Owing to the various difficulties that we were experiencing with the existing thymoma classifications, in 1999 we presented a novel proposal for the histological classification of thymic epithelial neoplasms.13
This proposal essentially represented a simplified approach to the morphological classification of these tumours that separated thymic epithelial neoplasms into three broad categories based on their degrees of organotypical differentiation. In our proposal, the histological grading of these tumours was based on the premise that, as in other organs, primary thymic epithelial neoplasms form part of a continuous spectrum of lesions that range from well differentiated to moderately differentiated to poorly differentiated neoplasms. Well‐differentiated tumours would correspond to tumours designated by convention as thymoma; poorly differentiated neoplasms are those conventionally designated as thymic carcinomas; and tumours showing intermediate features of differentiation are designated as atypical thymoma (table 1). The determination of the degree of differentiation for any given tumour in this system is established on the presence or absence of the characteristic organotypical features of differentiation of the normal thymus and on the degree of cytological atypia of the proliferating epithelial cells.13,14
Thus, tumours displaying most or all of the organotypical features of thymic differentiation (such as lobulation, dual cell population with a mixture of thymic epithelial cells and immature T lymphocytes, perivascular spaces, areas of so‐called medullary differentiation, and so on) and absence of cytological atypia are classified as well‐differentiated thymic epithelial neoplasms (ie, thymoma); tumours that retain some of the organotypical features of differentiation of the thymus, but which already display mild to moderate cytological atypia are classified as moderately differentiated thymic epithelial neoplasms (ie, atypical thymoma); and tumours characterised by total absence of the organotypical features of the thymus and showing overt cytological evidence of malignancy correspond to poorly differentiated thymic epithelial neoplasms (ie, thymic carcinoma). This classification is simple, easy to reproduce and does not depend on any purported histogenetic considerations or require the use of special stains or other specialised techniques. It can be easily applied on the basis of the examination of routinely stained slides by haematoxylin and eosin, and requires only familiarity with the organotypical features of differentiation for the different stages of maturation of the normal thymus, along with attention to the degree of cytological atypia displayed by the neoplastic epithelial cells.13
Moreover, the division of these tumours based on degrees of differentiation (as is the norm for most other organs) provides a functional substrate for a rational classification of these tumours, as the various organotypical features of differentiation of the thymus closely parallel the functional status of the organ.13
Table 1Suster and Moran classification of thymic epithelial neoplasms
One of the problems for understanding the relationship between organotypical differentiation and the functional status of the organ in the past has been the failure to realise that the thymus is unique among human organs in that its “normal” morphotype can vary considerably depending on the age of the patient and the stage of maturation of the organ.15
Unlike most other organs in the human body, the thymus reaches its functional maturity during childhood and adolescence and undergoes a process of loss of functional activity and progressive involution thereafter. This results in an organ whose “normal” histological appearance can vary widely depending on the age of the patient (fig 1A,B). Recent studies by Hale16
have mapped this process and shown that with loss of functional maturity, the lymphocytic component of the thymus is progressively replaced by fat and, although the thymus retains its normal size and shape even with advancing age, the residual thymic elements become atrophic and reduced to microscopic remnants. The epithelial cell component also undergoes a process of involution and with loss of functional activity, the cells lose their round shape and become smaller, with oval to spindle nuclei and scant cytoplasm.15,16
Well‐differentiated thymic epithelial neoplasms (ie, thymoma) therefore can show a wide spectrum of morphological appearances that can vary depending on whether the neoplastic cells are attempting to recapitulate the normal, mature thymus of infancy and adolescence or whether they resemble the normal involuted thymus of the adult.13,14,15
Most tumours that recapitulate the normal thymus of infants and adolescents are characterised by well‐developed lobules, with a predominance of small immature T lymphocytes and few intermingled neoplastic thymic epithelial cells (fig 2). The lobules are usually separated by fibrous bands of variable thickness that are often angulated. Dilated perivascular spaces are commonly present in these tumours. Focal areas of medullary differentiation characterised by pale foci containing a smaller number of lymphocytes than the surrounding tissue can also be seen. The proportion of small lymphocytes to epithelial cells can vary widely among tumours and within different areas of the same tumour. The epithelial cells are round, with large vesicular nuclei and single small eosinophilic nucleoli, and are surrounded by abundant cytoplasm with indistinct cell borders. The cells usually do not show any marked cytological atypia and are devoid of mitotic activity. Mitoses can often be observed in the more immature lymphoid cell elements. These tumours are the equivalent of the lymphocyte‐rich thymoma and mixed (lymphoepithelial) thymoma of the traditional classification,3
of the cortical and predominantly cortical thymoma of the Kirchner and Muller‐Hermelink classification,4
and of the types B1 and B2 in the WHO schema.1
Figure 1(A) Normal, mature thymus of childhood. (B) Normal thymus in a 57‐year‐old man. Note the massive involution of the thymus with extensive replacement by fat and thin strands of flattened, atrophic, spindle thymic epithelial (more ...)
Figure 2Thymoma showing features that recapitulate the mature, functionally active thymus of childhood and adolescence, with predominance of immature T lymphocytes admixed with scattered large, round thymic epithelial cells.
