Thymoma Histological Heterogeneity PDF

Seminars in Diagnostic Pathology 39 (2022) 99–104 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Thymoma: Histologically a heterogenous group of tumors Diana M. Oramas, Cesar A. Moran * Department of Pathology, The Universit...

Seminars in Diagnostic Pathology 39 (2022) 99–104 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Thymoma: Histologically a heterogenous group of tumors Diana M. Oramas, Cesar A. Moran * Department of Pathology, The University of Texas, M D Anderson Cancer Center, Houston, TX, USA A R T I C L E I N F O A B S T R A C T Keywords: thymus thymoma plasma cells myoid cells unusual Over the years the nomenclature of thymomas has been debated regarding the best manner in which these tu­ mors should be grouped. In every schema presented thus far, the main issue has been the presence or lack of lymphocytes and accordingly, the tumors have been place into a specific category. However, even though this concept applies for most of the cases, there are numerous tumors that do not necessarily fit into those categories as either the thymomas show another cellular proliferation associated with the epithelial cells or the epithelial cell themselves are arranged in a pattern that departs from the conventional features of the classic thymoma. Herein we will emphasize those features, which in some circumstances, mainly with small mediastinoscopic biopsies may pose a considerable problem in interpretation. We do consider that the most important issue is to be familiar with the different growth pattern that these tumors may show in order to avoid misdiagnosis. In addition, we consider that regardless of the growth pattern or cellular composition of the tumor, it is highly recommended that these tumors just like any other be carefully sampled and properly stage. Although we are fully aware of the different growth pattern and specific cellular details that thymoma may show, the discussion of each one of those tumors is beyond the scope of this review. Therefore, we have placed more emphasis in those, which in our judgment are more commonly encountered in the daily practice. Introduction Thymic epithelial neoplasms, namely thymoma accounts for the most common epithelial tumor in the anterior mediastinum. Although over the years there has been great interest in assigning a specific nomenclature and to predict prognosis based on histological features, it is important to highlight that thymomas contrary to common belief, expand a wide spectrum of histological patterns, which often pose a challenge in diagnosis, mainly when confronted with small media­ stinoscopic biopsies. Even in the most conventional histologies, it has been demonstrated that when properly sampled, these tumors more often than not, will show mixed histologies, which make any histological classification system rather impractical and misguided.1, 2 Therefore, the assessment of thymomas not only requires to be familiar with the conventional features of these tumors but also to be familiar with the unusual features and other important cellular component that may be associated with thymomas. Here we will emphasize the unusual histo­ logical features of thymomas to highlight that these tumors can be easily confused with other neoplasms. At the same time, we would like to highlight that regardless of the histological classification system employed –World Health Organization (WHO), Bernatz, Suster-Moran, * Corresponding author. E-mail address: [email protected] (C.A. Moran). https://doi.org/10.1053/j.semdp.2021.06.002 Available online 11 June 2021 0740-2570/© 2021 Elsevier Inc. All rights reserved. or Marino-Muller-Hermelink,3-6 the fact remains that those tumors need to be properly approached under the designation of thymoma, and more importantly that they do belong to specific categories rather than to a specific slot in any classification schema. Results All the histological schemas in the classification of thymomas spe­ cifically address the presence of progressive lost of lymphocytes and based on that feature, tumors are placed into specific categories. This concept derives from the association of the tumor to the normal histo­ logical features of the thymic gland. However, the thymic gland in addition to lymphocytes and epithelial cells may also display other cellular elements that in time may also become an important component of any thymoma. In addition, the conventional cellular features of epithelial cells –round or spindle, may in many cases of thymoma show features that depart from those characteristics and become a challenge in the diagnosis