Histologic features, growth patterns and classification of atypical thymomas

Introduction

The concept of atypical thymoma was first introduced by Suster and Moran in 1999 to designate primary thymic epithelial neoplasms that were characterized by displaying a variable degree of cytologic atypia while still retaining some of the organotypical features of thymic differentiation (1). Such tumors were conceptualized as occupying an intermediate position in the process of malignant progression in thymic epithelial neoplasms. Because thymomas, in general, are relatively heterogeneous neoplasms that can display a wide variety of morphologic appearances, it follows that atypical thymomas will also encompass a broad spectrum of histologic features that can lend themselves to confusion and serve to complicate the diagnosis. In addition to the various growth patterns that they can display, their cytologic features, particularly the degree of cytologic atypia displayed by the tumor cells, can also be quite variable (2-4). In this review we will detail the various morphologic appearances of these tumors with emphasis on some of the clues that can facilitate the diagnosis. Though some recent advances have been made regarding molecular and immunohistochemical diagnostics in thymoma, this review is focused on the morphologic evaluation of these tumors that we believe is still the most important component of the diagnostic work up (5-8).

Histological features of atypical thymoma

The term atypical thymoma is reserved for tumors which despite showing some degree of preservation of the organotypical features of thymic differentiation (such as encapsulation, lobulation, admixture of proliferating thymic epithelial cells with immature T-lymphocytes, dilated perivascular spaces) also display some degree of cytologic atypia that deviates from that observed in normal thymic epithelial cells (1-3,9,10). The problem for evaluating these tumors is that the “normal” thymus can display a variety of histologic appearances and cytologic features depending on its stage of maturation and age of the patient. The thymus is one of the few organs in the body that undergoes a normal process of involution early in puberty leading to almost complete disappearance of the organ in old age, with significant changes taking place in its cell composition and architecture (1,11). Studies by Hale (12), for example, have demonstrated that the thymus does not shrink in size with age; rather, it appears it undergoes a process of extensive replacement of the parenchyma by adipose tissue, with the residual microscopic islands of thymic tissue showing marked changes in their normal composition. Unlike the normal functioning thymus of infancy and childhood, in which thymic epithelial cells are involved in the active production of thymic hormones and are characterized by large nuclei containing prominent eosinophilic nucleoli surrounded by an ample rim of abundant cytoplasm, the cells in the involuted thymus of adults undergo a process of involution whereby the nucleus shrinks considerably in size and adopts an oval or spindled appearance, and the cytoplasm is reduced to a small indistinct rim around the nucleus. The chromatin pattern in such “effete”, involuted cells is also altered and the chromatin becomes diffuse and granular, with absence of nucleoli. These changes are simply the reflection of the non-functional state of the cells which are no longer involved in the production of thymic hormones, or at the very least have limited their capacity to produce them to a minimum (13). Because both the active, functional phase of the thymus during childhood and adolescence, and the involuted stage seen in adults and old age represent “normal” aspects of this organ, tumors that closely resemble either one of these evolutional stages can be regarded as showing features of good differentiation, i.e., they can be considered to represent well-differentiated neoplasms (1,11). This approach helps us account for the fact that both the thymic tumors containing few scattered epithelioid cells admixed with abundant lymphocytes that recapitulate the normal functioning thymus in childhood and tumors composed of abundant small spindle cells with scant or no lymphocytes resembling the involuted thymus of adults represent well-differentiated thymic epithelial neoplasms, one being primarily composed of spindle cells, and the other of round epithelioid cells. The same situation applies during the progression of malignancy, whereby tumors that are either composed of round, epithelioid cells or small oval to spindle epithelial cells can undergo further loss of differentiation leading to the development of tumors displaying various degrees of atypia ranging from atypical thymomas to bona-fide thymic carcinomas.

