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Evolution of Classification of Thymic Epithelial Tumors in the Era of Dr Thomas V. Colby.

Thymic epithelial tumors (TETs), including thymomas, thymic carcinomas, and thymic neuroendocrine tumors, are neoplasms that in general occur in the prevascular (anterior) mediastinum. Although TETs represent the most common primary prevascular mediastinal neoplasms in adults, encompassing approximately 20% of all primary tumors in that area, they are overall infrequent. The incidence for thymomas ranges between 1.3 and 2.5 per million per year. (1-3) Thymic carcinomas are even less frequent. Thymic epithelial tumors have been reported at any age but occur most commonly at 40 to 60 years of age, and are extremely rare in children. There is no sex predilection in TETs. (1,4-6)

Thymic epithelial tumors can be classified according to their histopathologic features or staged based on the presence and extent of invasion, implants, lymph node involvement, and/or distant metastases. At least 24 histomorphologic classifications and 14 staging systems have been proposed within the last century (Table 1).

CHALLENGES OF THE CLASSIFICATION OF THYMIC EPITHELIAL TUMORS

The classification of TET has been challenging because of (1) the presence of various combinations of epithelial cells and lymphocytes that compose these tumors; (2) the paucity of these neoplasms, making large studies difficult; (3) an uncertainty about the neoplastic component(s) of TET (thymic epithelial cells and/or lymphocytes) in early classifications; (4) controversies about the prognostic significance of classifications and the malignant potential of thymomas; and (5) the diversity of thymic-derived tumors (ie, TETs, lymphomas, germ cell tumors). Many pathologists have struggled with the classification of TET. For instance, Ewing (7) noted in 1916 that "no group of tumors has more successfully resisted attempts at interpretation and classification than those of the thymus." Lowenhaupt (8) stated in 1948 that "thymic tumors, because of their rarity and diversity, have long resisted attempts to reach valid conclusions from [the] variously described and variously interpreted material available from the literature." In 1961, Bernatz et al (9) began their article on classification of thymoma with the remarks that "a study of thymic tumors must enjoy a prominent but unenviable position in any list of frustrating experiences inherent in the pursuit of medical knowledge" and that "remarkable as is this dissidence all reports overwhelmingly agree that there is much confusion as well as controversy about this group of tumors."

In the early years of histomorphologic classification of TETs, it was not clear whether the epithelial cells and/or the lymphocytes were the neoplastic component. In 1917, Bell (10) noted, in a case report of a thymoma, that the tumor was "likely of epithelial origin." Ewing (11) mentioned in 1928 that "the chief source of [lymphosarcoma or thymoma] is probably the reticulum cell, but lymphocytes are often present in abundance." Although it was still debated, in 1948, Lowenhaupt (8) remarked on "the epithelial derivation of this entire group of neoplasms," seeming to conclude that the epithelial cells were the neoplastic cells. In 1972, Zeiller and Dolan12 showed in experiments in mice and rats that thymocytes are not derived from the thymus but rather originate from the bone marrow and migrate to the thymus. These findings suggested that although they are present in close vicinity in the same organ, the embryologic origin of thymic epithelial cells differs from that of thymocytes. Rosai and Levine (13) concluded in 1976 that a simultaneous neoplastic transformation of 2 cellular components, epithelial and lymphocytic, of different embryogenesis within the same organ would be unlikely. Rather, they suggested that the epithelial cells were the neoplastic cells of thymomas because (1) the epithelial cells have morphologic and biologic properties of neoplastic cells, (2) the epithelial cells are present in the invasive tumor and metastases, (3) some thymomas are only composed of epithelial cells, and (4) "in cytologically malignant thymomas the anaplastic features are restricted to [the epithelial cells]." The authors considered the lymphocytes of thymomas to be benign because (1) it had been shown that thymic lymphocytes are derived from the bone marrow, (2) light microscopic and ultrastructural features of lymphocytes in thymoma are not different from those of normal "resting" or stimulated lymphocytes, and (3) the lymphocytes lack biologic properties of neoplastic cells. Today the neoplastic nature of the epithelial cells and the benign/reactive properties of lymphocytes in TET have been well accepted.

EVOLUTION OF THE HISTOMORPHOLOGIC CLASSIFICATION OF THYMIC EPITHELIAL TUMORS

At least 24 histomorphologic classifications of TET have been proposed during the last century (Table 1). Eighty-eight years ago, in 1928, Ewing (11) categorized thymic tumors into 2 main groups, the "lymphosarcoma or thymoma" and the "carcinoma" (Table 2). A third category, "spindle-cell or myxosarcoma," comprised rare tumors that were thought to derive from the stroma. Although Ewing still questioned the cell of origin of the "lymphosarcoma or thymoma," he concluded from his own case studies that the reticulum [epithelial] cells are the main or sole source of the tumor and the lymphocytes are largely passive but "are often present in abundance." In 1948, Lowenhaupt (8) classified thymic tumors according to the stage of embryonic development of the normal thymus (Table 2). Although this classification was not used in subsequent classifications, Lowenhaupt8 introduced some fundamental thoughts that were later confirmed in other studies, such as that TETs are of epithelial origin and that "early surgical excision, if possible, is the treatment of choice." In 1955, Castleman (14) defined thymomas as tumors composed of lymphocytes and epithelial cells. Castleman did not divide thymomas into subtypes because he argued that "there are so many variations within a given tumor that there are no foolproof criteria differentiating the thymoma in a patient with myasthenia gravis from one without myasthenia gravis, and that there are no microscopic differences between the thymoma that is limited to the thymic gland and the one that extends beyond its confines...." He was not entirely convinced that thymomas are malignant, even though he described that in a quarter of thymomas the tumor replaces the entire thymic gland and invades into and through the pleura, pericardium, nerves, and/or blood vessels. In addition, he described the discrete nodules in the pleura and pericardium that are not connected with the primary tumor as implants rather than true metastases. However, although Castleman acknowledged lymph node metastases, he avoided terms such as malignant thymoma or carcinoma of the thymic gland because (1) he did not observe any thymomas with "embolic metastases" and (2) he noted that encapsulated thymomas were morphologically similar to thymomas that spread within the mediastinum. In his opinion, tumors that were previously classified as "malignant thymoma" with metastases to distant organs did not have typical morphologic features of thymomas but were usually lymphomas, teratomas, or primary tumors of the lung, pancreas, or stomach that presented with large metastases to mediastinal lymph nodes. Moreover, he suggested that although tumors with implants and/or extension, invasion, or penetration of neighboring structures might be considered malignant, surgical removal of these tumors before implants have occurred or before the tumor extended within the mediastinum might have cured the patients. Recurrences, he felt, occurred likely because of incomplete resection.

