The tumor was well-circumscribed and encapsulated but showed foci of infiltration through the capsule into perithymic adipose tissue. The cut surface showed a fleshy white to gray homogenous tissue with prominent lobulation. On scanning magnification, the tumor displayed a biphasic cellular composition. There were sheets of hyperchromatic oval to spindle cells surrounding small clusters of larger round cells with small nuclei and abundant, deeply eosinophilic, cytoplasm (Fig. 3). The scattered spindle cells contained oval to spindled nuclei with a dense chromatin pattern and occasionally prominent nucleoli surrounded by an indistinct rim of eosinophilic cytoplasm. Scattered mitotic figures could be observed in the spindle cell component (1 per 10 high power fields) (Fig. 4). The small clusters of larger cells showed small round nuclei devoid of atypia and were characterized by copious amounts of dense, deeply eosinophilic cytoplasm. These cells resembled mature rhabdomyocytes (skeletal muscle cells) and the majority had a round shape but some showed angulated, tadpole configurations, and a few displayed a strap-like, elongated appearance (Fig. 5). Cytoplasmic cross striations were not observed in these cells. In addition to these 2 components, there were also scattered microscopic foci displaying abrupt squamous differentiation with small islands of large epithelioid cells with clear cytoplasm, sharp cell borders, and occasional intercellular bridges, some of which contained central cystic spaces resembling Hassall’s corpuscles (Fig. 6). Immunohistochemical studies showed the spindle cells were strongly positive for cytokeratin AE1/AE3 and had strong and diffuse nuclear positivity for p63 (Figs. 7A, B). The large myoid cells were strongly positive for desmin (Fig. 8A), and also showed nuclear positivity for Myo-D1 (Fig. 8B) and myogenin but were negative for epithelial markers. A stain for CD117 showed focal membranous staining of the tumor cells (Fig. 8C), and the Ki-67 proliferation marker showed increase in the proliferation ratio of around 10% to 15% (Fig. 8D).
The pathologic diagnosis was atypical thymoma with rhabdomyomatous differentiation.
Thymomas are rare neoplasms derived from thymic epithelial cells. The classification of thymoma has been controversial over the years due to their varied morphologic appearances and the difficulties inherent in functionally and morphologically classifying such a heterogenous group of tumors. The current WHO classification (2015) has retained in modified form the proposal introduced by Dr Juan Rosai and a panel of international experts in 1999 who devised a schema based on a combination of letters and numbers to classify these tumors into types A, B, and AB, with the B type further subclassified into B1, 2, 3.1 The original proposal has undergone several revisions and modifications; however, the rationale for classifying these tumors has continued to be the same. In many instances, it has been quite difficult to apply the proposed criteria in clinical practice.
At the same time the initial WHO schema was being laid out, an alternate proposal was presented by Suster and Moran in 1999 to classify these tumors into 3 simple and reproducible categories: thymoma (for the well-differentiated examples), atypical thymoma (for moderately differentiated tumors), and thymic carcinoma (for the poorly differentiated tumors).2 The category of “atypical thymoma” thus emerged as an intermediate category for tumors that still retained many of the organotypical features of thymic differentiation (such as dual cell population composed of immature T-lymphocytes and epithelial cells, lobulation, encapsulation, dilated perivascular spaces, etc.) but also showed cytologic features commonly associated with more aggressive behavior, such as increased cytologic atypia, prominent nucleoli and mitoses.3 These tumors are roughly equivalent to thymoma of type B3 in the current WHO classification.