The concept of atypical thymoma has not yet been widely adopted and the current World Health Organization (WHO) schema for the classification of thymic epithelial neoplasms designates tumors showing similar features as “type B3 thymoma” (14). Although the WHO recognizes that B3 thymoma can also show spindle cell features and they implicitly acknowledge that the existence of a spindle cell type of B3 thymoma may exist, they have created a new category of “atypical type A” thymoma for tumors composed of spindle cells with atypical features (14). We have argued that tumors displaying such features represent the counterpart of conventional B3 thymoma of epithelioid or round cell type (10). In our experience, such tumors show an overall tendency to become more invasive, recur earlier, and are associated with an increased incidence of transformation to thymic carcinoma. We therefore recognize two basic patterns of growth in atypical thymomas: epithelioid or “squamoid” tumors, and spindle cell atypical thymoma. It must be emphasized, however, that these two patterns of growth refer to the predominant features observed in any given neoplasm, and that features corresponding to either of these patterns can be observed focally in most atypical thymomas.

Epithelioid (“squamoid”) atypical thymoma

These are the tumors which have been more commonly designated as type B3 by the WHO. They are characterized by a predominant sheet-like growth pattern composed of tightly cohesive epithelioid cells with enlarged nuclei and abundant rim of cytoplasm (Table 1). The tumors are easily identified on scanning magnification due to their “pink” appearance caused by the abundance of cytoplasm and the relative lower number of cells with hyperchromatic nuclear material. The most important distinction for separating them from conventional thymomas rich in lymphocytes (i.e., WHO types B1-B2) is their sheet-like growth pattern, whereby the tumor cells are closely packed together forming a syncytium rather than being scattered singly and separated by abundant lymphocytes.

At the architectural level, epithelioid atypical thymomas can grow in two main forms: as diffuse sheets of tumor cells or adopting a nodular growth pattern (10) (Table 1). The nodular pattern is characterized by well circumscribed nodules of varying sizes that are separated by bands of dense fibrous tissue (Figure 1A). The nodules tend to become smaller towards the periphery of the tumor and are often seen infiltrating irregularly into the capsule and into the surrounding mediastinal fat or adjacent pleura and lung parenchyma. The diffuse pattern of growth is one devoid of lobulation and fibrous bands; these tumors are usually punctuated by numerous dilated perivascular spaces (Figure 1B). A relatively common feature of the perivascular spaces in these tumors is prominent palisading of tumor cells around the lumen (Figure 1C).

Figure 1 Atypical squamoid thymoma. (A) Lobular growth pattern separated by fibrous bands is seen in atypical squamoid thymoma (H&E stain, 2× magnification); (B) sheet-like growth pattern showing tightly cohesive epithelioid cells with abundant dilated perivascular spaces (H&E stain, 4× magnification); (C) peripheral palisading of tumor cells is noted surrounding the lumen of a dilated perivascular space (H&E stain, 20× magnification); (D) squamoid appearance of the tumor is highlighted by the sharp cell membranes separating the tumor cells (H&E stain, 20× magnification); (E) abrupt small focus of squamous differentiation is present in this atypical thymoma; notice concentration of small lymphocytes around the squamoid cells (H&E stain, 40× magnification); (F) larger confluent are as of squamous differentiation are present in this example of atypical thymoma; notice the areas of central keratinization (H&E stain, 20× magnification). H&E, hematoxylin and eosin.

At the cellular level, most of the tumor cells adopt a “squamoid” appearance imparted by the close apposition of sharply delineated cell membranes resulting in a pavement-like organization (Figure 1D) (10). Despite the resemblance to squamous epithelium, the cells lack intercellular bridges or keratohyalin granules and do not produce keratin. This squamoid appearance has undoubtedly been responsible in the past for many of these tumors being incorrectly categorized as well-differentiated squamous cell carcinoma. In fact, several of the cases we published in a large prior study on thymic carcinoma have been deemed on reexamination to represent examples of atypical thymoma (15). The mimicry with squamous cell carcinoma is enhanced in about a third of these cases by abrupt foci of well-developed squamous differentiation, with small cellular islands showing occasional intercellular bridges and more obvious keratinization (Figure 1E,1F) (10). Unlike true squamous cell carcinomas, these squamous cell islands are not infiltrative, do not display jagged borders, and lack overt cytologic atypia or show increased mitotic activity.

