Thymoma, Atypical Thymoma, and Thymic Carcinoma A Novel ...

Anatomic Pathology / CLASSIFICATION OF THYMIC EPITHELIAL NEOPLASMS

Thymoma, Atypical Thymoma, and Thymic Carcinoma A Novel Conceptual Approach to the Classification of Thymic Epithelial Neoplasms Saul Suster, MD,, and Cesar A. Moran, MD2 Key Words: Thymoma; Atypical thymoma; Thymic carcinoma; Thymic neoplasms; Mediastinum; Differentiation

Abstract Primary thymic epithelial neoplasms have been the subject of much controversy in recent years owing to the difficulties posed by these tumors for precise histopathologic typing and prognosticaiion. A number of classification schemes using different terminology have been proposed, none of which has satisfactorily managed to address all the problems and concerns related to these tumors. We present a proposal for a novel approach to the histologic classification of primary thymic epithelial neoplasms that is based on morphologic features of differentiation. The principle behind this classification scheme is that the determinaiion of the cytologic degree ofatypia and the identification of the organotypical features of thymic differentiation may permit accurate classification of these neoplasms into 3 simple and reproducible diagnostic categories: thymoma, atypical thymoma, and thymic carcinoma. We further reiterate the traditional concept that tumor staging, not histopathologcc typing, has a more crucial role for accurate and reliable prognosiicaiion for the better differentiated forms of these tumors.

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The classification of thymic epithelial neoplasms has remained a subject of controversy for many years. The main reason for this has been our inability to predict the biologic behavior of these lesions from their morphologic features. Numerous examples are on record in the literature of perfectly "benign-appearing" thymomas that recurred, metastasized, and followed a fatal outcome.1-6 This has led to serious problems in terminology. When do we call a thymoma benign and when do we call it malignant? Most observers have noted that one of the most reliable features for predicting clinical behavior of thymomas is the status of capsular integrity, with the cases that are invasive having a greater propensity for aggressive behavior than those that are completely encapsulated.7-10 How then do we report on thymomas when they appear "typical" and show no invasion? Levine and Rosai" attempted to address this problem by designating thymomas as benign or malignant depending on a combination of cytologic features and the status of capsular integrity. Over time, all thymomas that were invasive came to be indiscriminately regarded as "malignant thymomas," irrespective of their histologic features. More recently, Muller-Hermelink and associates have proposed that histologic features of thymomas can be reliably correlated with prognosis and have created several categories, some of which are claimed to be benign, others low-grade or well-differentiated carcinomas, and others frankly high-grade malignant neoplasms.12_'4 Whereas the latter proposal has generated much attention as an attractive alternative for histologically categorizing these tumors, the application of such a scheme could be hazardous when carried to extremes, particularly when the status of capsular integrity is relegated to an obsolete or secondary role and

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Anatomic Pathology / REVIEW ARTICLE

histologic features are used as the single criterion for basing therapeutic decisions. Because of the often unpredictable nature of these tumors, we believe that all thymomas should be regarded as potentially malignant neoplasms and should, therefore, be approached as such irrespective of their histologic features or status of capsular integrity. In our opinion, the practical dilemma of how to separate the benign from the malignant cases based on histologic features may represent a futile exercise if we base our approach on the premise that all thymomas should be regarded as malignant neoplasms with a definite potential for fully aggressive and malignant behavior if left untreated. An analogy can be drawn with carcinoid tumors at various organs. Because of their generally indolent behavior and the fact that complete excision of small, well-circumscribed, and noninvasive lesions usually is curative, these tumors were for many years regarded as benign, with great care being taken to avoid the use of the term carcinoma or any other implication of malignancy. With recent progress in the understanding of these tumors, it has become increasingly apparent that carcinoids simply correspond to the better-differentiated end in the spectrum of a family of malignant neuroendocrine neoplasms and, as such, can be regarded for all practical purposes as essentially synonymous with well-differentiated or low-grade neuroendocrine carcinoma. 1516 The prognosis for these tumors, as in other tumor systems, depends on cytologic features and staging. If we acknowledge the premise that all thymomas should be regarded as potentially malignant neoplasms, then it follows that they, too, should be subject to standard grading and staging as in other tumor systems. The approach we present for the categorization of primary thymic epithelial neoplasms is thus based on the application of histologic grading as assessed by the degree of differentiation of the lesion combined with tumor staging. This combined approach, in our opinion, is likely to provide more clinically significant information for management and prognostication of these lesions than histologic typing or clinical staging alone.