Atypical thymoma (WHO B3) differs from conventional type B1-2 thymomas in many respects. The first and most noticeable difference is in the growth pattern; atypical thymoma grows as cohesive sheets of epithelial cells rather than presenting with individually scattered epithelial cells amidst a sea of small lymphocytes. Lymphoid cells are few and far apart in atypical thymoma, unlike B1 and B2 thymomas, in which they either predominate or account for at least 50% of the tumor. Another striking feature in these tumors is the presence of numerous dilated perivascular spaces, often displaying prominent palisading of the epithelial cells around the vessels. The character of the cells is also quite different in these tumors; although atypical thymoma (B3) can show a wide range in size of the tumor cells, they all share an increase in nuclear chromatin pattern and sharp cell borders.3,4 A spindle cell variant of atypical thymoma (B3) has also been recognized, in which the cells manifest more pronounced cytologic atypia than conventional type A thymoma and the nuclei display prominent nucleoli and scattered mitoses.3
Immunohistochemically, the cells of atypical thymoma are positive for cytokeratin and P63, as in all other thymomas, but in addition they can also show positivity for CD117, a marker that has been more commonly associated with thymic carcinoma.5,6 A useful stain for borderline cases is the proliferation marker, Ki-67. The proliferation rate in most conventional thymomas (type A, AB, B1, and B2) is usually very low (generally <5% nuclear positivity). In atypical thymoma (WHO B3) nuclear positivity for Ki-67 is usually above 10% to 15%.3,4
Since the introduction of the WHO classification, the authors of the WHO have recognized the existence of unusual variants of thymoma that do not fit neatly into their ABC/123 schema, including thymoma with pseudosarcomatous stroma (“metaplastic” thymoma), micronodular thymoma with B-cell hyperplasia, pleomorphic/anaplastic thymoma, microscopic thymoma, and sclerosing thymoma. The present case represents another unusual variant of thymoma that does not fit neatly into the current WHO schema. Tumors with these features have been the subject of only rare case reports.7–10 Most of the reported cases correspond to thymomas with myoid cells. A more recent study by De Queiroga et al in 2004 reported a tumor harboring a similar benign-appearing myoid cell component but in which the epithelial elements showed significant cytologic atypia thus qualifying for a diagnosis of rhabdomyomatous thymic carcinoma.11 The present case closes the loop for these unusual tumors by documenting the presence of benign rhabdomyomatous cells in an atypical thymoma (WHO B3), an intermediate form in this family of tumors.
The presence of rhabdomyomatous cells is difficult to explain in these tumors. Mature skeletal muscle cells have been observed in normal human thymuses in the adult and newborns as well as in other mammalian species.12 The histogenesis of myoid cells in human thymuses is still controversial. Various theories have been proposed to explain their origin, including derivation from pluripotential stem cells in the thymus, as the result of somatic maturation of intrathymic germ cells, or from muscle precursor cells of extrathymic origin in the surrounding mesoderm.12–14 An alternate proposal has been the occurrence of muscle-like differentiation of thymic epithelial cells in thymomas (ie, a process of transdifferentiation).15 This theory is supported by the demonstration made by Henry on electron microscopy of desmosomal attachments between striated muscle cells and epithelial cells in human thymus, as well as of cells with features that were intermediate between striated muscle cells and epithelial cells.7 It has been postulated that thymic myoid cells may be involved in thymic physiology by producing cytokines involved in thymic development and chemokines that protect thymocytes from apoptosis.15 These cells have also been postulated to play a role in myasthenia gravis due to their high content of acetylcholine receptors. The importance of recognizing this tumor is to avoid misdiagnosis for a more ominous malignancy such as carcinosarcoma, rhabdomyosarcoma, or a myoid sarcoma originating from a malignant germ cell tumor. At last follow-up (3 y after surgery), the patient is alive and well with no evidence of recurrence or metastasis.
CLUB MEMBERS’ OPINIONS AND COMMENTS
- I see the small spindle cells, the squamous islands, and the rhabdoid cells. Taken on their own I could see where the squamous cells would look atypical in a small needle biopsy without the benefit of context could be misinterpreted as malignant. The rhabdoid cells could be misinterpreted as dyskeratosis furthering the confusion.
- Wow! I will now be on the lookout for “rhabdoid cells” in my next thymoma.
- What a rarity, but very distinctive appearance. Very nice slide.
- Wow!! I remember reading this paper, but I did not think I would get to see a case of one. Spectacular.
- This is an interesting case of rhabdomyomatous thymoma, the rhabdoid cells remind me of the presence of cells in the fetal thymus with striated muscle differentiation.
- A beautiful, spectacular, and unusual case.
- Rhabdomyomatous thymoma. I have never seen this type of tumor, thank you for sharing this case.
- Nice example of rhabdomyomatous thymoma. The immunohistochemistry is convincing. Without doing it the rhabdoid cells may even be confused for atypical squamous cells.
- Fabulous myoid cells!
- What a spectacular case!
- I have never seen one before, thank you!
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
thymoma; atypical thymoma; rhabdoid cells; myoid tumors