In addition to the nodular and diffuse sheet-like pattern of growth, the tumors can sometimes also show a nested/trabecular growth pattern (Figure 2A) or will be characterized by coalescence of numerous multicystic spaces (Figure 2B). Stromal fibrosis and calcification are often seen, and metaplastic bone can also be present. Peripheral palisading of tumor cells can also be observed in approximately 10% of cases (Figure 2C); this feature can lend itself to confusion with basaloid thymic carcinoma. Vascular invasion is very rare in these tumors; most often small islands of tumor may be entrapped at the periphery and show retraction artifact from the surrounding connective tissue simulating lymphovascular invasion (Figure 2D). This retraction artifact may represent a diagnostic pitfall; use of vascular endothelial markers may be of aid in such instances to rule out true vascular invasion. Interestingly, true vascular invasion was not found to affect prognosis for these tumors in a large study (10). Another important feature of squamoid atypical thymomas is their paucity of lymphocytes. Unlike the more conventional types of thymoma composed of epithelioid cells (B1-B2) which are characterized by the abundance of stromal lymphocytes, atypical thymomas contain very few lymphocytes. The lymphocytes in atypical thymomas correspond mostly to immature T-lymphocytes and tend to be arranged around dilated perivascular spaces, although they can also be found scattered in the interstitium or concentrated around foci of abrupt keratinization. Some cases may show an increase in the number of lymphocytes, but the neoplastic cell population will still be composed of sheets of tightly cohesive epithelioid cells. Increase in stromal lymphocytes generally is seen adjacent to areas showing the features of type B1 and B2 thymoma, a phenomenon that has been cited to occur in approximately 1/3 of cases for these tumors (14). Finally, it bears emphasizing that most cases will show at least focally transitions with areas in which the cells show a streaming appearance and show spindled or oval nuclei indistinguishable from those of atypical spindle cell thymoma (Figure 2E).

Figure 2 Atypical squamoid thymoma. (A) Growth pattern characterized by small nests and trabeculae of epithelioid tumor cells is a common finding in these tumors (H&E stain, 20× magnification); (B) prominent cystic changes can be often observed in atypical thymomas (H&E stain, 2× magnification); (C) peripheral palisading of nuclei can also be a prominent feature of atypical thymoma that can lead to confusion with other basaloid neoplasms (H&E stain, 20× magnification); (D) prominent retraction artifact from the surrounding connective tissue stroma is often seen that can be mistaken for vascular invasion (H&E stain, 20× magnification); (E) focal streaming of spindled cells (top left) adjacent to areas of more conventional epithelioid atypical thymoma may be frequently seen (H&E stain, 40× magnification). H&E, hematoxylin and eosin.

The cytological features of squamoid atypical thymoma can also be quite variable. The size of the tumor cells can vary considerable from tumor to tumor and within the same tumor. Size of the tumor cells can range from small epithelioid cells the size of a histiocyte, to cells that are 2–3 times the size of a normal histiocyte (Figure 3A) (6). A distinguishing feature common to all, however, is the significant increase in the nuclear to cytoplasmic ratio. Another distinctive feature in these tumors is the presence of sharp cell membranes outlining the contours of the cells, imparting the tumors with a pavement-like or “squamoid” appearance (Figure 3B). The nuclei in atypical thymoma are always hyperchromatic unlike the nuclei in B1 and B2 thymoma, in which the nuclear chromatin is finely dispersed and scant. Atypical thymomas also often display basophilic nucleoli, unlike the round eosinophilic nucleoli seen in type B1-B2 cells. A frequent finding in these tumors is the presence of nuclear membrane irregularities that lead to a convoluted or “raisinoid” appearance of the nuclei, which is often accompanied by the development of a clear perinuclear halo (Figure 3C). Some nuclei can also display prominent nuclear membrane infoldings resulting in longitudinal nuclear grooves (Figure 3D). Two interesting cytoplasmic features that can be observed in these tumors are prominent clearing of the cytoplasm imparting the tumor with a clear cell appearance (Figure 3E), and the presence of abundant granular eosinophilic cytoplasm imparting the cells with an oncocytic appearance (Figure 3F). Such findings are usually focal but, in some instances, may be extensive and involve the entire tumor. Occasionally, the cells can also display marked cytologic atypia, with markedly enlarged nuclei, intranuclear pseudoinclusions, and multinucleated or multilobated nuclei (Figure 3G). The latter are particularly common in patients that have received neoadjuvant radiation prior to surgery. Unlike B1-B2 thymomas, mitotic activity is more conspicuous in atypical thymoma. Mitoses average 1–2 per 10 high power fields but may be increased in some cases up to 5 per 10 high power fields. Most of the mitoses in these tumors are normal, but abnormal and tripolar mitoses can also be rarely seen. An unusual but alarming finding in some tumors that can lead to confusion with a higher grade of malignancy is the presence of large areas of infarction and necrosis (Figure 3H). Such areas are usually associated with vaso-occlusive phenomena and result from thrombosis of small and medium-sized vessels in the vicinity of the affected areas secondary to rapid growth of the tumor (16). The areas of necrosis are usually sharply marginated and display a nodular contour and are often associated with cystic epithelial changes accompanied by stromal hemorrhage simulating a multilocular thymic cyst. The ischemic infarct-type large areas of necrosis in such instances should be distinguished from true tumor cell necrosis, which can also be seen in a minority of atypical thymomas and are usually very focal and small (Figure 3I).