Histologic Grading and Features of Differentiation of Thymic Epithelial Neoplasms Because of the complex nature of the thymus and the variegated appearance this organ is able to assume during the course of its maturation and involution, it has been difficult to identify the features that could serve as parameters for histologic grading of differentiation in these tumors. Traditionally, histologic grading has been based on the premise

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that most tumor systems evolve through a stepwise progression, leading to eventual loss of differentiation of the tumor cells. Unlike other epithelial tumor systems, in which a progression from a well-differentiated to moderately differentiated to poorly differentiated neoplasm generally is established easily, thymomas, because of their great variability in cytologic and architectural patterns, do not lend themselves easily to applying such criteria. In classic pathology, degrees of differentiation are based on the capability of a tumor to resemble its parent tissue. Thus, a well-differentiated adenocarcinoma is defined as a malignant epithelial neoplasm that forms glands that very closely resemble the normal epithelium from which it originated. The same principle should be expected to apply for thymoma, in which the degree of differentiation would be related to how closely the lesion resembles or recapitulates the "normal" gland. One of the problems encountered in applying this principle to the thymus is the variability in cell composition for the various cellular elements within the different compartments of the gland that will frequently result in tumors showing features that may partially or predominantly recapitulate the cortex or the medulla of the thymus. This has led to proposals for categorizing such tumors on a histogenetic basis depending on whether a cortical or medullary pattern of differentiation is observed.12-14 Our experience leads us to believe that thymomas, rather than differentiating exclusively in the direction of only one of the normal compartments of the thymus, will show a tendency to recapitulate the entire organ to various degrees. As such, even tumors showing features of differentiation that predominantly resemble the cortex or the medulla will, in many cases, at least focally disclose features characteristic of the other compartment of the gland when sufficiently sampled. Another difficulty is introduced by the fact that the normal thymus can differ dramatically in appearance depending on the age of the person. The normal mature thymus of a child, for example, will look quite different from the normal involuted thymus in older adults, which is characterized by a paucity of lymphoid elements and a predominance of small, oval to spindle, thymic epithelial cells, rather than the large round cells with vesicular nuclei typical of the mature thymus.17 In any event, the features in these tumors that resemble the organotypical features of the normal thymus (whether in its mature or involuted form) should serve as the criteria for determining a high degree of differentiation. Based on this principle, primary thymic epithelial neoplasms could be morphologically categorized depending on the degree to which they recapitulate the normal architecture and cytologic composition of the normal thymus. Tumors of the thymus in which all or most of the organotypical features of differentiation are present would correspond to well-differentiated neoplasms, whereas primary thymic

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epithelial neoplasms that lack most or all of the organotypical features of differentiation of the thymus would be categorized as poorly differentiated. In general, organotypical features of differentiation of the thymus refer to the features that most closely resemble the normal appearance of the thymus in its mature or involuted state. Some of the morphologic features that have been traditionally accepted as distinctive for thymic differentiation by conventional microscopy in the fully mature thymus include the following: (1) a well-developed lobular architecture as seen on scanning magnification, characterized by the formation of broad bands of fibrous tissue separating the tumor cells into angular lobules; (2) the presence of a dual cell population (neoplastic thymic epithelial cells and thymic lymphocytes) admixed in various proportions; (3) dilated perivascular spaces; (4) areas of medullary differentiation, as evidenced by the formation of well-circumscribed foci containing plump epithelial cells with scant lymphocytes within an otherwise cortical-appearing neoplastic population of cells, with or without the formation of Hassall corpuscles; and (5) the bland appearance of the neoplastic thymic epithelial cells, which generally lack cytologic features of malignancy (eg, increased nuclear/cytoplasmic ratio, nuclear pleomorphism and atypia, or mitotic activity). Because the thymus begins a process of involution shortly after puberty, the normal thymus in older adults will look quite different from that of children and adolescents and will be characterized by a predominance of small oval to spindle cells with scant lymphoid elements. The organotypical features of the thymus in adults will, thus, be quite different from those seen in the mature functional thymus of children and adolescents and often will include a bland-appearing proliferation of spindle cells with scant thymic l y m p h o c y t e s . Other features commonly encountered in the regressed thymus of older adults include cystic and glandular spaces and the formation of epithelial rosette-like structures, features that often are present in thymomas of spindle cell type. By using the aforementioned parameters and in keeping with conventional grading schemes applied to other organs, primary thymic epithelial neoplasms could be conceptually