In 1961, "with the hope that some prognostic significance could be gained through study of cell types," Bernatz et al (9) classified thymomas based on the predominant cell type (Table 2). Bernatz et al (9) reported on 138 patients who underwent surgery for thymoma at the Mayo Clinic Rochester. Based on the proposed morphologic classification, they found that patients with predominant lymphocytic or spindle cell thymomas have a better prognosis than patients with mixed cell type or predominant epithelial cell thymoma. Furthermore, predominant lymphocytic or spindle cell thymomas were more often encapsulated than thymomas with other predominant cell types. Moreover, based on the data from this study, Bernatz et al (9) concluded that lack of invasion is of more prognostic significance than cell type, although statistical analysis was not performed at that time. They realized, however, that the classification of thymomas would likely need to be further developed and concluded their article with the words from Effler and McCormack (15) "that the intriguing subject of thymic neoplasms still requires new thought and clarification." The study by Bernatz et al (9) also showed the previously disputed benefit of thymectomy for at least some patients with myasthenia gravis. Eighteen of 64 patients (28.1%) with thymoma in the setting of myasthenia gravis who underwent thymectomy were well either without (n = 11) or with (n = 7) medication after a mean follow-up of 8 years. In a subsequent study, Bernatz et al (16) applied statistical analysis to outcome data of 80 patients with thymoma and myasthenia gravis (64 of which were also included in the original study of Bernatz et al (9) from 1961). The authors confirmed that myasthenia gravis did not affect survival of invasive thymomas. However, in noninvasive thymomas the survival of patients with myasthenia gravis was worse than for patients without that disease. Wilkins and Castleman (17) in 1979 did not find myasthenia gravis to be an adverse prognostic factor (anymore), possibly because of improved treatment. This was also confirmed in 1981 by Masaoka et al, (18) who showed that the 5-year survival of patients with thymoma and myasthenia gravis was similar to patients with thymoma without myasthenia gravis. However, the 10-year survival of patients with myasthenia gravis was worse in that study, which might have been because many deaths due to myasthenia gravis occurred during the early years of the study and, therefore, influenced the 10-year survival. A recent analysis of the retrospective Japanese database of TETs that included 598 TETs in patients with myasthenia gravis did not reveal any difference in 5- and 10-year overall or recurrence-free survival. (19) A recent multicenter study from Italy including 375 patients with thymoma showed a slight protective effect of the presence of myasthenia gravis on overall survival, although that was not confirmed in multivariate analysis. (20) These findings suggest that today the outcome of patients with thymoma and myasthenia gravis is at least as good as the outcome of patients with thymoma without myasthenia gravis.

In 1976, Rosai and Levine (13) defined thymoma simply as an epithelial tumor originating from the thymic gland. The authors proposed to restrict the designation of thymoma to neoplasms of thymic epithelial cells regardless of the proportion of accompanying lymphocytes. The authors suggested that terms such as seminomatous thymoma, round cell thymoma, or granulomatous thymoma should not be used anymore; these tumors should be designated according to the cell of origin, that is, germinoma (seminoma) of thymus, thymic carcinoid, or Hodgkin disease, respectively. Rosai and Levine supported their belief that "once the term thymoma is restricted to the tumor of epithelial thymic cells, with or without a lymphocytic component, all further subdivisions are artificial" based on the review of 164 cases of thymoma. In a subsequent review, Levine and Rosai (21) added a component of thymic carcinoma to the classification (Table 2).

Subsequently, TETs were classified in more detail and classifications focused on the relationship between neoplastic cells and their possible origin from the cortex and/or medulla of the benign thymic gland. Evidence had shown that in the benign thymic gland medullary epithelial cells are distinct from cortical epithelial cells based on morphology, ultrastructure, and immunology and therefore provide different microenvironments. (22) Furthermore, it was suggested that differences in nuclear and cytoplasmic features allowed the distinction between medullary and cortical thymic epithelial cells by microscopy (Table 3; Figure 1, A and B). Therefore, a classification into medullary predominant, cortical predominant, and mixed cell types was appealing. In 1985, Marino and Mueller-Hermelink (22) first proposed a classification of TET based on the compartment of the normal thymic gland from which the neoplastic epithelial cells likely arose (Table 2). In addition, thymic carcinomas were defined by the presence of invasive growth and almost pure composition of epithelial cells with cytologic criteria of malignancy. They applied this classification to a series of 58 thymomas and 13 thymic carcinomas and found that cortical thymomas had a tendency to occur in younger patients than other thymomas. (22) Furthermore, myasthenia gravis was only identified in patients with cortical thymoma. The more aggressive nature of cortical thymomas was reflected by their tendency for invasive growth and their clinical behavior, with 14 of 25 cases (56%) being locally invasive and/or having intrathoracic (13; 52%) or extrathoracic (1; 4%) metastases. A single case recurred. In addition, the authors noted differences in the lymphoid component, with medium- and large-sized lymphocytes more commonly seen in pure or predominantly cortical thymoma whereas small pleomorphic lymphocytes were mostly seen in medullary or mixed thymoma with medullary predominance. Moreover, the number of lymphocytes was high in cortical and mixed thymomas, whereas pure medullary thymomas had only rare lymphocytes. The concept by Marino and Muller-Hermelink (22) of classifying TET according to the structural components of the normal thymus was further developed by Kirchner et al (23) in 1989 based on a study of 95 TETs, patient's outcome, and proliferation assays of 12 TETs (Table 2). Kirchner et al (23) introduced a category of well-differentiated thymic carcinoma, defined as TET with incomplete loss of organotypic differentiation, tightly packed epithelial cells with slight to moderate atypia, and some immature CD1-positive T cells. Small areas of cortical differentiation could be present in well-differentiated thymic carcinoma. In contrast to well-differentiated thymic carcinoma, other thymic carcinomas were defined by lack of organotypic features. Based on outcome studies, Kirchner et al (23) considered medullary and mixed thymomas as benign; predominantly cortical thymomas, cortical thymomas, and well-differentiated thymic carcinomas as low-grade malignant tumors with increasing invasiveness and metastatic capacity; and thymic carcinoma as overtly malignant tumors. In vitro studies confirmed that the proliferative rate of neoplastic epithelial cells correlates with the different tumor types and their growth behavior in vivo. For instance, cells from mixed thymomas (n = 3) did not grow in vitro or ceased to proliferate after less than 3 passages, whereas cells from well-differentiated thymic carcinomas (n = 3) had the highest growth rate among the TETs tested, could be passaged for a maximum of 35 times, and were kept in culture for up to 8 months. The proliferative rate of epithelial cells of cortical (n = 3) and predominantly cortical thymomas (n = 3) was between that of mixed thymomas and well-differentiated thymic carcinomas.

In 1999, Suster and Moran (24,25) proposed a 3-tiered classification that was based upon morphologic features of differentiation (Table 2). This classification subtyped TETs according to their degree of cytologic atypia, presence of organotypic features of thymic differentiation, and "closeness to benign thymus." Organotypic features of differentiation were defined as features that "most closely resemble the normal appearance of the thymus in its mature or involuted state" and are summarized in Table 4. Areas of medullary differentiation were described as well-circumscribed foci containing plump epithelial cells with scant lymphocytes within an otherwise cortical-appearing neoplastic population of cells, with or without Hassall corpuscles. According to this classification, thymomas exhibit all or most organotypic features, thymic carcinomas do not have any or have only minimal organotypic features, and atypical thymomas show intermediate morphologic features. The classification is illustrated in Figure 2, A through D. In addition, the authors considered all thymomas to potentially be malignant.