Figure 3 Atypical squamoid thymoma. (A) Higher magnification of squamoid atypical thymoma showing variability in cell size (H&E stain, 40× magnification); (B) striking squamoid appearance is imparted by the sharp cell borders separating the tumor cells, imparting the lesion with a pavement-like architecture (H&E stain, 40× magnification); (C) sharp cell membranes and clear perinuclear haloes are a frequent finding in atypical thymoma; notice the dense chromatin of the nuclei and irregular, often convoluted nuclear contours (H&E stain, 40× magnification); (D) prominent longitudinal nuclear grooves are observed in this example of atypical thymoma; notice the glassy “hyaline” appearance of the cytoplasm and the sharp cell membranes (H&E stain, 40× magnification); (E) striking clearing of the cytoplasm is demonstrated in this atypical thymoma which can lead to confusion with metastases of clear cell carcinoma from other sources (H&E stain, 20× magnification); (F) oncocytic appearance of the tumor cells caused by the abundance of finely granular eosinophilic cytoplasm (H&E stain, 40× magnification); (G) scattered multilobated and multinucleated cells are seen in some atypical thymomas, most likely representing a degenerative phenomenon (H&E stain, 40× magnification); (H) extensive area of infarct-like necrosis is seen surrounded by a residual rim of atypical thymoma; this is often seen in association with vaso-occlusive phenomena in the surrounding stroma (H&E stain, 4× magnification); (I) pinpoint focus of comedo-type necrosis is present in this squamoid atypical thymoma (H&E stain, 20× magnification). H&E, hematoxylin and eosin.

While these tumors may exhibit a wide variety of nuclear and cytoplasmic features, the most characteristic finding is the tightly cohesive nature of the tumor cell population which often displays a sheet-like growth pattern, with thick, sharply delineated cell membranes lacking intercellular bridges imparting the tumors with a pavement-like architecture.