divided into 3 categories: well-differentiated, moderately differentiated, and poorly differentiated neoplasms. The well-differentiated neoplasms correspond to the tumors in which all or most of the organotypical features of thymic differentiation are present, the poorly differentiated neoplasms are those in which all such features are lost or minimal, and the moderately differentiated category is represented by tumors showing features intermediate between the other 2. One of the problems encountered in the application of this classification is that of terminology. Traditionally, thymic epithelial neoplasms have been designated as thymoma or thymic carcinoma, with a third intermediate category, atypical thymoma, being increasingly recognized in recent years. Because the first 2 terms have been firmly entrenched in the literature, we have adapted the existing terminology into our classification scheme; thus, we classify primary thymic epithelial neoplasms into the following 3 categories: (1) thymoma, (2) atypical thymoma, and (3) thymic carcinoma (corresponding to well-differentiated, moderately differentiated, and poorly differentiated neoplasms, respectively) ITable II.1 8 Although this choice of terminology may not be viewed by all as nosologically ideal, it stands as a practical compromise that may offer an easily understandable vehicle for the application of the aforementioned scheme. Owing to historic precedent, we retained the designation of thymoma in this classification to categorize the better differentiated tumors, whereas the poorly differentiated neoplasms that already demonstrate total loss of the organotypical features of thymic differentiation and display overt cytologic features of malignancy are categorized, also in keeping with historic precedent, as thymic carcinoma. We have chosen the designation of atypical thymoma for the tumors that are characterized by histologic features that are intermediate between those of thymoma and thymic carcinoma. The first to formally acknowledge the existence of such intermediate forms were Lewis et al 6 from the Mayo Clinic (Rochester, MN) in a study that cited cases showing variable degrees of cytologic atypia that made them difficult to classify into any of the existing schemes. The authors indicated that such tumors

ITable II Comparison of Main Histologic Classifications of Thymic Epithelial Neoplasms Bernatzet al/1961-3 Predominantly thymoma Predominantly Predominantly Predominantly

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epithelial lymphocytic mixed spindle cell

Lcvine and Rosai/1v/s Benign thymoma (encapsulated) Malignant thymoma (invasive) Type I: without cytologic evidence of atypia Type II: with cytologic evidence of atypia (thymic carcinoma)

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Kirchner and MiillerHermelink/19891•, Medullary thymoma Mixed thymoma Cortical thymoma Predominantly cortical (organoid thymoma) Well-differentiated thymic carcinoma

Suster and Moran/1997l Thymoma (well-differentiated thymic epithelial neoplasm) Atypical thymoma (moderately differentiated thymic epithelial neoplasm) Thymic carcinoma (poorly differentiated thymic epithelial neoplasm)

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Anatomic Pathology / REVIEW ARTICLE

should be expected to behave in an intermediate manner between conventional thymoma and thymic carcinoma. In the past, such intermediate lesions often have been included in the category of epithelial-rich thymoma or thymoma of polygonal cell type; however, the existence of such intermediate forms has become increasingly recognized in the recent literature.101925 We fully acknowledge, however, that atypical thymoma, despite the presence of increased cytologic atypia and loss of some of the organotypical features of the normal thymus, is closer in the spectrum of differentiation to thymoma than to thymic carcinoma. Moreover, our experience and that of others has shown that the natural biologic behavior of these tumors is much closer to conventional thymoma than to thymic carcinoma.10'21,25 However, and for the sake of convenience, we believe it is of value to have an intermediate category of lesions as a practical means for categorizing tumors that already display cytologic and architectural features that are one step beyond what is expected in thymoma but do not quite fulfill the criteria for the diagnosis of thymic carcinoma. Staging of such tumors, as with their better differentiated counterparts (thymoma), should have a critical role for the assessment of prognosis.

