rich thymoma. Am. J. Clin. Pathol. 1994,102, 199–201. [CrossRef] [PubMed]
39.
Perez, Y.E.; Moran, C.A. The thymus: General concepts on embryology, anatomy, histology and immunohistochemistry. Semin.
Diagn. Pathol. 2022,39, 86–91. [CrossRef] [PubMed]
40.
Suster, S.; Moran, C.A.; Chan, J.K. Thymoma with pseudosarcomatous stroma: Report of an unusual histologic variant of thymic
epithelial neoplasm that may simulate carcinosarcoma. Am. J. Surg. Pathol. 1997,21, 1316–1323. [CrossRef] [PubMed]
41.
Weissferdt, A.; Moran, C.A. Pax8 expression in thymic epithelial neoplasms: An immunohistochemical analysis. Am. J. Surg.
Pathol. 2011,35, 1305–1310. [CrossRef]
42.
Weissferdt, A.; Fujimoto, J.; Kalhor, N.; Rodriguez, J.; Bassett, R.; Wistuba, I.I.; Moran, C.A. Expression of PD-1 and PD-L1 in
thymic epithelial neoplasms. Mod. Pathol. 2017,30, 826–833. [CrossRef]
43.
Wei, Y.-F.; Chu, C.-Y.; Chang, C.-C.; Lin, S.-H.; Su, W.-C.; Tseng, Y.-L.; Lin, C.-C.; Yen, Y.-T. Different pattern of PD-L1, IDO, and
FOXP3 Tregs expression with survival in thymoma and thymic carcinoma. Lung Cancer 2018,125, 35–42. [CrossRef]
44.
Enkner, F.; Pichlhöfer, B.; Zaharie, A.T.; Krunic, M.; Holper, T.M.; Janik, S.; Moser, B.; Schlangen, K.; Neudert, B.; Walter, K.
Molecular profiling of thymoma and thymic carcinoma: Genetic differences and potential novel therapeutic targets. Pathol. Oncol.
Res. 2017,23, 551–564. [CrossRef]
45.
Liu, D.; Zhang, P.; Zhao, J.; Yang, L.; Wang, W. Identification of molecular characteristics and new prognostic targets for thymoma
by multiomics analysis. BioMed Res. Int. 2021,2021, 5587441. [CrossRef]
46.
Pardini, E.; Cucchiara, F.; Palumbo, S.; Tarrini, G.; Di Vita, A.; Coppedè, F.; Nicolì, V.; Guida, M.; Maestri, M.; Ricciardi, R. Somatic
mutations of thymic epithelial tumors with myasthenia gravis. Front. Oncol. 2023,13, 1224491. [CrossRef] [PubMed]
47.
Ströbel, P.; Hohenberger, P.; Marx, A. Thymoma and thymic carcinoma: Molecular pathology and targeted therapy. J. Thorac.
Oncol. 2010,5, S286–S290. [CrossRef] [PubMed]
48.
Suster, D.I.; Basu, M.K.; Mackinnon, A.C. Molecular pathology of thymoma and thymic carcinoma. Rev. J. Cancer Metastasis Treat.
2022,5, 8–19. [CrossRef]
49.
Valavanis, C.; Stanc, G.M.; Baltayiannis, N. Classification, histopathology and molecular pathology of thymic epithelial tumors: A
review. J. BUON 2021,26, 1198–1207.
50. Yu, L.; Ke, J.; Du, X.; Yu, Z.; Gao, D. Genetic characterization of thymoma. Sci. Rep. 2019,9, 2369. [CrossRef]
51.
Masaoka, A.; Monden, Y.; Nakahara, K.; Tanioka, T. Follow-up study of thymomas with special reference to their clinical stages.
Cancer 1981,48, 2485–2492. [CrossRef] [PubMed]
Diagnostics 2023,13, 2982 13 of 13
52.
Detterbeck, F.C.; Nicholson, A.G.; Kondo, K.; Van Schil, P.; Moran, C. The Masaoka-Koga stage classification for thymic
malignancies: Clarification and definition of terms. J. Thorac. Oncol. 2011,6, S1710–S1716. [CrossRef] [PubMed]
53. Moran, C.A. Thymoma Staging: An analysis of the different schemas. Adv. Anat. Pathol. 2021,28, 298–306. [CrossRef]
54.