and also in the proper histological classification. Although we cannot be completely inclusive and provide a specific account of every case of thymoma that shows unusual features, we will describe in this writing the more often encountered unusual features of D.M. Oramas and C.A. Moran Seminars in Diagnostic Pathology 39 (2022) 99–104 thymoma that depart from the conventional. We also want to highlight the challenge that these variants of thymoma may pose in small mediastinoscopic biopsies in which only a component of the tumor may be sampled, which in turn may lead to an incorrect interpretation. Plasma cell thymoma: in general terms, the presence of an inflam­ matory reaction composed of plasma cells is a feature more commonly associated with thymic carcinoma. However, unusual cases of thymoma with a mixture of epithelial and plasma cell cells has been reported in the literature7(Fig. 1A,B). It is possible that this type of association may be the product of an associated autoimmune disorder including myasthenia gravis, while it also may represent another associated plasma cell con­ dition. It is important to highlight that the normal thymus may also show the presence of plasma cells, not in the same proportion of lymphocytes but plasma cells are part of the normal cellular component of the normal thymus. Thymoma with pseudosarcomatous stroma: this term was originally coined in 1997.8 However, follow up publication on similar tumor employed the name of “metaplastic carcinoma”.9 Unfortunately, other authors have followed suit and have added other terms such as “low-­ grade metaplastic carcinoma”.10 At this point it is important to high­ light that both publication have almost similar number of cases and more interesting is that the clinical behavior observed in both publica­ tions was more in keeping with thymoma than thymic carcinoma. More recently, the authors of WHO without a publication of their own renamed the tumor as “metaplastic thymoma.” The use of the term “metaplastic” is questionable and the tumor in truth does not show any metaplastic changes. It is possible that in the incorrect description of the tumor as “metaplastic carcinoma” the authors may have drawn an analogy with tumors of the breast that carried that designation. Nevertheless, the important point is to recognize this tumor as thymoma and to properly know the specific features of it as well as to properly stage the tumor at the time of diagnosis. The tumor characteristically shows an epithelial cellular proliferation with minimal presence of lymphocytes (Fig. 2A, B). That feature alone would be enough to classify the tumor as an atypical thymoma (WHO type B3). However, the tumor also shows the presence of a spindle cell component, likely representing a fibroblastic proliferation from remnants of the fibrocollagenous bands that characteristically are present in conventional cases of thymoma. Therefore, there is nothing metaplastic about these tumors as its com­ ponents are part of the normal frame and cellularity of the normal thymus. Thymomas with myoid cells: this type of thymoma has also been named “Rhadomyomatous thymoma” due to the presence of the myoid cell component. These tumors also show the presence of an epithelial cellular proliferation, which could correspond to round or spindle cells (Fig. 3A, B). However, contrary to the conventional histology of lym­ phocytic component, these tumors lack the lymphoid component, which is replaced by myoid cellular proliferation.11, 12 Also important to mention is that the myoid cell component is not an exclusive feature of thymoma, as it has also been reported in thymic carcinoma.13 Once again, even though we are not able in the majority of cases to identify myoid cells in the normal thymus, the presence of such component has been well described in the literature. Therefore, their presence as an important component in some thymomas may obey to an immunoreg­ ulatory function of the normal thymus as it has been documented to occur in patients with myasthenia gravis.14–17 Ancient (Sclerosing) thymoma: as it names implies, these tumors are characterized by the presence of an epithelial cellular proliferation lacking any lymphocytic component.18, 19 The cellular proliferation may show different histological features and can vary from round to spindle cells arranged in unusual growth patterns (Fig. 4). The most important pitfall in the diagnosis of these tumors is in the proper separation from sclerosing/fibrosing mediastinitis.20 Thymoma with papillary and pseudopapillary features: although papil­ lary features have been described in thymic