In 1989, a "WHO [World Health Organization] committee for the histologic classification of tumours of the thymus" was organized by Dr Juan Rosai. Subsequently, pathologists from 8 countries debated during 1 decade whether a histologic subclassification of thymomas is possible and useful. Although some pathologists favored a classification that just distinguished noninvasive from invasive thymomas, others thought that histologic types of thymoma correlated with their aggressiveness and clinical behavior and therefore further morphologic subclassification would be useful. Subsequently, a "compromised" histologic classification was published. (26) Because the association between thymoma subtype and compartment of normal thymic gland was still controversial, the terminology chosen by the WHO was "noncommittal" and was designated by letters and numbers (Table 2). All thymomas composed of bland-appearing spindle and/or oval cells were classified as type A; thymomas that contained dendritic or plump ("epithelioid") cells were categorized as type B. Type B thymomas were further subdivided based on the proportional increase in tumor cells in relation to thymocytes, increasing cytologic atypia, and presence or absence of medullary differentiation. Figure 3, A through F, illustrates the morphologic features of the WHO classification. In addition to these " classic" thymomas, uncommon thymomas were described, including micronodular thymoma (Figure 4, A), microscopic thymoma (Figure 4, B), and metaplastic thymoma (Figure 4, C and D). Thymic neuroendocrine tumors were defined identically to neuroendocrine tumors in the lung, including typical carcinoid tumor, atypical carcinoid tumor (defined as 2-10 mitoses per 10 high-power fields and/or necrosis), large cell neuroendocrine carcinoma, and small cell carcinoma. The 1999 WHO classification (26) emphasized that the classification of cytoarchitectural features of thymoma should occur independent of staging because the classification "based on invasive/metastasizing properties of the tumour relates more closely to recurrence and outcome than the one based on cytoarchitectural features." The WHO classification was revised in 2004 to include descriptions of clinical symptoms, macroscopic findings, immunohistochemical characteristics, genetic features, and prognostic data. (27) Type C thymoma (1999 WHO classification (26)) was now defined as thymic carcinoma; the morphologic subtypes of thymomas remained unchanged. The most recent WHO classification, (28) published in 2015, advocated a similar histomorphologic classification that had retained the designation of the tumors by letters and numbers. The 2015 WHO classification used an interdisciplinary approach to the diagnosis of TET and included contributions from radiologists, thoracic surgeons, and oncologists. Epidemiologic and prognostic data for the WHO classification were derived, in part, from the worldwide retrospective database of the International Thymic Malignancy Interest Group (ITMIG), which comprises more than 6000 cases. Findings on imaging studies, specifically computer tomography/positron emission tomography and cytologic features, were also included. Some histomorphologic features and immunohistochemical criteria were refined in an attempt to enhance the reproducibility of subtyping of thymomas and to facilitate the distinction between thymomas and thymic carcinomas. (29) For instance, to help with the distinction between type B1 and B2 thymoma, the definition of type B1 thymomas included features such as thymuslike architecture and cytology, abundance of immature T cells, areas of medullary differentiation (medullary islands), and paucity of polygonal or dendritic epithelial cells without clustering (<3 contiguous epithelial cells) (Figure 5, A and B). Hassall corpuscles or perivascular spaces were considered optional. In addition, the distinction between type A and type AB thymomas was discussed in more detail. Although both types contain bland-appearing spindle/oval cells, they should be distinguished from each other by a low ("easily countable," type A) or high (TdT-positive, "T-cells impossible to count," and/or "moderate infiltrate of TdT+ lymphocytes [difficult to count] in > 10% of the tumour areas," type AB) content of lymphocytes. Furthermore, an atypical type A thymoma variant was introduced. This TET is characterized by features of conventional type A thymoma with bland-appearing spindle/oval cells and atypical findings including hypercellularity, increased mitotic activity, and focal necrosis. This variant was included in the WHO classification because studies have shown an association between necrosis in type A thymomas and recurrence and extrathoracic metastasis. (30) Moreover, in a study of type A and AB thymomas, necrosis was associated with stage in univariate and multivariate analysis. (31) However, neither study showed an association between mitotic activity and stage or outcome in type A (30) or type A and AB thymomas. (31) The 2015 WHO classification recommended reporting of all thymoma subtypes in 10% increments (except type AB thymomas) if more than one subtype is identified in a resection specimen. Furthermore, all subtypes of thymoma were considered malignant because they can show an aggressive behavior. Exceptions were micronodular and microscopic thymoma, in which no fatal outcome has been reported. It was also suggested that immunohistochemistry might be used for the diagnosis and subtyping of thymomas with ambiguous histology. Thymic carcinoma subtypes have been broadened and now include the NUT carcinoma (Table 5).

EVOLUTION OF THE STAGING CLASSIFICATION OF THYMIC EPITHELIAL TUMORS

Staging classifications of TET in general are based upon invasion, implants, lymph node involvement, and/or distant metastases. During the past half-century, at least 14 staging systems have been proposed, even though many of these were not outright designated as "staging systems" (Table 1). This review will focus on those that introduced new and interesting concepts of classification. In 1961, Bernatz et al (9) divided thymomas into noninvasive and invasive thymomas (Table 6).9 This categorization was based on their study that showed that only 6 of 27 patients (22.2%) with invasive thymoma lived 5 or more years following surgery, in contrast to 49 of 64 patients (76.5%) with noninvasive thymoma, suggesting that patients with invasive thymoma had worse survival than patients with noninvasive thymoma. Similarly, in 1976, Rosai and Levine (13) suggested that thymomas need only be separated into encapsulated versus invasive tumors for predicting outcome and guiding therapy. Rosai and Levine found that well-encapsulated thymomas without myasthenia gravis remain stable and surgical excision is curative, even though the patient might develop a paraneoplastic syndrome or local recurrence, which can occur either as multiple pleural implants or as localized mediastinal tumor. In contrast, invasive thymomas, although histologically indistinguishable from encapsulated thymoma, have a worse outcome.

In 1978, Bergh et al (32) developed a 3-tiered staging system that further subclassified invasive thymomas (Table 6). When applied to 43 thymomas, that staging system revealed "considerable" differences in survival between stage II and III thymomas, supporting that the extent of invasion has prognostic value. Wilkins and Castleman (17) modified the classification by Bergh et al slightly in 1979, adding invasion into pleura and pericardium to stage II (Table 6). The authors confirmed that patients with invasive thymomas had an overall worse outcome than patients with noninvasive thymomas; however, the authors did not reach any conclusions in regards to outcome of patients with stage II versus stage III thymoma.

In 1981, Masaoka et al (18) pioneered todays most commonly used staging system for thymomas (Table 6). This system was developed for clinical staging of thymomas assuming that all thymomas have a variable degree of malignant potential and prognosis of thymoma is determined from its stage, which is based on invasiveness of the tumor through the capsule into surrounding tissue and organs and metastases. This classification was designed upon their observation that thymomas initially grow locally, subsequently infiltrate or disseminate, and finally metastasize. It was sought to guide therapy, to evaluate the results of surgery, and to define the prognosis of a patient. When this staging system was applied to 96 thymomas, they showed that survival differed based on stage, with 5-year survivals of 92.6% (stage I), 85.7% (stage II), 69.6% (stage III), and 50% (stage IV). In 1994, Koga et al (33) modified the Masaoka staging, changing invasion into the tumor capsule (Masaoka stage II/2) to microscopic invasion through the capsule (transcapsular; Koga stage IIA) to accommodate the most common point of view of pathologists that a tumor is invasive if it grows through the tumor capsule (Table 6). Therefore, thymomas invading into but not through the tumor capsule were now classified as stage I in the Koga staging system. It was confirmed later by Roden et al (4) that the prognosis is similar for patients with thymomas infiltrating into but not through the tumor capsule when compared with patients with encapsulated thymomas. Applying this system to 79 thymomas, Koga et al found that although the outcome did not differ significantly between stages I and II, there were significant differences between stages II and III and stages II and IV. The Koga staging system is now often referred to as the modified Masaoka or the Masaoka-Koga staging system. This staging system is probably worldwide the most commonly used staging system for thymomas today and is recommended by the WHO. (29)