Clinical Staging of Thymic Epithelial Neoplasms As with many other tumor systems, it is to be acknowledged that histologic categorization alone is insufficient to adequately predict biologic behavior and serve as a guide for therapy for patients with primary thymic epithelial neoplasms. The clinical staging of thymic epithelial neoplasms has undergone various revisions and updates over the years. The idea of clinically staging thymoma was introduced by Berg et al26 and later modified by Wilkins and Castleman.27 Rosai and Levine9 also emphasized that classifying thymomas as encapsulated and invasive was more valuable than any other method for predicting the outcome of these tumors. The most popular staging system for thymoma was that introduced by Masaoka et al28 in 1981, which essentially stratified patients depending on the gross and microscopic status of the capsule, spread of the tumor into adjacent structures, and the presence or absence of metastases ITable 21. A simplified modification of this staging scheme was later presented by Koga et al29 in which the tumors were divided into noninvasive (circumscribed and confined within the thymus) and invasive categories. The authors concluded that the application of this simplified staging scheme coupled with cytologic grading of the lesions offered the best parameters for predicting the prognosis for patients with thymoma. Unfortunately, this staging scheme did not make allowances for tumors corresponding to the spectrum of thymic carcinoma. To address

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this issue, these same authors subsequently developed a proposal for a separate pathologic TNM system for staging thymic carcinoma.30 It is our belief that a system for pathologic and clinical staging should be adopted that will apply to the entire spectrum of thymic epithelial neoplasms. Because of the rarity of thymic carcinomas and of lymph node metastases in thymoma, a very detailed TNM staging classification scheme would seem impractical for these tumors. Until more data become available on such neoplasms, a simplified working version of this scheme that can be applied across the entire spectrum of these lesions would incorporate the following stages: I, wellencapsulated tumors; II, grossly or microscopically invasive tumors; and III, tumors with evidence of lymph node or other distant metastases (Table 2). Combining this staging scheme with histopathologic characterization and grading of the lesions should provide a simplified and easily reproducible means of classifying and guiding the treatment of primary thymic epithelial neoplasms in clinical practice.

Histologic Characteristics of Thymoma, Atypical Thymoma, and Thymic Carcinoma The great morphologic variability and heterogeneity of the proliferating epithelial cell component in thymoma has been acknowledged amply and documented. Neoplastic epithelial cells in thymoma may show great variability in size and shape, nuclear features, and cytoplasmic characteristics. Such variability in their features may reflect different functional states or varying degrees of realized differentiation within any given neoplasm. The existence of a continuum of cytologic features is not uncommonly observed in thymomas.21'31 In fact, areas of transition between the various types of thymoma, atypical thymoma, and thymic carcinoma have been well documented.8'21'25,32~35 Categorization of thymic epithelial neoplasms should, thus, consider this variability, and tumors should be ideally classified by the predominant features as observed on examination of multiple sections from an adequately sampled specimen. Definitive categorization of thymic epithelial neoplasms based on limited biopsy sample material can become a hazardous exercise, and pathologists should limit themselves to stating the features seen in the available sample without attempting to make predictions about biologic behavior, status of capsular integrity, or malignant potential on such material, particularly when dealing with tumors in the better differentiated end of the spectrum. Ideally, the management of thymoma should include complete excision of the tumor, whenever clinically feasible, with thorough histologic examination to assess for cytoarchitectural features of atypia and status of capsular infiltration.

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•Table 21 Comparison of Clinical Staging Schemes for Primary Thymic Epithelial Neoplasms Investigators/Year Stage I II

III

IVa IVb

Masaoka et al28/1981 Macroscopically completely encapsulated and microscopically no capsular invasion 1. Macroscopic invasion into surrounding fatty tissue or mediastinal pleura, or 2. Microscopic invasion into capsule Macroscopic invasion into neighboring organ, (ie, pericardium, great vessels, or lung) Pleural or pericardial dissemination Lymphogenous or hematogenous metastases

