Tumors of the Mediastinum
Paul E. Wakely, Jr.
Section 1 -
Primary Thymic Epithelial Neoplasms
The Ohio State University
Columbus, OH, USA
The histologic classification of primary thymic epithelial neoplasms has been a source of
controversy for many years. A number of classification schemes have been proposed over the years, none
of which seems to have attained sufficiently wide acceptance.
Historically, the morphologic classification that gained the widest acceptance was the one
proposed by Bernatz and associated from the Mayo Clinic in 1961,  which classified thymomas
into 4 groups according to the shape of the neoplastic epithelial cells (round vs. spindle cells) and the
relative proportion of lymphocytes. The Bernatz et al  classification, and variants thereof,
have come to be known collectively as the "traditional" classification of thymoma.
Despite apparently good reproducibility among pathologists for the use of this
classification, it was soon acknowledged that the various histologic types did not permit a good
correlation with clinical outcome, and was therefore not very useful for prognostication. 
The majority of studies seemed to indicate that the most reliable parameter for assessing clinical
behavior in these tumors was the status of capsular integrity.
Based on these observations,
Levine and Rosai  in a review article on thymic hyperplasia and neoplasia published in 1978,
proposed that the encapsulated tumors were benign and that all invasive tumors should be regarded as
malignant. They further proposed subdividing the malignant tumors into two categories: malignant
thymoma type I for those cases that showed identical histology to the benign thymomas, except for their
invasive properties; and malignant thymoma type II for those tumors that displayed overt cytologic
evidence of malignancy (also designated as thymic carcinoma).
Two additional approaches to the histologic classification of thymic epithelial neoplasms
were introduced in 1985. One was a proposal by Drs. Marino and Muller-Hermelink that
thymomas be classified from a histogenetic point of view based on whether the tumor cells were derived
from the thymic cortex or the medulla, or from a combination of both. The authors thus classified
thymomas into cortical, medullary, and mixed. This schema was later modified by Kirschner and
Muller-Hermelink  to add two additional categories, the predominantly cortical (also known as
"organoid") and the well-differentiated thymic carcinoma.
The other histologic classification of thymoma presented the same year was that of Verley
and Hollman  from France . They divided these tumors into 4 categories: spindle cell
thymoma, lymphocyte-rich thymoma, differentiated epithelial thymoma, and undifferentiated epithelial
thymoma. In their study, the authors found that although invasiveness often paralleled the histologic
subtype, these two parameters seemed to represent distinct variables of independent prognostic
By the year 1990, the nomenclature of thymic epithelial neoplasms was sufficiently
confusing that the World Health Organization (WHO) commissioned Juan Rosai to select a panel of
experts for devising a new, uniform histologic classification for these tumors. After several years of
deliberation, this panel produced a compromise formula that designated thymic epithelial neoplasms
according to letters and numbers into 6 categories. This WHO schema was published in 1999, 
and soon achieved wide acceptance and recognition. It is interesting to note that in the WHO monograph
the authors indicated that the new schema was not meant as a new
classification, but rather as a means for facilitating comparison among the various terms from the
already existing classifications. 
The WHO classification of thymic epithelial neoplasms divided these tumors based on the
cytologic appearance of the tumor cells into three classes designated as types A, B and C. Type A thymoma
was defined as a tumor primarily composed of a proliferation of oval or spindle epithelial cells, usually
with scant lymphocytes. Type B was defined as a tumor composed of round, dendritic or epithelioid cells
with variable numbers of lymphocytes. These tumors were further subdivided according to the proportional
increase (in relation to the lymphocytes) and emergence of atypia of the neoplastic epithelial cells into
types B1, B2 and B3. Tumors showing a combination of the above were designated as type AB. Tumors
showing overt cytologic features of malignancy were designated as thymoma type C.