Spindle cell atypical thymoma

The current WHO classification of thymic epithelial neoplasms does not formally recognize a spindle cell type of B3 thymoma. In the last edition of the WHO it was stated that “whether a pure spindle cell subtype of type B3 thymoma exists is unclear” (14). Instead, the WHO has introduced a provisional category of “atypical type A thymoma”, which they define as a tumor composed of spindle cells showing “some degree of atypia”. The latter is regarded as a variant of type A thymoma and the WHO appears to equate its malignant potential with that of conventional type A thymoma (14). In our recent study we demonstrated that these tumors behave more closely like squamoid atypical thymomas (conventional type B3 thymoma) rather than like conventional type A thymomas; we therefore regard the WHO “atypical type A thymoma” as the equivalent of a spindle cell type of B3 thymoma (10). These tumors are characterized by a neoplastic cell population that is predominantly composed of oval to spindle, elongated cells with increased nuclear chromatin, visible nucleoli, and relatively scant cytoplasm (10). As with the squamoid variant, lymphocytes are scarce and mostly distributed around dilated perivascular spaces. The tumors can grow as sheets or show a lobulated appearance on scanning magnification (Figure 4A). In addition to sheets of spindle cells, they can also form short fascicles or display a storiform or herringbone pattern (Figure 4B). In rare instances, they can display a trabecular pattern of growth, but the most common appearance is that of streaming sheets of ovoid to spindle cells (Figure 4C). Peripheral palisading of nuclei can also be observed in some cases (Figure 4D). A pseudonodular pattern of growth focally resembling whorls of tumor cells is another feature that can be seen in these tumors (Figure 4E). A trabecular pattern of growth with slender cords of tumor cells circumscribing dilated perivascular spaces can be seen and represents a pitfall for diagnosis by suggesting neuroendocrine tumor (Figure 4F). Mitotic activity is present and ranges from 0 to 12 per 10 high power fields (mean: 2.5 per 10 high power field). The nuclear chromatin is usually dense and evenly dispersed and nucleoli are generally prominent (Figure 4G). The tumor cells display an indistinct rim of eosinophilic cytoplasm with absence of the sharp cell membranes that are frequently observed in the epithelioid tumors, they therefore do not display the “squamoid” appearance of the round and polygonal cell tumors but are more closely reminiscent of the spindle cell areas observed in conventional B3 thymomas. Marked degenerative atypia can be observed focally, especially in tumors that were treated preoperatively (Figure 4H). Dilated perivascular spaces with palisading of tumor cells around the lumens are frequently identified. Large areas of ischemic-type infarction with focal cystic changes can also be seen in these tumors. Small, pinpoint foci of tumor cell necrosis can also be occasionally encountered and does not appear to affect the prognosis for these tumors. A lymphocyte-rich spindle cell atypical thymoma also exists, similar to type AB thymomas but showing significantly increased cytologic atypia on higher magnification, with enlargement of nuclei, prominent nucleoli, and scattered mitoses.

Figure 4 Spindle cell atypical thymoma. (A) Scanning magnification shows sheets of spindle cells with focal nodular pattern separated by bands of fibroconnective tissue (H&E stain, 2× magnification); (B) atypical spindle cell thymoma showing focal fascicular and herringbone pattern (H&E stain, 10× magnification); (C) higher magnification of atypical spindle cell thymoma showing streaming of spindle cells with dense chromatin pattern and prominent nucleoli (H&E stain, 20× magnification); (D) focal peripheral palisading of nuclei is observed in this atypical spindle cell thymoma (H&E stain, 20× magnification); (E) atypical spindle cell thymoma showing a nodular pattern with focal areas reminiscent of meningothelial whorls (H&E stain, 4× magnification); (F) a trabecular growth pattern with slender cords of tumor cells circumscribing dilated perivascular spaces is seen; tumors like this can be readily confused for thymic carcinoid (H&E stain, 4× magnification); (G) higher magnification shows the cytologic features of spindle cell atypical thymoma, with cells containing oval to spindle nuclei with dense chromatin and prominent nucleoli, and scattered mitoses (center) (H&E stain, 20× magnification); (H) focal striking nuclear pleomorphism can be seen in these tumors, especially following preoperative radiation treatment (H&E stain, 40× magnification). H&E, hematoxylin and eosin.

Combination of squamoid and spindle cell atypical thymoma

Some cases of atypical thymoma can show a combination of areas that show the features of epithelioid (“squamoid”) atypical thymoma and atypical spindle cell thymoma. In a recent study, 10% of cases in a large series corresponded to admixtures of both types in which an approximately equal proportion of the tumor was composed of either of these two histologic types (10).