In 1982, the French Groupe d'Etude des Tumeurs Thymiques proposed a clinical classification that encompassed not only extent of invasion and metastases but also completeness of resection (Table 6). (34,35)

In 1991, Yamakawa and colleagues (36) proposed a tentative tumor-node-metastasis (TNM) classification that was similar to the Masaoka staging system but distinguished between lymphogenous and hematogenous metastases (Table 6). Lymphogenous metastases occurred in a few patients and were thought to progress from anterior mediastinal lymph nodes to intrathoracic and later to extrathoracic lymph nodes. Hematogenous metastases did not reveal any particular characteristics. The T stage was adopted from the Masaoka classification. In contrast to TNM classifications of other organs, the T stage for TET did not consider size of the tumor because it was thought that the malignant potential of thymoma was due to its invasiveness and its tendency to disseminate rather than its size. The TNM classification was applied to 207 thymomas. When evaluating stage IVB cases (thymomas with lymphogenous and/or hematogenous metastases), no association between stage and prognosis or treatment was identified, possibly because of the small number of cases (8 of 207; 3.9%). The classification was also applied to 13 thymic carcinomas and 6 thymic carcinoid tumors. In this population, there was a much higher frequency of stage IVB cases, and the TNM classification was considered to be more useful in these tumors. Tsuchiya et al (37) thought that a pathologic TNM staging system would be applicable to thymic carcinomas and thymic carcinoid tumors but not to thymomas, as Yamakawa et al (36) had suggested, and proposed a modification to the TNM staging system in 1994 (Table 6). Stage pT2 now included thymic carcinomas with invasion through the tumor capsule; tumors that invaded through the pleura or the pericardium were classified as stage pT3. The staging groups were also modified. Tumors with N1 disease were now distributed into stages II to IV based upon the T stage because N1 disease was considered resectable and curable. The authors validated the modified TNM staging system on 16 thymic carcinomas. Although there were no stage II thymic carcinomas in this study, survival curves separated them between stages I and III or IV and stages III and IV; the differences were not statistically significant, likely again because of the small number of cases. Moreover, this study predominantly included squamous cell carcinomas and 2 undifferentiated and 1 basaloid carcinoma, and lacked other carcinoma types of high-grade histology such as small cell carcinoma, lymphoepithelioma-like carcinoma, sarcomatoid carcinoma, and clear cell carcinoma. Carcinoid tumors were also not evaluated.

In 1997, Suster and Moran (25) developed a simple 3-tiered staging classification that was proposed to be usable to stage both thymic carcinomas and thymomas (Table 7). Weissferdt and Moran (38) proposed a 3-tiered staging classification for thymic carcinomas in 2012 (Table 7) with the purpose of simplifying the existing TNM classification. This classification was developed based on outcome data of 33 patients with thymic carcinoma. At the same time, Moran et al (39) recommended a staging solely for thymomas (Table 7). The authors introduced a stage 0 or in situ malignancy, which most likely could be controlled by complete resection alone. Only invasive tumors were assigned a stage. However, the authors acknowledged that recurrence has been reported even in encapsulated thymomas. When the authors applied this staging system to 250 patients with thymoma, significant differences in overall and recurrence-free survival were identified when comparing stages 0 and I with stages II and III; no differences were found in outcome between stages 0 and I. Furthermore, there were no differences in outcome between stages IIa, b, and c. The authors considered, however, that distinction was still important because of possible differences in treatment. The prognostic significance of the proposed Moran staging for thymomas was later confirmed by Roden et al, (40) although in that study, patients with stage 0 disease had a significantly better overall survival than stage I patients.

Currently, neither the American Joint Committee on Cancer nor the Union for International Cancer Control provides a staging system for thymoma or thymic carcinoma. The modified Masaoka staging system (Masaoka-Koga staging system) appears to be the most commonly used staging system for thymomas, whereas the TNM staging as recommended by the WHO (Table 6) might be used for thymic carcinoma. (28,41) To facilitate staging, the 1999 and 2004 WHO included morphologic criteria to facilitate the evaluation of invasion and metastases (Table 8; Figure 6, A through F). (26,27)

There is a need for a staging system that can be applied to all TETs, including thymomas, thymic carcinomas, and thymic neuroendocrine tumors. (42) Therefore, the International Association for the Study of Lung Cancer (IASLC) together with ITMIG proposed a staging system in 2014 for the forthcoming (eighth) edition of the TNM classification of malignant tumors (Table 7). (42) This classification requires microscopic evidence of findings for pathologic staging. This staging system was validated using a worldwide retrospective database led by ITMIG and supplemented by cases from the Japanese Association for Research on the Thymus and the European Society of Thoracic Surgeons that encompassed more than 10 000 TETs. This proposed TNM classification is different from previous staging classifications of TET in that encapsulated TET and TET invading into the surrounding connective tissue are both classified as T1a because data from the retrospective database did not identify differences in outcome between these tumors. Some aspects of the proposed staging were considered speculative and still need to be validated, such as the distinction between stages IIIa and IIIb, N1 and N2, and M1a and M1b. Overall, subset analysis showed that this staging proposal is applicable to thymomas and thymic carcinomas. The number of thymic neuroendocrine tumors was too low for statistically meaningful conclusions.

Although most studies showed that staging is an important prognostic parameter for TET, there are controversies with regard to significance of the individual elements of staging systems. Some studies did not find any significant differences in outcome between patients with encapsulated thymomas and patients with thymomas that invade into the thymic or perithymic adipose tissue. (33,42,43) In contrast, a recent study by Roden et al (40) showed significantly worse overall survival for patients with thymomas that invaded through the capsule versus encapsulated thymomas. This controversy might, at least in part, be due to interobserver variability. Therefore, Roden et al (40) studied the interobserver reproducibility of 3 different staging systems, including the modified Masaoka (Masaoka-Koga), proposed Moran, and proposed IASLC/ITMIG staging system. In that study, the agreement among 3 thoracic pathologists from the same institution was almost perfect for the modified Masaoka staging system ([kappa] = 0.85, n = 315) and the proposed Moran staging system ([kappa] = 0.81, n = 290) and substantial for the proposed IASLC/ITMIG staging system ([kappa] = 0.75, n = 81). (4) If evaluating only the T component of the proposed IASLC/ITMIG ([kappa] = 297), the agreement was also substantial ([kappa] = 0.75). Most common disagreements occurred between encapsulated and minimally invasive tumors, which would correspond to stage I and IIA tumors of the modified Masaoka staging system (15.8% of cases). When studying cases in which all 3 reviewers agreed upon extent of invasion, there was a significant difference in overall survival between modified Masaoka stage I and II patients. (40)

