Combined thymic epithelial tumors are rare and characterized by at least two distinct areas each corresponding to one of the histological thymoma and thymic carcinoma types . The etiology of these tumors remains enigmatic. Some genetic studies suggested that combined thymic epithelial tumors could arise by dedifferentiation of thymoma/thymic carcinoma or by biphasic differentiation of a multipotential thymic epithelial precursor. However, the concept of tumor collision awaits genetic evidence . Clinically, almost all reported cases of combined thymic tumors were observed in the anterior mediastinum, and there were no differences in the clinical manifestations of combined tumors as compared to the individual component. Myasthenia gravis (MG) is by far the most common paraneoplastic manifestation. Histologically, over 80% of combined tumors have type B2 and B3 component. But rare cases of combined type AB thymoma or spindle cell (type A) thymoma with thymic carcinoma has also been described [18, 19]. The carcinoma component in the most cases is squamous cell carcinoma. Lymphoepithelioma-like, sarcomatoid/anaplastic or undifferentiated carcinomas are uncommon. In the present case, the typical MEC and type B2 thymoma could be identified in different areas of the same tumor. The patient showed a mass in anterior mediastinum with typical manifestations of myasthenia gravis. These findings were consistent with the diagnostic criteria of combined type B2 thymoma/MEC of thymus. To our best knowledge, so far there is no report to describe a coexistence of thymoma and primary MEC within thymic tumor. Our case is the first case of combined thymic epithelial tumor with MEC component.
MEC is a relatively common neoplasm of the salivary glands, which rarely arises in other sites, including esophagus, anal canal, skin of the breast, lachrymal sac, thyroid gland, or uterine cervix [20–23]. Primary thymic MEC is rare. It was first described by Snover DC and his colleagues in 1982 . Since then, no more than 30 cases have been reported in the English literature [4–15]. Despite its distinct histological morphology, the pathogenesis of MEC of thymus is still unknown. It has been suggested that thymic MECs might arise from thymic epithelium because, in some cases, a transition between tumor cells and benign cyst-lining epithelium and the finding of residual non-neoplastic thymic parenchyma within the walls of the cysts has been reported in some cases . However, pluripotent epithelial stem cells of endodermal origin have been also postulated in the pathogenesis of MEC of the thymus by some authors . A strong association between MEC and t (11; 19) (q21; p13) has been observed in non-thymic anatomical sites [24, 25]. Recent study has demonstrated that MAML2 rearrangement, a member of the Master Mind Like gene family on chromosome 11q21, is harbored specifically in thymic MEC similar to MEC in other anatomical sites, suggesting thymic MEC is not only histologically but also biologically related to non-thymic cases of MEC . It is necessary for the further study to clarify if MAML2 rearrangement presents in the rare MEC component of combined thymic epithelial tumors.
The establishment of a preoperative diagnosis of thymic MEC is difficult because of the rarity of this tumor and the fact that there are no specific landmarks in the radiologic examinations. Therefore, percutaneous biopsy is needed for this tumor to obtain a definite diagnosis preoperatively . In the current study, a CT guided fine needle biopsy of the anterior mediastinal mass was performed. However, only type B2 thymoma was observed in the biopsy because it was difficult for pathologists to provide a precise diagnosis from a few very small tumor tissues in rare combined thymic tumor. Under these extremely rare conditions, sufficient tissue from different parts of the lesion and thoroughly histological inspection are necessary for accurate diagnosis. Even if a diagnosis of thymic MEC is confirmed by biopsy examination, the possibility of a metastasis from primary MEC occurring in common sites should also be excluded. Thoroughly body examination and a whole body PET/CT study are useful to find the potentially primary tumor. In our case, no primary tumor of MEC was found by whole body PET/CT study.
Histologically, MEC in thymus and other anatomical sites are characterized by squamoid (epidermoid), mucin-producing and cells of intermediate type with varying proportion and architectural configuration in and between tumors . The presence of mucin-producing cells in the tumor is the key diagnostic clue for MEC. However, the presence of mucinous differentiation in a thymic neoplasm is not uncommon. Mucinous epithelium can be occasionally noted in the normal human thymus and in thymomas . It more frequently occurs in the thymus of dogs and other animals, and reflects the potential of the thymic epithelium to differentiate along multiple cell lines . Thus, thymic MEC might be confused by thymomas with mucinous differentiation. However, the latter lacks the intermediate type cells and invasive nests of epidermoid cells with desmoplastic stroma. Thymic MEC is sometimes misdiagnosed as squamous cell carcinoma of thymus as the tumor presents predominantly nests of invasive epidermoid cells with inconspicuous mucin-producing cells component. Since the MEC is rare in thymus, these morphological features might be erroneously interpreted squamous cell carcinoma by those who were not familiar with this condition. However, mucin-producing cell is absent in the squamous cell carcinoma, which can be demonstrated in majority of tumor by Alcian blue and diastase-PAS staining. Sufficient tissue from different parts of the tumor and thorough inspection to find the mucin-producing cells will facilitate the precise diagnosis of MEC. More importantly, thymic squamous cell carcinomas are immunoreactive to CD5, which are quite useful to distinguish it from thymic MEC and other non-thymic origin squamous cell carcinoma. Like most of reported cases, the MEC component of our case also presented the immunohistochemical negativity to CD5, supporting the diagnosis of MEC rather than squamous cell carcinoma. However, only one previously reported case of thymic MEC showed tumor cells were positive to CD5 . It is not clear whether this immunoreaction represents a specifically diagnostic marker or an aberrant expression. More cases of primary thymic MEC should be needed to confirm this immunophenotype. In addition, multilocular cystic structures may be frequently observed in thymic MEC, the differential diagnosis of cystic masses in anterior mediastinum, even rare ectopic pancreatic pseudocyst, should be included .
Available data on combined thymic epithelial tumors suggest that the most aggressive component of tumor determines the clinical outcome. As to thymic MEC, high-grade tumors have been demonstrated more invasive and shown stronger tendency for metastasis compared with low-grade tumors [18, 19]. Among the cases reported with known pathological grades and clinical courses, mortality was limited to the high-grade type of MEC. In the present case, the MEC component was low-grade type according to the WHO grading criteria because the tumor lacked the histological features of neural invasion, cystic formation, necrosis and active mitotic figures . Type B2 thymoma is a tumor of moderate malignancy with invasiveness and recurrence, even after complete resection. Recent study has demonstrated that the overexpression of c-Jun, p73 and Caspase-9 in thymic epithelial tumors is closely related with the pathogenesis and biological behavior of the neoplasms . To date, there are no established therapeutic regimens for thymic MEC because of the rarity of this tumor. The published experience with chemotherapy for MEC has been limited, but the tumors have been suggested to be chemosensitive . Most regimens for thymic carcinoma are similar to those for thymoma and include cisplatin [31, 32]. Significant beneficial effect of cisplatin-based combination chemotherapy for inoperable thymic carcinomas has been suggested in several studies [31–33]. In the present case, there was no evidence of tumor recurrence during the period of postoperative follow-up. We presume that low-grade of tumor and chemotherapy with cisplatin regimen might be associated with favorable results. Of course, a longer follow-up period and laboratory examinations are needed to inspect the long term prognosis of our patient.