Combinations of atypical thymoma with other histologic types of thymoma

In keeping with the concept that thymomas are heterogeneous tumors that form part of a spectrum of maturation and differentiation of thymic epithelial cells, it is no surprise that admixtures and transitions between atypical thymomas and other histologic types of thymoma should be observed in these tumors. The WHO has also acknowledged these mixed types of thymoma, and states that approximately 30% of cases of type B3 thymoma can show areas of type B1 or B2 (14). In our study of 120 cases of atypical thymoma, 56 cases (46%) showed admixtures with areas of other types of thymoma (Table 2) (6). Interestingly, transitions were observed with other histologic types of thymoma irrespective of whether the atypical thymomas was squamoid or of spindle cell type. The most common admixtures observed were between squamoid atypical thymoma and type B2 thymoma, but combinations of atypical squamoid thymoma with type B1, type A, and type AB were also seen (Figure 5A,5B). Likewise, the atypical spindle cell thymomas were most often seen in association with areas of preexisting conventional type A thymoma, as well as areas of type A plus type AB, and in one case with areas of type B1 and B2 (Figure 5C). Interestingly, 3 cases in that study showed transitions between spindle atypical thymoma and a rare variant of thymoma known as micronodular thymoma with B-cell hyperplasia in which the tumor cells are also spindled and therefore equivalent to type A cells (Figure 5D).

Figure 5 Transitions of atypical thymomas with other types of thymoma and thymic carcinoma. (A) Gradual transition is observed between a type B1 thymoma (left) and an atypical squamoid thymoma (right) (H&E stain, 10× magnification); (B) sharp transition is seen between atypical squamoid thymoma (left) and B2 thymoma (right) (H&E stain, 10× magnification); (C) transition between atypical spindle cell thymoma (left) and B2 thymoma are present in this tumor (H&E stain, 10× magnification); (D) atypical spindle cell thymoma is seen to emerge from background of a micronodular thymoma with B-cell hyperplasia; notice the lymphoid follicle with reactive germinal center entrapped within the tumor, characteristic of the latter (H&E stain, 10× magnification); (E) transition between atypical spindle cell thymoma is seen in this tumor with areas of thymic carcinoma of lymphoepithelial type (H&E stain, 4× magnification); (F) anaplastic transformation is observed in this atypical squamoid thymoma, characterized by bizarre tumor cells with abnormal mitoses alongside more conventional epithelioid cells (H&E stain, 40× magnification). H&E, hematoxylin and eosin.

Development of thymic carcinoma from atypical thymoma

The fact that conventional low-grade thymomas can evolve into a higher-grade type of malignancy has been well-documented previously in the literature (10,15-21). In our recent study of atypical thymomas (10), 16 cases (13%) showed the emergence of thymic carcinoma from atypical thymoma. 7 cases of squamoid atypical thymoma and 5 cases of spindle cell atypical thymoma showed transitions with areas of poorly differentiated non-keratinizing (so-called “lymphoepithelial”) squamous cell thymic carcinoma (Figure 5E). One case of squamoid atypical thymoma showed transitions with spindle cell thymic carcinoma and 1 case of atypical spindle cell thymoma showed a combination of spindle cell thymic carcinoma, basaloid carcinoma, and anaplastic carcinoma (Figure 5F). It appears from this study and from the literature that the development of thymic carcinoma is a relatively frequent occurrence in atypical thymomas, with the most common type of carcinoma emerging from these tumors being the lymphoepithelial type, irrespective of whether the original tumor was composed of round squamoid cells or spindle cells.

