—  SHORT COURSE #07  —

Tumors of the Mediastinum
Saul Suster
Cesar Moran
Paul E. Wakely, Jr.

Section 1 - Primary Thymic Epithelial Neoplasms

Saul Suster
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, [1] 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 [1] 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. [2] 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. [2, 3, 4, 5, 6, 7, 8, 9] Based on these observations, Levine and Rosai [10] 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 [11]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 [12] 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 [13] 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 significance.

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, [14] 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. [14]

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).

TABLE I
WHO14 Traditional
(Bernatz et al)[1]		Kirchner & Muller-Hermelink[12]
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. [15] 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. [16]

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 specimen. [17, 18]

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 [14] 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. [15] 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, [19] thymoma with pseudosarcomatous stroma (so-called "metaplastic" thymoma), [20] 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 [21] 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, [16] by other independent studies. In fact, conflicting results have been published in the literature. For example, in a study by Chalabreysse et al [22], 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 [21], 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. [23]

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. [24] 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. [24] 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 neoplasms.

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 adulthood.

In a recent large multicenter study by Rieker and colleagues, [21] 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 [25] 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 multifactorial.

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, [26] 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. [27]

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). [27] 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.


References:
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