carcinoma, in unusual cases similar features of papillary and pseudopapillary structures may be the main feature of thymoma21 (Fig. 5). In this setting other tumoral con­ dition that may occur in the mediastinum such as papillary thyroid carcinoma or pulmonary papillary adenocarcinoma need to be consid­ ered in the differential diagnosis. Both of those conditions, either by clinical history, diagnostic imaging, or immunohistochemistry can be properly excluded. Thymomas with adenomatoid-like, alveolar, glandular, signet ring cell, and clear cell features: these four distinct growth patterns may also pose a diagnostic challenge in small mediastinoscopic biopsies or even in resected specimens22–26 (Fig. 6A–E). In the adenomatoid-like growth pattern composed of cord or nests of cells with round to spindle cell morphology but without increased nuclear atypia or mitotic activity. On the other hand, the tumor show an “alveolar-like” growth pattern in which the tumor cells are arranged in a manner similar to that seen in “pulmonary edema,” while in other tumors the cellular proliferation is arranged in a more glandular-like appearance giving the impression of gland forming neoplasm. In some unusual cases, the cellular prolifera­ tion present in thymomas resembles the signet ring cell appearance that is present in signet ring cell carcinomas, while in other cases the pres­ ence of clear cells, which has been often associate with thymic carci­ nomas, may also be prominent in thymoma. These latter features in small biopsies may pose considerable challenge in diagnosis and the use of more specific immunohistochemistry is often needed. Thymoma with neuroendocrine morphology: although not uncommon, Fig. 1. – A) low power view of a plasma cell rich thymoma, B) higher magnification showing the presence of plasma cells admixed with epithelial cells. 100 D.M. Oramas and C.A. Moran Seminars in Diagnostic Pathology 39 (2022) 99–104 Fig. 2. – A) thymoma with pseudosarcomatous stroma (metaplastic thymoma) showing two different cell populations, B) higher magnification showing the fibroblastic-like spindle cell component in association with more conventional epithelial areas. Fig. 3. – Rhabodmyomatous thymoma showing epithelial and myoid cells, B) Spindle cell thymoma with myoid cells. Fig. 4. – Ancient (sclerosing) thymoma with extensive area of sclerosis. Fig. 5. – Thymoma with papillary features. spindle cell thymomas often show a growth pattern in which the tumor is arranged in what at low power may appear as rosette formation giving the appearance of a thymic neuroendocrine carcinoma27 (Fig. 7). Important to highlight is that these tumors do not show areas of comedo-like necrosis, nuclear atypia, or increase mitotic activity. However, in this setting it is important to mention that some cases of 101 D.M. Oramas and C.A. Moran Seminars in Diagnostic Pathology 39 (2022) 99–104 Fig. 6. – A) thymoma with clear cell component, B) thymoma with alveolar growth pattern, C) Signet ring cell thymoma, D) Adenomatoid thymoma, E) glan­ dular thymoma. may pose a diagnostic challenge as both of these conditions may show B-cell lymphoid hyperplasia.29 Desmoplastic thymoma: this term has been coined for thymomas in which the conventional spindle cell growth pattern is rather lost and the proliferation of spindle cells mimic that of a fibroblastic proliferation in a rather loose myxoid-like background (Fig. 9). The tumor lack necrosis and increase mitotic activity and in some areas it may appear as a reactive process.30 Thymoma with sebaceous differentiation: this particular differentiation has been described more in thymomas than in thymic carcinomas. The tumors are characterized by the presence of strands of epithelial cells with ample clear cytoplasm, which may or may not be associated with a lymphoid component.31 Xanthomatous thymoma: this type of thymoma can be seen in cases with spindle cell or round cell morphology in which the tumor cells are admixed with a prominent xanthomatous component (Fig. 10). In some cases, the xanthomatous component may be the most prominent component of the tumor.32 Fig. 7. – Thymoma showing numerous rosette-like structures mimicking a neuroendocrine neoplasm. Comment thymomas may show positive staining for synaptophysin, which may add to the confusion in these types of cases. However, the use of other markers such as negative chromogranin and positive staining for keratin 5/6, p63, and p40 will lead to the correct interpretation. Micronodular thymoma: this unusual variant of thymoma is charac­ terized by islands of different sizes and shapes of spindle cells embedded