Discussion

Atypical thymoma (equivalent to WHO type B3) is one of the least common types of thymoma. These tumors have not been studied at length in the literature and difficulties still exist regarding their terminology and diagnostic criteria. The current classification of thymoma sponsored by the WHO is based on a compromise formula proposed by Dr. Rosai at the time of its first edition (22). The formula adopted a schema based on a combination of letters and numbers to designate the various histologic categories of thymoma in existence at the time The letter A was adopted for tumors that were primarily composed of spindle cells, and the letter B was reserved for tumors composed of round, polygonal, or epithelioid cells. The B category was further subdivided into type B1, B2 and B3, based on the increase in cytologic atypia of the tumor cells and the decrease in the number of lymphocytes. A new category of thymoma, type AB, was created for tumors that were thought to combine features of both type A and type B cells within the same tumor. This schema has essentially remained unchanged and the WHO has retained the same formula and terminology for the past 24 years. Recent observations, however, have demonstrated that some of the concepts and definitions espoused by the WHO have been incorrect and require a reassessment of the classification of thymoma (10,11,23). For example, the category of type AB thymoma which is defined by the WHO as a tumor showing areas that contain cells of both type A and type B has been proven incorrect and recent studies have demonstrated that the proliferating epithelial cells in type AB thymoma are spindle cells which happen to be associated with abundant stromal lymphocytes, thus resembling type B thymoma, but without having the actual cell composition of a type B thymoma (24). Likewise, it has been argued that the provisional category introduced by the WHO in its last 2 editions of “atypical type A thymoma” corresponds to a tumor that deviates significantly in its cytology from conventional type A thymoma and should not be included as a variant of type A thymoma (14). In a review of the topic, we pointed out that if the WHO wished to maintain the old nomenclature based on letters and numbers for the classification of thymoma, and if it was willing to abide by the criteria that were originally espoused by Dr. Rosai in the first edition, the classification would need to be modified to create subcategories of type A thymoma similar to those that exist for type B thymomas; i.e., they should be subclassified into type A1, A2 and A3 (11). Given that the basic underlying premise of the WHO classification for type B thymoma is that they are divided according to the increase in cytologic atypia of the epithelial cells and the decrease in proportion of background lymphocytes, a more correct approach would be to acknowledge that “type AB”, which is basically a type A thymoma rich in lymphocytes, should fall into the category of A1; the conventional type A in the current WHO classification, which has fewer lymphocytes but does not show an increase in cytologic atypia, would correspond to an A2, and the spindle cell tumors that already show evidence of cytologic atypia (that we designate as atypical spindle cell thymoma) would correspond to the A3 category (Table 3). The current classification system would not allow for classification of unusual variants of atypical thymoma such as tumors with rhabdomyomatous differentiation or mucoepidermoid-like atypical thymomas (25,26). Although we do not believe there is a real need to retain the “numbers and letters” schema, following this approach would correspond more closely to the stated premise of the WHO on which their classification is based (1). We do believe, however, that it is time to reassess this topic and abandon the use of the “letters and numbers” formula to designate thymomas and replace them with terms that are more intuitive and understandable for most practicing pathologists (11).

Conclusions

Atypical thymomas are a rare form of primary thymic epithelial neoplasm that can present with a broad spectrum of morphologic appearances, including a variety of growth patterns and cytologic features; the latter can be manifested both in terms of cell size, cell shape, and nuclear and cytoplasmic features. The two principal features that serve to distinguish these tumors from other forms of thymoma are the cohesive nature of the tumor cell population, which grows forming sheets of tightly cohesive cells rather than as isolated tumor cells surrounded by abundant lymphocytes, and the increase in cytologic atypia of the tumor cells as evidenced by increased nuclear to cytoplasmic ratio, increased chromaticity with prominence of nucleoli, and various degrees of cytologic atypia and pleomorphism, including low grade mitotic activity. Use of the MIB1 proliferation marker can be of assistance in problem cases by demonstrating a significant increase in Ki-67 nuclear staining (>10%) compared with conventional type A, AB and B1-2 thymomas (average 1–2%) (6). Distinction from thymic carcinoma, in particular well-differentiated squamous cell carcinoma can be more problematic and needs to rely on the overall assessment of a resected specimen. In general, a tumor growth that forms sheets of squamoid cells devoid of intercellular bridges in concert with numerous dilated perivascular spaces would favor atypical thymoma over squamous cell carcinoma, which is characterized by infiltrating irregular islands of atypical squamous cells with overt evidence of keratinization and significant cytologic atypia and mitoses. Because of the close resemblance of many of these tumors to squamous epithelium, it is likely that many cases reported in the past as examples squamous cell carcinoma of the thymus have corresponded to this unusual type of thymoma. Familiarity with the morphologic features of these tumors is therefore of importance to avoid an incorrect diagnosis.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-15/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-15/coif). D.I.S. serves as an unpaid editorial board member of Mediastinum from December 2024 to November 2026. S.S. serves as an unpaid editorial board member of Mediastinum from January 2024 to December 2025. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All clinical procedures described in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this article and accompanying images.

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