STAGING IS PROGNOSTICALLY SUPERIOR TO HISTOMORPHOLOGIC CLASSIFICATION IN THYMIC EPITHELIAL TUMORS

Although thymic carcinomas have consistently been shown to have a worse outcome than thymomas, (44-47) the prognostic significance of thymomas has been debated and reports in the literature are conflicting. This debate also gave rise to some histomorphologic classifications. The prognostic significance of the histomorphologic classification of thymomas was especially debated in the years leading up to the first WHO classification. Some pathologists suggested that the classification of thymomas into noninvasive and invasive tumors might be sufficient because there is no additional prognostic significance of more elaborated classifications. Others proposed to subclassify thymomas further because histology might correlate with outcome. Indeed, some evidence suggested that WHO and Bernatz classifications have prognostic value. (46,48-50) For instance, studies have shown significantly worse survival of B3 thymoma versus types A through B2 thymoma, (51) types A and AB thymoma, (52) or types A, AB, and B1 thymoma. (53) Recently, a study by Weis et al (54) evaluating 4221 thymomas submitted to the ITMIG retrospective database (including cases between 1983 and 2012) also showed that the WHO classification of thymomas was significantly associated with overall survival in univariate analysis, and although not all thymoma types differed from each other significantly, B3 thymomas had a worse overall survival in R0 resected patients than B1 thymomas. However, after adjusting for age, stage, and resection status, the WHO classification was no longer significant for overall survival. Other studies did not find differences in survival between type B3 thymoma or atypical thymoma and other thymomas (45,55) and failed to show an association of WHO or proposed Suster and Moran classification with outcome. (45,56,57)

These varying results might have been, at least in part, due to interobserver variation. Indeed, studies reported an only fair to moderate reproducibility of the 2004 WHO classification of TET, with [kappa] values ranging between 0.39 and 0.53 or an overall concordance rate of 63% to 70%. (58-61) Only if a weighted [kappa] was used, 1 study achieved good agreement for the 1999 WHO and the Bernatz classification ([kappa] = 0.87). (48) Interobserver agreement for the Mueller-Hermelink classification was reported as 78%. (62) Roden et al (4) compared the reproducibility of the 2004 WHO with the proposed Suster and Moran classification and the classification by Bernatz reviewing 456 TETs. Reproducibility was best for the proposed Suster and Moran classification ([kappa] = 0.74, substantial agreement) followed by the 2004 WHO classification ([kappa] = 0.65, substantial agreement) and the Bernatz classification ([kappa] = 0.52, moderate agreement). The most common disagreements occurred between B1 and B2 thymoma (2004 WHO classification), thymoma and atypical thymoma (proposed Suster and Moran classification), and lymphocyte predominant and mixed lymphocyte and epithelial cell thymoma (Bernatz classification). Moreover, this study showed that the only moderate to substantial reproducibility of histomorphologic classifications indeed plays a role in determining the prognostic significance of TET, with differences in prognosis between the 3 reviewers in multivariate analysis. (4) Therefore, Roden et al (40) evaluated the prognostic significance of thymoma using cases in which all 3 thoracic pathologists independently agreed upon a diagnosis. Univariate analysis confirmed that all histomorphologic classifications studied, including Bernatz, Suster and Moran, and WHO (2004), are of prognostic significance for overall and disease-free survival. However, in multivariate analysis, only Bernatz was prognostic for overall survival if adjusted for modified Masaoka staging. On the other hand, modified Masaoka staging and thymoma size were prognostic factors independent of histologic classification. Similarly, in the study by Weis et al (54) of the ITMIG retrospective database, stage, resection status, and age were independently associated with overall survival.

Taken together, these results suggest that histomorphologic classification is not an independent prognostic marker for thymoma and that staging plays an important role for outcome and therefore for management of thymomas, independent of the histomorphologic classification.

GENETIC ALTERATIONS IN THYMIC EPITHELIAL TUMORS

Loss of heterozygosity on chromosome 6q25.2-25.3 is common and has been identified in all types of TET except type B1 thymoma (Table 9). (28) A potential target of loss of heterozygosity in 6q25.2-25.3 is the tumor suppressor gene FOXC1. (28) In addition, Petrini et al (63) showed that frequent copy number loss of FOXC1 is associated with more aggressive tumors and correlates with decreased protein expression. More recently, GTF2I missense mutations have been found in types A and AB thymomas and less commonly in types B1, B2, and B3 thymomas. (64) These mutations were rather uncommon in thymic carcinoma (Table 9).

Using array comparative genomic hybridization, Petrini et al (65) identified homozygous 9p21.3 copy number loss in 2 of 7 thymic carcinomas (28.6%) and 2 of 20 type B3 thymomas (10%) but no other thymomas. The copy number loss peak of 9p21.3 included only CDKN2A/B loci. CDKN2A is a known tumor suppressor gene involved in the control of the cell cycle and may be related to uncontrolled tumor cell proliferation. In fact, focal deletion of 9p21.3 is a frequent event in cancer (40% overall and 16% focal copy number loss) (66) and is associated with poor outcome in patients with lymphoblastic leukemia. (67) Copy number loss of CDKN2A/B was associated with poor outcome (including disease-related survival and time to progression), suggesting that CDKN2A/B may be of potential value in the prognosis of TET. In addition, copy number loss of CDKN2A correlated with lack of expression of its related protein [p16.sup.INK4] (p16) in TET.

In vitro studies showed that siRNA knockdown of antiapoptotic molecules BCL2 and MCL1 leads to reduction of the proliferation of TET cell lines. (65) Gx15-070 (pan-BCL2 inhibitor) induced necrosis in TET cells and inhibited TET xenograft growth. ABT263 (inhibitor of BCL2/BCL-XL/BCLW) led to decreased TET cell proliferation when combined with sorafenib, a tyrosine kinase inhibitor.

Overall, biology and genetic findings appear to vary with the histomorphologic type of TET according to the WHO.

SUMMARY

A variety and a large number of histomorphologic and staging classifications for TET have been proposed during the era of Dr Thomas V. Colby, reflecting challenges to develop an easy-to-follow, reproducible, and therapeutically and prognostically meaningful classification that can be used for the evaluation of thymomas, thymic carcinomas, and thymic neuroendocrine tumors. The rarity of the disease makes its study even more difficult. Overall, staging is a prognostic marker of TET independent of histomorphologic classification. However, despite many attempts of staging classifications, currently there is no perfect staging system available that is suitable for treatment decisions and prognosis for all TETs. The recently proposed staging classification of IASLC/ITMIG shows promise when applied to a large global retrospective database. Although histomorphologic classifications are not prognostically significant independent of staging, tumor biologic and genetic features appear to differ among histologic subtypes of TET.

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Accepted for publication June 2, 2016.

From the Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota.

The author has no relevant financial interest in the products or companies described in this article.

Portions based on a presentation given at the 2016 Mayo Clinic Pathology Update: A Tribute to the Career of Thomas V. Colby, MD meeting; February 4, 2016;Phoenix, Arizona.

Reprints: Anja C. Roden, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905 (email: roden.anja@mayo.edu). Please Note: Illustration(s) are not available due to copyright restrictions.

Caption: Figure 1. Epithelial cells in the benign thymic gland. The benign thymic gland contains large, stellate cortical epithelial cells that are characterized by round or oval medium-to-large nuclei with prominent nucleoli and scant eosinophilic cytoplasm (A, arrows) and spindle medullary epithelial cells with oval-to-spindle small-to-medium nuclei without or with inconspicuous nucleoli and scant eosinophilic cytoplasm (B, arrow). The epithelial cells are highlighted by keratin AE1/AE3 immunostain (A and B, insets) (hematoxylin-eosin, original magnification X600 [A and B]; keratin AE1/AE3 immunostain, original magnification X600 [A and B, insets]).