in a prominent lymphoid background, which may show prominent germinal centers28 (Fig. 8A, B). By immunohistochemistry, it has been determined that the lymphocytic background is B-cell type so these tu­ mors are known as micronodular thymoma with B-cell lymphoid hy­ perplasia. More recently, these tumors have also been described in association with multilocular thymic cyst (MTC)-like areas, which also As it has been illustrated, the numerous histological growth patterns that may be seen in thymomas are wide and represent pitfalls in the diagnosis of thymoma. The heterogeneity of thymomas clearly repre­ sents a challenge also in the histological classification of thymomas. It is exactly this heterogeneity that makes any histological schema somewhat impractical and places more emphasis on the staging of the tumor at the time of diagnosis so that proper management can be determined. However, more importantly is to highlight that familiarity with specific types of thymoma that depart from the conventional cellular component of cell shapes is of great importance in arriving at a final interpretation. Furthermore, the current immunohistochemistry cannot be viewed as pathognomonic of thymoma, as there is not a single stain that can be specific for the diagnosis of thymoma. The tumor will show positive 102 D.M. Oramas and C.A. Moran Seminars in Diagnostic Pathology 39 (2022) 99–104 Fig. 8. – A) Micronodular thymoma with B-cell lymphoid hyperplasia, B) Micronodular thymoma showing germinal centers. importance of being familiar with the different histological features that thymomas may display. It has been well demonstrated in the literature in large series of thymomas that the use of letters and numbers to designate specific types of thymoma does not correlate with clinical behavior1, 33 leaving the staging of the tumor at the time of diagnosis as the most important parameter to predict possible clinical outcome. In terms of staging, one of the shortcomings with the newly proposed TNM staging system for thymomas in addition to having been developed by borrowing terms from previous well developed staging schemas34, 35 is the lack of cor­ relation between the size of the tumor and the invasiveness of it.33 Therefore, relegating the staging of thymoma to the better well-developed and tested schemas.34, 35 We consider that it is also doubtful that any unusual features of thymoma will follow a more aggressive or less aggressive clinical behavior. Therefore, we consider that the most important consideration in cases with unusual features is the proper assessment and diagnosis of the tumor as a thymoma rather than any other type of mediastinal neoplasm. One important aspect that is commonly ignored in the assessment of thymomas is that even in cases in which the cellular component is not the conventional lymphocytic, it is important to re-evaluate the normal cellular components of the normal thymus.36 The presence of striated muscle, plasma cells, dendritic cells, and other types of cells are part of the normal thymus and possibly in different autoimmune processes their expression may become more prominent in tumoral conditions such as thymomas. In addition, the immunohistochemistry of the normal thymus is also another issue that commonly confounds the assessment of thymomas. The immunohistochemical features of the normal thymus recapitulate in cases of thymoma,36 thus, providing limited help in terms of finding the “magic bullet” of any particular immune stain in the diagnosis of thymoma. In short, we have highlighted the numerous pitfalls that may be observed in cases that depart from the conventional histology of thy­ momas. Needless to say, the conventional features of lymphocytes and epithelial cells and the nomenclature that deals with those common histologies is important as the majority of tumors will fall into those categories. However, a meaningful and sizable number of thymomas fall into their own categories and as such should be recognized and properly diagnosed. Currently, the best method to evaluate possible clinical outcome is the capsular integrity of the tumor and the staging at the time of diagnosis. Therefore, careful assessment of capsular integrity in any type of thymoma is of crucial importance. Fig. 9-. Thymoma with desmoplastic features. Fig. 10. – Xanthomatous thymoma showing numerous xanthoma cells associ­ ated with focal spindle cells. staining for different antibodies that may also be positive in other tu­ moral conditions of different origins. Therefore, in the final analysis, the diagnosis of thymoma still remains a morphological approach thus the 103