Weissferdt, A.; Moran, C.A. Staging of thymic epithelial neoplasms: Thymoma and thymic carcinoma. Pathol.-Res. Pract.
2015
,
211, 2–11. [CrossRef] [PubMed]
55. Weissferdt, A.; Moran, C.A. Staging of primary mediastinal tumors. Adv. Anat. Pathol. 2013,20, 1–9. [CrossRef] [PubMed]
56.
Kalhor, N.; Moran, C.A. Thymoma and thymic carcinoma: A perspective on the NCCN clinical practice guidelines in oncology.
Mediastinum 2018,2, 49. [CrossRef]
57. Markowiak, T.; Hofmann, H.-S.; Ried, M. Classification and staging of thymoma. J. Thorac. Dis. 2020,12, 7607. [CrossRef]
58.
Amin, M.B.; Edge, S.B.; Greene, F.L.; Byrd, D.R.; Brookland, R.K.; Washington, M.K.; Gershenwald, J.E.; Compton, C.C.; Hess,
K.R.; Sullivan, D.C. AJCC Cancer Staging Manual; Springer: Berlin/Heidelberg, Germany, 2017; Volume 1024.
59.
Nicholson, A.G.; Detterbeck, F.C.; Marino, M.; Kim, J.; Stratton, K.; Giroux, D.; Asamura, H.; Crowley, J.; Falkson, C.; Filosso, P.L.
The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: Proposals for the T Component for the forthcoming (8th) edition of
the TNM classification of malignant tumors. J. Thorac. Oncol. 2014,9, S73–S80. [CrossRef]
60.
Tamburini, N.; Maniscalco, P.; Migliorelli, A.; Nigim, F.; Quarantotto, F.; Maietti, E.; Cavallesco, G. Thymic epithelial tumors:
Prognostic significance and relationship between histology and the new TNM staging system. Thorac. Cardiovasc. Surg.
2020
,68,
433–439. [CrossRef] [PubMed]
61.
Yamakawa, Y.; Masaoka, A.; Hashimoto, T.; Niwa, H.; Mizuno, T.; Fujii, Y.; Nakahara, K. A tentative tumor–node–metastasis
classification of thymoma. Cancer 1991,68, 1984–1987. [CrossRef]
62.
Berghmans, T.; Durieux, V.; Holbrechts, S.; Jungels, C.; Lafitte, J.-J.; Meert, A.-P.; Moretti, L.; Ocak, S.; Roelandts, M.; Girard,
N. Systemic treatments for thymoma and thymic carcinoma: A systematic review. Lung Cancer
2018
,126, 25–31. [CrossRef]
[PubMed]
63.
Givel, J.-C. Surgery of the Thymus: Pathology, Associated Disorders and Surgical Technique; Springer Science & Business Media:
Berlin/Heidelberg, Germany, 2012.
64. Schmitt, J.; Loehrer, P.J., Sr. The role of chemotherapy in advanced thymoma. J. Thorac. Oncol. 2010,5, S357–S360. [CrossRef]
65.
Zhu, G.; He, S.; Fu, X.; Jiang, G.; Liu, T. Radiotherapy and prognostic factors for thymoma: A retrospective study of 175 patients.
Int. J. Radiat. Oncol. Biol. Phys. 2004,60, 1113–1119. [CrossRef]
66.
Mangi, A.A.; Wright, C.D.; Allan, J.S.; Wain, J.C.; Donahue, D.M.; Grillo, H.C.; Mathisen, D.J. Adjuvant radiation therapy for
stage II thymoma. Ann. Thorac. Surg. 2002,74, 1033–1037. [CrossRef] [PubMed]
67.
Aprile, V.; Bacchin, D.; Korasidis, S.; Nesti, A.; Marrama, E.; Ricciardi, R.; Petrini, I.; Ambrogi, M.C.; Paladini, P.; Lucchi,
M. Surgical treatment of pleural recurrence of thymoma: Is hyperthermic intrathoracic chemotherapy worthwhile? Interact.
CardioVascular Thorac. Surg. 2020,30, 765–772. [CrossRef] [PubMed]
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