Caption: Figure 2. Histomorphologic classification by Suster and Moran. (24) A, The well-differentiated thymoma is characterized by preserved organotypic features including lobulated growth pattern and a mixture of epithelial tumor cells and thymocytes (inset). B, The moderately differentiated atypical thymoma shows a lobulated architecture; however, the neoplastic epithelial cells are cytologically more atypical and at most only occasional thymocytes are scattered throughout the tumor (inset). C and D, The poorly differentiated thymic epithelial tumor, the thymic carcinoma, lacks a lobulated architecture and is characterized by irregular tumor cell nests surrounded by a desmoplastic stromal reaction (C). The tumor cells are cytologically atypical and thymocytes are absent (D) (hematoxylin-eosin, original magnifications X12.5 [A and B], X20 [C], and X400 [A and B, insets, and D]).

Caption: Figure 3. Histomorphologic classification by the World Health Organization. A, Type A thymomas are characterized by bland-appearing spindle cells with absent or only scattered thymocytes (inset). B, This type AB thymoma comprises a type B2 component (upper left-hand side, upper inset) and a type A component (lower right-hand side, lower inset), which are next to each other in this case. C, At low magnification a type B1 thymoma is in general recognized by medullary islands (arrows) that sometimes contain Hassall corpuscle-like particles (upper inset). There are only scattered neoplastic epithelial cells in a background of predominantly thymocytes (lower inset). D, On low magnification type B2 thymomas often have a starry-sky appearance because of the mixture of medium-to-large neoplastic epithelial cells and thymocytes (inset). E, Type B3 thymomas have a lobulated appearance on low power; thymocytes are only scattered or absent (inset). F, The thymic carcinoma has a distorted architecture and is composed of irregular nests of cytologically atypical tumor cells (inset) surrounded by a desmoplastic stroma (hematoxylin-eosin, original magnifications X40 [A, B, and D through F], X20 [C], and X600 [A through F, insets]).

Caption: Figure 4. Uncommon thymomas. A, The micronodular thymoma with lymphoid stroma is characterized by nests and strands of bland-appearing spindle tumor cells (inset) in a lymphocytic background. The background might contain germinal centers (arrow). B, This microscopic thymoma measures 0.9 mm in greatest dimension and lacks a distinct tumor capsule. It is composed of bland-appearing spindle cells (inset). C and D, A metaplastic thymoma is composed of nests and strands of bland-appearing tumor epithelial cells, some of which can contain nuclear pseudoinclusions (D, right-hand side) and are surrounded by metaplastic spindle cells (D, left-hand side) (hematoxylin- eosin, original magnifications X20 [A and C], X40 [B], and X400 [A and B, insets, and D]).

Caption: Figure 5. Distinction of type B1 from type B2 thymoma using the World Health Organization 2015 criteria. A type Bi thymoma (A) is defined by scattered epithelial tumor cells with fewer than 3 clustering together (arrows), in contrast to a type B2 thymoma (B), in which 3 or more tumor cells might cluster (arrows) (hematoxylin-eosin, original magnification X600).

Caption: Figure 6. Pathologic criteria (2004 World Health Organization) to facilitate staging according to the modified Masaoka (Masaoka-Koga) staging system. A, Encapsulated thymoma, stage I. In some thymomas, the tumor capsule might be thin or the tumor might invade into the capsule (arrow and inset); however, no invasion of the tumor through the capsule is identified. B, Minimally invasive thymoma, stage IIA. The thymoma has invaded through the tumor capsule into the surrounding adipose tissue (arrow and inset). C, Widely invasive thymoma, stage IIIA. This thymoma invades directly into lung parenchyma. D through F, Metastatic thymoma, stage IVB. Thymoma can metastasize to various organs, including the lung (D, type A thymoma; D inset), ovary (E; arrow points toward ovarian stroma) or bone (F; F inset shows metastatic thymic carcinoma on the left and a megakaryocyte of the bone marrow on the right with arrow pointing toward a megakaryocyte) (hematoxylin-eosin, original magnifications X12.5 [A through D], X100 [A, inset], X200 [B, inset], X400 [D and F, insets], and X40 [E and F]).
Table 1. Histomorphologic Classifications and Staging Systems
of Thymic Epithelial Tumors Proposed During the Last Century

Histomorphologic Classifications

Year   Author                                 Country

1928   James Ewing                            United States
1932   Douglas Symmers                        United States
1940   James Ewing                            United States
1941   C. Alexander Hellwig                   United States
1948   Elizabeth Lowenhaupt                   United States
1950   William D. Seybold                     United States
1955   Benjamin Castleman                     United States
1956   Lalla Iverson                          United States
1956   Donald B. Effler                       United States
1957   Raffaele Lattes                        United States
1957   A. D. Thomson                          United Kingdom
1959   George D. Andritsakis                  United States
1961   Philipp E. Bernatz                     United States
1965   Merle A. Legg                          United States
1966   Hiroshi Watanabe                       Japan
1976   Juan Rosai and Gerald D. Levine        United States
1978   Gerald D. Levine and Juan Rosai        United States
1985   Mirella Marino and Hans Konrad         Germany
         Muller-Hermelink
1989   Thomas Kirchnerand Hans                Germany
         Konrad Muller-Hermelink
1999   Saul Suster and Cesar A. Moran         United States
1999   World Health Organization
2000   T.-T. Kuo                              Taiwan
2004   World Health Organization
2015   World Health Organization

Staging Systems

1961   Philipp E. Bernatz                     United States
1978   N. P. Bergh                            Sweden
1978   Gerald D. Levine and Juan Rosai        United States
1979   Earle W. Wilkins and Benjamin          United States
         Castleman
1981   Akira Masaoka                          Japan
1982   Groupe d'Etude des Tumeurs             France
         Thymiques
1985   Jeanne M. Verle                        France
1991   Yosuke Yamakawa and Akira              Japan
         Masaoka (TNM)
1994   Kenji Koga                             Japan
1994   Ryosuke Tsuchiya and Kenji Koga        Japan
         (TNM)
1997   Saul Suster and Cesar A. Moran         United States
2003   Tumor-Node-Metastasis
2012   Cesar A. Moran                         United States
2014   International Association for Study
         of Lung Cancer/International
         Thymic Malignancy Interest
         Group

Table 2. Selected Histomorphologic Classifications of Thymic
Epithelial Tumors

Ewing, (11) 1928
Lymphosarcoma or thymoma
Carcinoma arising from reticulum cells
Spindle cell or myxosarcoma
Lowenhaupt, (8) 1948
  I. Carcinoma of primitive epithelial reticulum
 II. Carcinoma of variegated cell pattern (carcinoma of early
  Hassall corpuscles)
III. Carcinoma of granulomatous pattern (carcinoma of late
  Hassall corpuscles)
IV. Carcinoma of thymic round cell: lymphoepithelioma
 V. Encapsulated thymoma
VI. Carcinoma of adamantinomatous pattern
Bernatz et al, (9) 1961
Thymoma of predominantly
  Spindle cell type
  Lymphocytic type
  Mixed type (reticuloepithelial-lymphocytic)
  Epithelial type
Levine and Rosai, (21) 1978
Encapsulated thymoma
Malignant thymoma
  I. Locally invasive thymoma
  Thymoma with lymphatic or hematogenous spread
  II. Cytologically malignant (thymic carcinoma)
Marino and Muller-Hermelink, (22) 1985
Medullary thymoma (medullary epithelial cells and scant, usually
  negligible lymphoid cells)
Mixed thymoma (cortical and medullary epithelial cells, high
  number of lymphocytes)
Predominantly cortical
Predominantly medullary
Cortical thymoma (cortical epithelial cells)
Thymic carcinoma
Kirchner et al, (23) 1989
Medullary thymoma
Mixed thymoma
Predominantly cortical thymoma
Cortical thymoma
Well-differentiated thymic carcinoma
Thymic carcinoma
Suster and Moran, (24) 1999
Thymoma                                Well differentiated
Atypical thymoma                       Moderately differentiated
Thymic carcinoma                       Poorly differentiated
WHO, (26-28) 1999, 2004, 2015
WHO Type
A
Atypical type A varianta