The introduction of the WHO schema in 1999 was a major step forward in the field for
several reasons. First, it provided for the first time a unified schema supported by a reputable
international organization and a distinguished panel of experts for the histologic classification of
these tumors. The schema also recognized several of the standard morphologic appearances that these
tumors can adopt. By providing a means of equating these tumors among the different existing
classifications, they helped dispel the misconception that the different terms from the competing
classifications represented different biologic entities, when in reality they all referred to the same
morphotypes, only under different designations (Table I).
(Bernatz et al)
|Kirchner & Muller-Hermelink|
|Type A ||Spindle cell thymoma ||Medullary thymoma|
|Type AB ||(Combined thymoma) ||Mixed thymoma|
|Type B1 ||Lymphocyte-rich thymoma ||Predominantly cortical|
|Type B2 ||Mixed lymphoepithelial ||Cortical thymoma|
|Type B3 ||Epithelial-rich thymoma ||Well-differentiated thymic Carcinoma|
|Type C ||---- ||Other types of thymic carcinoma|
A new version of the classification of thymic epithelial neoplasms was recently published
by the WHO.  This new version has essentially retained the same criteria and terminology as
the one in the original proposal for the types A, AB, and B1, 2 and 3. The only significant change was
the elimination of the type C thymoma from the original schema, which has now been relegated to a
separate category under the designation of thymic carcinoma. There are, however, two important additions
to the new schema. The first is the introduction of several unusual morphologic types of thymoma that
could not adequately fit into any of the other existing categories, including "metaplastic" thymoma,
micronodular thymoma with B-cell hyperplasia, and others. The second innovation was the proposal of a
grading of malignancy for the various histologic types. Thus, thymomas of type A and AB are claimed to
represent benign tumors without competence for metastasis or fatal outcome; type B1 is designated as a
low-grade malignant tumor; type B2 as a slightly more aggressive tumor; and type B3 (in advanced stages)
as an aggressive malignant neoplasm similar to thymic carcinoma. This claim was based on a single study
of 200 cases from China by Chen and colleagues. 
Problem Areas in the WHO Classification of Thymoma
Despite the progress achieved with the introduction of the WHO schema, several problems
still remain with the application of this classification in clinical practice. These problems include:
difficulties with some of the histopathologic criteria for the various subtypes; the existence of
histologic variants that cannot be fit into any of the standard types in the current schema; problems
associated with interobserver variability and reproducibility; and conflicting claims regarding the
clinical significance and prognostic value for the various WHO subtypes of thymoma.
A significant problem is posed in clinical practice by the great variability and overlap
that exists between some of the various types in the WHO classification, particularly for the type B
thymoma. The various definitions proposed by the WHO for the various subtypes in the B group can show a
great degree of overlap. It is claimed that the main difference between types B1 and B2 lies in the size
of the epithelial cells, these being larger and more numerous in type B2 than in B1. The problem in real
life is that thymomas are characterized by marked cellular heterogeneity, and the histologic features of
the tumor, including the size of the epithelial cells as well as their relative proportion of
lymphocytes, can vary considerably from field to field within the same lesion. Thus, correctly assigning
a tumor to any given WHO type may be relatively simple on small biopsy samples but can turn into a
frustrating exercise when reviewing numerous sections from an adequately sampled resected
Another problem with the morphologic definition of type B thymoma is that the published
criteria do not actually match the proposed rationale for their terminology. In the original proposal by
the WHO  it was stated that type B thymomas were to be subdivided on the basis of the
"proportional increase (in relation to the lymphocytes) and emergence of atypia of the neoplastic
epithelial cells" into 3 subtypes (B1 through 3). According to the histologic definition of the WHO,
however, type B3 is defined as a tumor composed of medium-sized, polygonal epithelial cells that are
smaller than those in type B2, with less prominent nucleoli, an obvious
contradiction with the proposed rationale.  Moreover, gradations and transitions between
these different cell types, are extremely common in these tumors, making it difficult sometimes to draw
the line between the various subtypes.