The topic of cellular differentiation in thymomas has been addressed frequently in the literature. It has been observed that several features in thymoma bear a strong resemblance to some transitory phases in the development of the thymus, as well as to the otherwise normal adult thymus.7 Haynes, on the basis of topographically determined antigenic patterns, proposed the existence of a maturation sequence of thymic epithelial cells from the subcapsular cortex to the Hassall corpuscles analogous to that of epidermal keratinocytes from the basal layer to the stratum corneum.36 The fully keratinized cells in Hassall corpuscles, however, generally have been regarded as a manifestation of a degenerative state of thymic epithelium without functional capacity.37-39 In other words, keratinization of thymic epithelial cells, contrary to that observed in squamous cells of the epidermis, represents a regressive phenomenon denoting loss of functional properties with reversion to an inactive status within the gland. Whereas subcapsular, inner cortical, and medullary epithelial cells have the functional capacity to secrete thymic hormones, express class I and II major histocompatibility antigens, and are actively involved in the immunologic development of T cells, 17,40 the keratinized cells in Hassall corpuscles generally are acknowledged to be hormonally inactive and have been credited as serving only as local sites for antigen and antibody localization.41-42 The implication, therefore, from the functional point of view, is that cells showing terminal squamous differentiation in the thymus typified by those of Hassall corpuscles represent the least specialized and, therefore, the least differentiated among thymic epithelial cells. Reverting to a squamous epithelial phenotype in the thymus is therefore, analogous to a process of dedifferentiation or loss of functional maturation within the thymic microenvironment. Based on these observations, a spectrum of differentiation could be visualized for thymic epithelial cells that correlates with functional status of the gland and that would range from the mature subcortical and outer cortical epithelial cell 830

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Suster and Moran/199718 Encapsulated tumors confined to the thymus Locally invasive tumors (ie, mediastinal fat, lung, pleura, pericardium) or tumors with pleural or pericardial implants Tumors with hematogenous or lymphatic metastases lll-a, Intrathoracic metastases (ie, lung, lymph nodes); lll-b, Extrathoracic metastases — —

to the medullary thymic epithelial cell to the fully keratinized cell of Hassall corpuscles, the latter corresponding to the least specialized or inactive phase of thymic epithelium in the mature thymus. In addition to this maturation sequence in the mature thymus, it also must be acknowledged that thymic epithelial cells can show a strikingly different appearance in the involuted thymus of the adult, characterized by the presence of relatively small, spindle-shaped cells with oval nuclei, scant cytoplasm, and inconspicuous nucleoli. Such cells generally are distributed in small clusters or surrounding small lymphoid aggregates embedded within the mediastinal fat and have been generally regarded as "effete" cells without functional capacity.43 Occasionally, these cells form rosette-like structures or may be associated with the formation of primitive cyst-like or tubular structures, features commonly recapitulated in thymomas of the spindle cell type.17 The existence of thymomas that are predominantly or exclusively composed of a similar population of spindle cells thus may be explained as an attempt by such tumors to recapitulate the inactive, involuted cell population found in the thymus of older adults rather than as an expression of "medullary" differentiation. Thus, thymic epithelial neoplasms could be conceptualized as forming a continuous spectrum of lesions; at one end are tumors that closely resemble the fully mature thymus of childhood or adolescence or the involuted thymus of adulthood (ie, well-differentiated thymic epithelial neoplasms or thymomas), and at the other end are tumors that have lost all or most of the features of their parent tissues (ie, poorly differentiated thymic epithelial neoplasms or thymic carcinoma). Cases showing intermediate features would correspond to moderately differentiated lesions (ie, atypical thymoma in our classification). As would be expected for neoplasms in any other location, increased cytologic atypia will become evident with increasing loss of differentiation and with malignancy. Likewise, with increasing loss of functional differentiation, prominence of the epithelial component will become more

