Ectopic thymomas are a rare cancer. As a subtype of ectopic thymoma, ectopic pulmonary thymoma accounts for 20%[2], which was first described by McBurney et al. in 1951. Up to 2017, only 37 cases of ectopic pulmonary thymoma have been reported[7]. The histogenesis of ectopic thymomas remains unclear. Displacement, one of the theories explaining the existence of such tumors, is widely accepted. Embryologically, the thymus develops from the third and fourth pharyngeal pouches and migrates into the anterosuperior mediastinum by the fifth or sixth week of gestation[1]. Ectopic thymomas may develop from the displacement of thymic tissue during embryogenesis. This theory explains proficiently the existence of thymic tissue in the cervical region, thyroid and pericardium. However, it fails to explain the presence of thymic tissue in the lung, because the pulmonary system develops much earlier than the thymus[8]. Therefore, another popular hypothesis, stem cell theory, was proposed that ectopic thymomas could originate from stem cells. Primary intrapulmonary tumors deriving from ectopic tissues not native to the lung, such as meningiomas[9] or melanoma[10], support the hypothesis that ectopic thymic neoplasms may be able to originate from stem cells. In our case, the patient was diagnosed as an ectopic pulmonary thymoma, as well as a thymoma in thymus. By applying the stem cell theory, it made sense that the patient in our report developed thymomas in both locations.
Though the cytologic features of ectopic thymomas and thymic carcinoma are identical to those of mediastinal thymomas and thymic carcinoma, the correct diagnosis is extremely challenging to make because of the rarity of being found in such an unusual location and the variety of histology patterns seen. Some pathologists lack of awareness of this entity and lack of typical features of the thymoma or thymic carcinoma make the diagnosis even more difficult.The exact diagnosis is based on histologic findings, and ectopic pulmonary thymoma displays the same characteristic histological features of mediastinal thymoma[11]. However, it is easy to confuse this lesion with other tumors. To reach this purpose, several IHC markers are recommended, such as p40, TdT, SMA, S100, CD5 and desmin[7, 12, 13]. The strong collagen IV deposits among the spindle cells and the extensive co-expression of cytokeratins and CD20 were considered highly diagnostic for type A thymoma according to the World Class Organization classification system of TET. The hemangiopericytic pattern is a frequent feature in spindle cell (type A) thymoma. Furthermore, the diagnostic value of the co-expression of cytokeratins and CD20 was considered. In our case, positive staining for p40 and PCK were observed in both tumor tissues, while the other IHC markers were negative. These results together with the histological features revealed by hematoxylin and eosin stain helped the diagnosis of type A thymomas in the anterior mediastinum and lung according to the WHO classification. Type A thymoma are usually characterized by a low grade of malignancy.
The recommended treatment of thymomas is surgical resection because of the significant better survival rate[14]. Besides, adjuvant therapy like radiation or chemotherapy was suggested in case of the incomplete resection or expansion of the tumor tissue. In our case, the masses were low-risk thymomas without invasion, therefore, no adjuvant therapy after surgical treatment was conducted.
Established the thymic tissue origin of the lesion the metastatic nature was the most probable nevertheless it was excluded and the tumour considered primary because both FDG-PET and total body CT-SCAN didn't detect other lesions or ectopic thymus. In our study, we further performed WES to reveal some molecular profiles. Literarily, Petrini et al. analyzed 28 thymic epithelial tumors (TETs) and identified a high frequency of GTF2I (general transcription factor II I) mutation at type A thymomas but not in the aggressive subtypes[15]. In our case, we did not find GTF2I mutation in either ectopic pulmonary thymoma or mediastinal thymoma. Eight genes were found to be co-mutated in both lesions, among which, HRAS, a driven gene, was included. HRAS mutation was identified as one of the recurrent somatic mutations in thymic carcinoma (the most aggressive type of TETs)[16]. In addition, combined with previous published mutational profiles [4-6], the mutational landscape of both mediastinal lesion and lung lesion tissues have a significant different.
Patial heterogeneity complicates the analysis of solid tumors, as distinct regions of a tumor may harbor different subclonal populations. Assaying multiple regions of heterogeneous tumors should assist in uncovering the full spectrum of mutations and subclones present in a tumor and help identify the spatial origins of subclones. Through sequencing multiple surgically resected tumor regions, we were able to unravel both the extent of genomic heterogeneity and the evolution history of mediastinal thymoma and ectopic pulmonary thymoma. we constructed phylogenetic trees of disease evolution taking all mutations in mediastinal thymoma and ectopic pulmonary thymoma. PyClone detected two clusters in ectopic pulmonary thymoma and the mediastinal thymoma showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to five clusters. For the patient, the mediastinal lesion and pulmonary tissue were each polyclonal, and the clonal populations differed from one thymoma to another, the mediastinal lesion tissue had a highly degree of heterogeneity and the pulmonary tissue showed a relatively low amount of variant heterogeneity. The result implied the case represents a disease of multicentric origin.
In conclusion, we reported a rare case with type A ectopic pulmonary thymoma and mediastinal thymoma. Our data demonstrated an evident heterogeneity between ectopic pulmonary thymoma and mediastinal thymoma.