AB
B1

B2

B3
C/thymic carcinoma (b)

Morphologic Features

Bland spindle/oval tumor cells, rare or no thymocytes
Type A criteria and atypia (hypercellularity, increased
  mitotic count, focal tumor necrosis)
Type A and type B1 or type B2
Scattered neoplastic cells in a background of thymocytes
Presence of medullary elements
Mixture of neoplastic cells and thymocytes
Increased cytologic atypia of neoplastic cells
Polygonal neoplastic cells with conspicuous nucleoli
Thymic carcinoma
Cytologic atypia
Architecture distorted
Desmoplasia

Abbreviation: WHO, World Health Organization.

(a) 2015 classification only.

(b) Type C (1999 classification) was designated as thymic carcinoma
in the 2004 and 2015 WHO classifications.

Table 3. Cytologic Characteristics of Epithelial
Cells of the Benign Thymic Gland (22)

Thymic
Epithelial Cell   Medullary            Cortical

Shape             Spindle              Stellate
Nucleus           Oval-spindle         Oval-round
Size              Small-medium         Medium-large
Nucleolus         +/-, not prominent   Prominent
                  if present
Cytoplasm         Scant, dense         Scant, clear or
                  eosinophilic         faintly
                                       eosinophilic

Abbreviation: +/-, nucleolus might or might not be present
and if a nucleolus is present then it is not prominent.

Table 4. Organotypic Features of Differentiation of
the Thymus as Defined by Suster and Moran (24)

Lobular architecture

Dual cell population (neoplastic thymic epithelial cells,
  thymic lymphocytes)
Dilated perivascular spaces
Areas of medullary differentiation (+/- Hassall corpuscles) (a)
(a) +/-, may or may not be present.

Table 5. Thymic Carcinoma Subtypes According to
2015 World Health Organization Classification (28)

Squamous cell carcinoma
Basaloid carcinoma
Mucoepidermoid carcinoma
Lymphoepithelioma-like carcinoma
Clear cell carcinoma
Sarcomatoid carcinoma
Adenocarcinomas
Thymic carcinoma
NUT carcinoma
Undifferentiated carcinoma
Others

Thymic neuroendocrine tumors including:
  Carcinoid tumors (typical, atypical carcinoid)
  Large cell neuroendocrine carcinoma
  Small cell carcinoma

Abbreviation: NUT, nuclear protein of testis.

Table 6. Selected Proposed Staging Systems for
Thymic Epithelial Tumors 1961 Through 1994

Bernatz et al, (9) 1961
Noninvasive
Invasive

Bergh et al, (32) 1978

Stage             Definition

I                 Intact capsule; growth within capsule
II                Pericapsular growth into mediastinal
                    fat tissue
III               Invasive growth into surrounding
                    organs, intrathoracic metastases or
                    both

Wilkins and Castleman, (17) 1979

Stage             Definition

I                 Intact capsule or growth within
                    capsule
II                Pericapsular growth into the
                    mediastinal fat tissue or adjacent
                    pleura or pericardium
III               Invasive growth into the surrounding
                    organs, intrathoracic metastases, or
                    both

Masaoka et al, (18) 1981, and modified Masaoka
(Koga et al, (33) 1994) staging

Stage             Masaoka

I                 Macroscopically completely
                     encapsulated, microscopically no
                     capsular invasion
II                2. Microscopic invasion into capsule
                  1. Macroscopic invasion into
                     surrounding fat or mediastinal
                     pleura

III               Macroscopic invasion into
                     neighboring organs
IV                A. Pleural or pericardial
                     dissemination
                  B. Lymphogenous or
                     hematogenous metastasis

Staging Classification of the Groupe d'Etude des
Tumeurs Thymiques, (34) 1982

Stage             Definition

IA                Encapsulated tumor, totally resected
IB                Macroscopically encapsulated tumor,
                    totally resected, perioperative
                    suspicion of mediastinal adhesion
                    or potential capsular invasion
II                Invasive tumor, totally resected
IIIA              Invasive tumor, subtotally resected
IIIB              Invasive tumor, biopsy
IVA               Supraclavicular metastasis or distant
                    pleural droplets
IVB               Distant metastasis

TNM classification of thymic epithelial tumors by Yamakawa
et al, (36) 1991; pathologic TNM classification of thymic
epithelial tumors by Tsuchiya et al, (37) 1994; and TNM
classification of malignant thymic epithelial tumors as
recommended by the 2015 World Health Organization (28)
classification

                  Yamakawa et al

TX
T0
T1                Macroscopically completely
                    encapsulated and microscopically
                    no capsular invasion

T2                Macroscopically adhesion or invasion
                    into surrounding fatty tissue or
                    mediastinal pleura, or microscopic
                    invasion into capsules

T3                Invasion into neighboring organs,
                    such as pericardium, great vessels,
                    and lung

T4                Pleural or pericardial dissemination

NX

N0                No lymph node metastasis

N1                Metastasis to anterior mediastinal

                    lymph nodes

N2                Metastasis to intrathoracic lymph
                    nodes except anterior mediastinal
                    lymph nodes

N3                Metastasis to extrathoracic lymph
                    nodes

M0                No hematogenous metastasis

M1                Hematogenous metastasis

Stage

I                 T1 N0 M0

II                T2 N0 M0

III               T3 N0 M0

IV

IVa               T4 NO MO

IVb               [T.sub.any] N1,2 or 3 M0
                  [T.sub.any] [N.sub.any] M1

IVc

Bernatz et al, (9) 1961
Noninvasive
Invasive

Bergh et al, (32) 1978

Stage

I
II

III

Wilkins and Castleman, (17) 1979

Stage

I

II

III

Masaoka et al, (18) 1981, and modified Masaoka
(Koga et al, (33) 1994) staging

Stage             Modified Masaoka (Koga)

I                 Macroscopically completely
                     encapsulated, microscopically no
                     capsular invasion
II                A. Microscopic transcapsular invasion
                  B. Macroscopic invasion into
                     extracapsular soft tissue, or
                     tumor grossly adherent to
                     mediastinal pleura or
                     pericardium
III               Macroscopic invasion into
                    neighboring organs
IV                A. Pleural or pericardial
                     dissemination
                  B. Lymphogenous or hematogenous
                     metastasis

Staging Classification of the Groupe d'Etude des
Tumeurs Thymiques, (34) 1982

Stage

IA
IB

II
IIIA
IIIB
IVA

IVB

TNM classification of thymic epithelial tumors by Yamakawa
et al, (36) 1991; pathologic TNM classification of thymic
epithelial tumors by Tsuchiya et al, (37) 1994; and TNM
classification of malignant thymic epithelial tumors as
recommended by the 2015 World Health Organization (28)
classification

                  Tsuchiya et al

TX
T0
T1                Macroscopically completely
                    encapsulated and microscopically
                    no capsular invasion