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Anatomic Pathology /REVIEW ARTICLE

evident, and the number of lymphoid elements will decrease progressively.44 Since the most important function of mature thymic epithelium lies in its role in the maturation of T lymphocytes, it follows that the better differentiated neoplasms will be those in which the prevailing cell population will most closely resemble the active thymic cortex. In fact, the tumors (variously referred to as cortical, predominantly cortical, or lymphocyte-rich thymomas) that are characterized by a predominance of T lymphocytes admixed with a scant number of thymic epithelial cells are the ones that most closely resemble the normal or mature thymus and, therefore, in our scheme, represent the better differentiated examples of these lesions llmage II. Likewise, tumors composed predominantly of small, bland-appearing spindle cells with scant lymphocytes are the ones that most closely resemble the normal involuted thymus of older adults and, thus, represent another manifestation of a well-differentiated thymic epithelial neoplasm llmage 21. In more advanced stages of the process, the lymphoid cell component will become more sparse, and the epithelial component will predominate; the progressive loss of functional differentiation in such tumors will be marked by the emergence of features of squamous differentiation indicative of regression to a more inactive functional state. The final stages of this process eventually will lead to complete loss of functional differentiation, and the tumors then will acquire the features of squamous cell carcinoma and its variants (ie, mucoepidermoid carcinoma, clear cell carcinoma), followed by poorly differentiated squamous cell carcinoma (lymphoepithelioma-like carcinoma), neuroendocrine carcinoma, and, finally, anaplastic and sarcomatoid forms of carcinoma, analogous to the sequence of tumor progression commonly observed in other organ systems.

Thus, the defining morphologic criteria for the diagnosis of thymic epithelial neoplasms would be as follows: (1) thymoma (well-differentiated thymic epithelial neoplasms), tumors that are characterized by a population of blandappearing round or spindle epithelial cells, without cytologic evidence of atypia, intimately admixed with lymphocytes in various proportions and that show many or all of the architectural organotypical features of thymic differentiation of the normal mature thymus or features that recapitulate the normal involuted thymus of the adult; (2) atypical thymoma (moderately differentiated thymic epithelial neoplasms), tumors that are characterized by a predominantly epithelial cell population displaying a moderate degree of cytologic atypia (ie, increased nuclear/cytoplasmic ratio, hyperchromasia, nucleolar prominence, and occasional mitotic figures) but that retain some of the organotypical features of thymic differentiation (eg, lobulation, perivascular spaces, immature T lymphocytes); and (3) thymic carcinoma (poorly differentiated thymic epithelial neoplasms), tumors characterized by overt cytologic features of malignancy with total loss of the organotypical features of differentiation of the normal thymus. The present system of classification is essentially based on the degree of differentiation of thymic epithelial neoplasms as judged by their morphologic resemblance on routine microscopy to the normal thymus, be it in its fully mature, functional state in children and adolescents or in the involuted nonfunctional state seen in adults. The advantage of this system is that it provides a simple and reproducible method for morphologically categorizing these tumors that may be easily applied in clinical practice. Most pathologists would not have difficulties distinguishing between typical and atypical epithelial cells, squamous epithelial cells, and frankly malignant

•Image I I A, Appearance of the normal thymus in a child. B, Well-differentiated thymic epithelial neoplasm (thymoma) of the "lymphocyte-rich" type. Note the cl ose resemblance to the norlal thymus in A.

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S u s t e r a n d Moran / CLASSIFICATION OF THYMIC EPITHELIAL NEOPLASMS

•Image 21 A, Involuted thymus of the adult composed of islands lymphocytes. B, Spindle cell thymoma.

(carcinomatous) epithelial cells. Attention to the architectural features alluded to previously (organotypical features of thymic differentiation) easily will permit the inclusion of a tumor into any of the categories in the present classification.

Conclusions The proposed classification scheme offers the flexibility of assigning these tumors to various categories based on simple and easily reproducible morphologic criteria. Accurate prognostication of these lesions subsequently can be accomplished by application of strict clinical and pathologic staging criteria. We believe the most reliable parameter for assessing prognosis in the better differentiated examples of thymoma is staging, as determined by the status of capsular integrity. There should be no need for identifying or separating benign from malignant forms based on histologic features, since, in all likelihood, these tumors all represent malignant neoplasms from inception. The different degrees of malignancy will correlate, as in other tumor systems, with the histologic grading and clinical staging of the lesions. It is hoped that the application of this simplified classification scheme may facilitate interobserver comparison and reproducibility among workers in the field and lend itself more easily to the evaluation and categorization of these tumors for clinical practice.

oval to spindle thymic epithelial cells admixed with scant

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