Another problem with the current WHO classification of thymoma is the existence of unusual
morphologic variants that cannot be fit into any of the existing categories in the schema. These include
micronodular thymoma with B-cell hyperplasia,  thymoma with pseudosarcomatous stroma
(so-called "metaplastic" thymoma),  and others. It is not stated in the WHO monograph where
such tumors lie within their schema of biologic behavior for these lesions. As more of these unusual
variants of thymoma are described, what criteria are to be applied for their prognostication?
Another significant problem with the current WHO schema is the lack of interobserver
reproducibility. In a recent large, multicenter study by Rieker et al  it was shown that
interobserver agreement for the subgroup of WHO type B thymomas was poor (0.49 using Kappa statistics,
with a value over 0.8 indicating excellent agreement, and a value of 0.4 or less indicating poor
agreement). The fact is that interobserver agreement for the WHO schema can be quite poor, particularly
for pathologists who are not very experienced with these tumors. Application of this schema therefore
often requires seeking consultation with an "expert" for correct classification of the lesions. Such
difficulties are always inherent to any system of classification that involves complex categories with
some degree of overlap among the different subtypes, such as occurs with thymic epithelial neoplasms
which are characterized by marked morphologic heterogeneity.
Finally, the purported stepwise correlation between the various alphabetic and numerical
types of thymoma in the WHO schema and their clinical behavior has not been reproduced, other than in the
single study by Chen et al,  by other independent studies. In fact, conflicting results have
been published in the literature. For example, in a study by Chalabreysse et al , type A and
AB thymomas showed a more aggressive behavior than all type B tumors, and the differences in survival
between types B1-3 were minimal. In the study by Rieker et al , type AB and B1 thymoma
showed the most favorable outcome, while type A and B2 behaved much worse, with overlapping survival
curves. Moreover, there is a large body of literature that contradicts the claim of the WHO panel that
type A thymoma is a benign tumor without capability for aggressive and malignant behavior. There are
numerous cases on record of spindle cell thymoma (WHO type A) that invaded, recurred, metastasized and
lead to the demise of the patient. 
Novel Approaches to the Classification of Thymoma
Several novel approaches to the classification of thymic epithelial neoplasms other than
the WHO schema have been proposed in recent years.I will only refer here to
one in particular. In the same year that the original WHO proposal was published (1999), we also
presented a novel conceptual approach for the histologic classification of primary thymic epithelial
neoplasms.  This proposal was based on the premise that these tumors form part of a
continuous spectrum of lesions that range from well-differentiated, to moderately-differentiated, to
poorly-differentiated neoplasms. The well-differentiated tumors in our schema corresponded to those
designated by convention as thymoma. The poorly-differentiated tumors corresponded to cases designated
by convention as thymic carcinoma. The moderately-differentiated neoplasm in our schema corresponded to
intermediate forms for which we proposed the term "atypical thymoma".
The determination of the degree of differentiation in these tumors can be established based on the
identification of the organotypical features of differentiation of the thymus and the degree of cytologic
atypia of the neoplastic epithelial cells.  Thus, tumors displaying most or all of the
organotypical features of differentiation of the thymus and without atypia are classified as
well-differentiated (i.e., thymoma); tumors showing only partial preservation of the organotypical
features of the thymus with mild to moderate nuclear atypia are categorized as moderately-differentiated
(i.e., atypical thymoma); and tumors showing complete loss of the organotypical features of
differentiation of the thymus with overt cytologic evidence of atypia are designated as
poorly-differentiated (i.e., thymic carcinoma).