T2                Tumor breaking through capsule,
                    invading thymus or fatty tissue
                    (maybe adherent to mediastinal
                    pleura but not invading
                    neighboring organs)

T3                Breaking through the mediastinal
                    pleura or pericardium, or invading
                    neighboring organs, such as great
                    vessels and lung

T4                Pleural or pericardial dissemination

NX

N0                No lymph node metastasis

N1                Metastasis to anterior mediastinal
                    lymph nodes

N2                Metastasis to intrathoracic lymph
                    nodes except anterior mediastinal
                    lymph nodes

N3                Metastasis to extrathoracic lymph
                    nodes

M0                No hematogenous metastasis

M1                Hematogenous metastasis

Stage

I                 T1,2 N0 M0

II                T1,2 N1 M0

III               T3 NO,1 M0

IV

IVa               T4 N0,1 M0

IVb               Tany N2,3 M0

IVc               [T.sub.any] [N.sub.any] M1

Bernatz et al, (9) 1961
Noninvasive
Invasive

Bergh et al, (32) 1978

Stage

I
II

III

Wilkins and Castleman, (17) 1979

Stage

I

II

III

Masaoka et al, (18) 1981, and modified Masaoka
(Koga et al, (33) 1994) staging

Stage

I

II

III

IV

Staging Classification of the Groupe d'Etude des
Tumeurs Thymiques, (34) 1982

Stage

IA
IB

II
IIIA
IIIB
IVA

IVB

TNM classification of thymic epithelial tumors by Yamakawa
et al, (36) 1991; pathologic TNM classification of thymic
epithelial tumors by Tsuchiya et al, (37) 1994; and TNM
classification of malignant thymic epithelial tumors as
recommended by the 2015 World Health Organization (28)
classification

                  World Health Organization 2015

TX                Primary tumor cannot be assessed
T0                No evidence of primary tumor
T1                Macroscopically completely
                    encapsulated and
                    microscopically no capsular
                    invasion
T2                Tumor invades pericapsular
                    connective tissue

T3                Tumor invades into neighboring
                    structures, such as pericardium,
                    mediastinal pleura, thoracic
                    wall, great vessels, and lung

T4                Pleural or pericardial dissemination

NX                Regional lymph nodes cannot be
                    assessed

N0                No lymph node metastasis

N1                Metastasis to anterior mediastinal
                    lymph nodes

N2                Metastasis to intrathoracic lymph
                    nodes except anterior
                    mediastinal lymph nodes

N3                Metastases in scalene and/or
                    supraclavicular lymph nodes

M0                No distant metastasis

M1                Distant metastasis

Stage

I                 T1 N0 M0

II                T2 N0 M0

III               T1,2 N1 M0
                  T3 N0,1 M0

IV                T4 [N.sub.any] M0
                  [T.sub.any] N2,3 M0
                  [T.sub.any] [N.sub.any] M1

IVa

IVb

IVc

Table 7. Selected Proposed Staging Systems for
Thymic Epithelial Tumors From 1997 Through 2014

Suster and Moran, (25) 1997

Stage    Definition

I        Well encapsulated tumor
II       Infiltrative or locally invasive tumor
III      Lymph node or distant metastasis

Staging of Thymic Carcinomas as Proposed by Weissferdt
and Moran, (38) 2012

         Definition

T1       Tumor limited to thymic gland
T2       Tumor invading visceral pleura, lung, pericardium,
           great vessels, chest wall or diaphragm
T3       Direct extrathoracic tumor extension, beyond thoracic
           inlet or diaphragm
N0       No lymph node metastasis
N1       Lymph node metastasis to intrathoracic lymph node
M0       No distant metastasis
M1       Distant metastasis

Stage

I        T1 N0 M0
II       T2 N0 M0
III      T3 N0 M0
           Tany N1 M0
           [T.sub.any] [N.sub.any] M1

Staging of Thymomas as Proposed by Moran et al, (39) 2012

Stage    Definition

0        Encapsulated tumor
I        Tumor invasive into perithymic adipose tissue
II       Direct invasion
A        Innominate vein, mediastinal pleura, lung
B        Pericardium
C        Great vessels (aorta, superior vena cava), heart
III      Metastatic disease
A        Intrathoracic structures, diaphragm, lymph nodes
B        Extrathoracic invasion

Staging of Thymic Epithelial Tumors as Proposed
by IASLC/ITMIG, (42) 2014

T1       Definition (Involvement of) (a)
a        Encapsulated or unencapsulated, with or without
           extension into mediastinal fat
b        Extension into mediastinal pleura
T2       Pericardium
T3       Lung, brachiocephalic vein, superior vena cava, chest
           wall, phrenic nerve, hilar (extrapericardial),
           pulmonary vessels
T4       Aorta, arch vessels, main pulmonary artery,
           myocardium, trachea, esophagus
N0       No lymph node involvement
N1       Anterior (perithymic) lymph nodes
N2       Deep intrathoracic or cervical lymph nodes
M0       No metastatic pleural, pericardial, or distant sites
M1
a        Separate pleural or pericardial nodule(s)
b        Pulmonary intraparenchymal nodule or distant organ
         metastasis

Stage

I        T1 N0 M0
II       T2 N0 M0
IIIa     T3 N0 M0
IIIb     T4 N0 M0
IVa      [T.sub.any] [N.sub.1] M0
         [T.sub.any] N0 or 1 M1a
IVb      [T.sub.any] N2 M0 or 1a
         [T.sub.any] [N.sub.any] M1b

Abbreviations: IASLC, International Association of Study of Lung
Cancer;ITMIG, International Thymic Malignancy Interest Group.

(a) A tumor is classified according to the highest level
of invasion regardless whether invasion of structures
of lower levels is present or not.

Table 8. 1999 and 2004 World Health Organization
Criteria for Invasion and Metastasis (26,27)

World Health
Organization Category   Definition

Encapsulated            No invasion through the tumor
                        capsule

Minimally invasive      Invasion through tumor capsule
                        into surrounding adipose
                        tissue

Widely invasive         Invasion into neighboring
                        organs including lung,
                        pericardium, great vessels

Implants                Tumor nodules on pleura,
                        pericardium, and diaphragm

Lymph node metastasis   Mediastinal and supraclavicular
                        lymph nodes

Distant metastases      Lung, liver, skeletal system,
                        others

Table 9. Common Genetic Abnormalities in
Thymic Epithelial Tumors (a)

World Health   Loss of Heterozygosity in   GTF2I Missense Mutation,
Organization    6q25.2-25.3 Identified            % of Cases

A                         Yes                         82
AB                        Yes                         74
B1                        No                          32
B2                        Yes                         22
B3                        Yes                         21

Thymic                    Yes                          8
carcinoma

World Health
Organization   Other Genetic Abnormalities

A
AB             Genetic alterations are more frequent and complex
                 than for type A thymoma
               Type A areas appear genetically different from type A
                 thymomas
               Similar high frequency of GTF2I mutation to type A
                 thymomas
B1
B2             More alterations than type A, less than type B3
B3             Copy number gain of BCL2, loss of CDKN2A/B-
                 associated with poor outcome
Thymic         KIT mutation (up to 11% of cases)
carcinoma      Copy number gain of BCL2, loss of CDKN2A

(a) Data derived from World Health Organization 2015 classification,
(28) Petrini et al, (64,65) and Beroukhim et al. (66)
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Author:Roden, Anja C.
Publication:Archives of Pathology & Laboratory Medicine
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Date:Feb 1, 2017
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