Tumours recapitulating the features of the normal involuted thymus of the adult are characterised by a solid proliferation of oval to spindle cells, with small elongated nuclei showing a dense chromatin pattern with occasional small, inconspicuous nucleoli and scant rim of cytoplasm (fig 3). The cells often adopt a fascicular growth pattern, but may grow as sheets admixed with variable numbers of small lymphocytes, or they can adopt a variety of unusual growth patterns, such as the creation of rosette‐like structures, storiform pattern, hemangiopericytic pattern, micronodular pattern, trabecular (adenoid) pattern and others.17
The epithelial tumour cells are completely devoid of cytological atypia or mitotic activity. These tumours are usually characterised by a paucity of lymphocytes, although some cases can show a considerable number of T lymphocytes admixed with the epithelial cells. These tumours correspond to the spindle cell type of thymoma in the traditional classification3
and to the medullary type of thymoma in the Kirchner and Muller‐Hermelink classification,4
and are also the equivalent of type A thymoma in the WHO schema.1
Patients showing admixtures of spindle cell areas with round cells and lymphocyte‐rich areas are often encountered and correspond to the mixed category in the Kirchner and Muller‐Hermelink classification4
and to the type AB thymoma in the WHO schema.1
Figure 3Thymoma showing features that recapitulate the atrophic or involuted, non‐functional thymus of the adult. Sheets of bland‐appearing spindled epithelial cells with occasional small T lymphocytes can be observed.
Moderately differentiated thymic epithelial neoplasms (ie, atypical thymomas) are defined as tumours that retain some of the organotypical features of differentiation of the thymus, but already show some degree of cytological atypia in the neoplastic epithelial cells (fig 4). Such tumours are the equivalent of the predominantly epithelial thymomas in the traditional classification,3
of the well‐differentiated thymic carcinoma of the Kirchner and Muller‐Hermelink classification4
and of the type B3 thymoma in the WHO schema.1
The tumours are histologically characterised by sheets of large, round to polygonal epithelial cells with large, irregular and hyperchromatic nuclei showing frequent prominent eosinophilic nucleoli and occasional mitotic figures. The nuclei often have irregular, raisin‐like contours. The cytoplasm of the cells is generally abundant and deeply eosinophilic, with very sharp cell borders often imparting the lesion with a “squamoid” appearance. Foci of early squamous differentiation can be encountered. The cells can sometimes show clear cytoplasm and often show a tendency to palisade around vessels or perivascular spaces. The tumours also show at least some of the organotypical features of the thymus, such as lobulation, prominent dilated perivascular spaces and an admixture of epithelial cells with small lymphocytes. These tumours are more often invasive than other types of thymoma, with a tendency for earlier recurrences. Atypical thymoma can also be composed of spindle to oval cells rather than round or polygonal cells. In such instances, the spindle cells will show increased nuclear size, with prominent nucleoli and occasional mitotic figures.
Figure 4Atypical thymoma, characterised by partial preservation of the organotypical features of the thymus (perivascular spaces and dual cell population), but showing paucity of lymphocytes and sheets of large polygonal epithelial cells with (more ...)
Poorly differentiated thymic epithelial neoplasms (ie, thymic carcinoma) are characterised by loss of the organotypical features of differentiation of the thymus and the presence of marked or overt cytological features of malignancy (fig 5). These tumours are the equivalent of thymoma type C in the original proposal of the WHO classification2
and they essentially resemble carcinomas similar to those arising in other epithelial organs.17
Thymic carcinoma represents a diagnosis of exclusion. Currently, as no reliable specific markers are available that can help us determine the primary nature of these tumours, definitive diagnosis depends on the demonstration of the absence of a primary tumour elsewhere by thorough clinical and imaging studies or at the time of autopsy.18,19
A large variety of histological variants have been described, including keratinising squamous cell carcinoma, non‐keratinising, poorly differentiated (lymphoepithelioma‐like) squamous cell carcinoma, mucoepidermoid carcinoma, clear cell carcinoma, basaloid carcinoma, spindle cell (sarcomatoid) carcinoma, anaplastic carcinoma, neuroendocrine carcinoma and others.17,18,19
The main problem associated with their diagnosis lies in making a determination as to whether they are primary or metastatic.
Figure 5Thymic carcinoma characterised by absence of the organotypical features of the thymus, with overt cytological evidence of malignancy.
Although our proposal was initially severely criticised, this approach has been recently validated in a large study of thymoma in which it was shown that further simplification of the WHO schema into three subgroups led to classes with good discriminatory power with respect to survival and superior interobserver agreement.20
Thus, by simplifying the WHO classification (ie, merging types A, AB, B1 and B2 into a single group, B3 as a separate group and type C as another group), three subgroups with distinct survival could be identified in that study.20
The authors concluded “our results are in favour of classifications that permit accurate allocation of these neoplasms into simple and reproducible diagnostic categories, as proposed by Suster and Moran”.20
This simplified approach also has the advantage of allowing general pathologists to confidently report thymomas without the need to struggle with often conflicting, confusing or ambiguous histological criteria that define some of the WHO categories11,12
Table 2Comparison of World Health Organization schema and the Suster and Moran histological classification of thymoma