The problem with applying this schema is that the "normal" thymus can vary in its morphologic
appearance depending on the age of the patient and the functional status of the gland. Thus, the
"normal" thymus of infancy and childhood is quite different from the "normal" thymus in the adult. In
childhood and infancy, when the gland is at its peak of functional activity, the characteristic
cortico-medullary architecture of the thymus is well preserved, the thymic epithelial cells are
predominantly round with vesicular nuclei and ample cytoplasm, and the stroma contains abundant immature
T-lymphocytes. With loss of the functional activity of the thymus (i.e., recruitment and programming of
T-memory cells), the thymus undergoes a process of involution, whereby the lymphocytes decrease in number
and are replaced by fat, and the epithelial cells undergo atrophy and diminish in size, adopting a small,
spindled appearance. Thus, tumors in which the cells are recapitulating either the involuted spindle
cells of the adult thymus, or the large, round, epithelioid cells admixed with abundant lymphocytes of
the normal thymus of childhood and adolescence, can be regarded as examples of well-differentiated
This classification is simple, easily reproducible, and does not depend on any special stains or
techniques for diagnosis. It can be applied based on the examination of routinely stained sections, and
only requires familiarity with the organotypical features of differentiation of the normal thymus,
whether in its functionally active phase during infancy and childhood, or in its inactive phase during
In a recent large multicenter study by Rieker and colleagues,  the authors found that when
their tumors were lumped into three categories (by merging the WHO types A, AB, B1 and B2 into a single
category; B3 as a second category, and WHO type C as a third category), classes with good discriminatory
power with respect to survival were obtained and superior interobserver reproducibility was achieved for
the classification of their tumors. Similar results were also previously obtained by Quintanilla et
al  utilizing the histogenetic classification. It thus appears that simplifying the current
WHO schema by merging some of its categories may actually not only improve our ability to correctly
diagnose these tumors but may also facilitate their accurate prognostication (Table II).
Table II: Comparison of Suster & Moran Classification with WHO.
|Suster & Moran ||WHO|
|Thymoma ||Types A, AB, B1, B2|
|Atypical Thymoma ||Type B3|
|Thymic Carcinoma ||Type C (thymic carcinoma)|
Prognostication in Thymoma
The issue of prognostication in thymoma is still controversial. For many years it was
held that staging was the only reliable parameter for assessing the behavior of these tumors. In more
recent years, histology has been pushed to the forefront as another important and independent prognostic
parameter. We believe that prognosis of thymoma cannot be based on a single parameter but is
Another important parameter that has been studied in recent years for the prognosis of
thymoma is the status of resectability of the tumor. In a large study by Regnard et al, 
complete surgical excision of the tumor at the time of the initial surgery was found to be the most
significant independent prognostic factor by multivariate regression analysis (P <0.00001). A meta-analysis of several large studies on thymoma over a 23
year period also showed that status of resectability was one of the most significant prognostic
parameters for the assessment of clinical behavior in these tumors. 
It thus becomes apparent that prognosis in thymoma is multifactorial and requires taking
into consideration at least three circumstances, including histology, staging and status of
resectability. We have previously proposed a combined approach to the assessment of prognosis for these
tumors that takes into consideration these three parameters and divides the lesions into favorable and
unfavorable prognostic categories (Table III).  Although this still requires validation
through clinical studies, we believe adoption of this system could help improve our ability to predict
the clinical behavior of these lesions and adequately plan for the management of these patients.
Table III: Proposed prognostic categories for thymic epithelial neoplasms
(excluding thymic carcinoma).
|FAVORABLE PROGNOSTIC CATEGORIES:|
|Group I: Encapsulated or minimally invasive thymoma; completely excised; WHO types A, AB, B1, B2.|
|Group II: Encapsulated or minimally invasive thymoma; completely excised; WHO type B3.|
|Group III: Widely invasive thymoma or thymoma with implants; completely excised; all histologic types.|
|UNFAVORABLE PROGNOSTIC CATEGORIES:|
|Group IV: Widely invasive thymoma or thymoma with implants; incompletely excised; allhistologic categories.|
|Group V: Widely invasive thymoma with or without intrathoracic metastases; unresectable/biopsy only; all histologic types.|
|Group VI: Widely invasive thymoma with distant metastasis; unresectable/biopsy only; all histologic types.|
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