TFE3 is located at Xp11.23, and its protein belongs to the microphthalmia-associated transcription factor (MiTF) family, which plays an important role in the regulation of lysosomal biogenesis and autophagy [25]. The TFE/MiTF family consists of four important members: (i) TFEB, (ii) TFEC, (iii) TFE3, and (iv) MITF [26]. By searching the human protein atlas webtool (https://www.proteinatlas.org/), TFE3 was found to be expressed in adipose tissue, urinary bladder, ovary, testis, breast, etc. TFE3 protein can be transported to the nucleus when cells are starved and/or stressed. The expression and activity of TFE3 are upregulated in many types of human cancers, and are associated with enhanced proliferation and motility of cancer cells. The main tumours related to TFE3 gene fusion include epithelioid haemangioendothelioma, alveolar soft-part sarcoma (ASPS), renal cell carcinoma, malignant chondroid syringoma, rare ossifying fibromyxoid tumours, and perivascular epithelioid cell tumor [27–34].
Park CK and Kim HS had reported that TFE3 was expressed in sclerosing stromal tumors, but there was no abnormality in TFE3 gene [22]. Our research got the same result that TFE3 was specifically expressed in sclerosing stromal tumours, but not in other sex cord stromal tumours. Moreover, TFE3 was specifically expressed in luteinized cells, but not in other two cells.
Sclerosing stromal tumours often occur in young women, and a few cases have the secretion of estrogen and/or androgen. The clinical results of all cases were benign. This study analyzed 8 cases of sclerosing stromal tumours, ranging in age from 17 to 39 years old. No hormone abnormality was found clinically, but 2 patients had irregular menstruation. Follow-up results showed no recurrence.The lobulated structure and three types of cell composition are the unique morphological characteristics of ovarian sclerosing stromal tumours. Due to the young age of SST and good prognosis, accurate pathological diagnosis is very important in order to avoid over-treatment. In most cases, we can obtain a positive pathological diagnosis based on the above findings. However, due to the diversity and variety of ovarian sex cord stromal tumours, we need more specific indicators to assist the pathologist in diagnosis in a few cases.For example, the cystic case in Fig. 1.
Our experimental results show that the luteinized tumor cells in sclerosing stromal tumors have abundant intracellular lipids, and Oil red O staining is obvious. Although microencapsulated stromal tumors and granulosa cell tumors have no intracellular lipids, and Oil red O is negative, there can also be intracellular lipids in thecal cell tumors. Meanwhile, there was no significant difference in immunohistochemical results between SSTs and other ovarian sexual cord stromal tumours, because SF-1, calretinin and inhibin were also expressed in these tumours. Therefore, the positive expression of TFE3 immunohistochemistry is of great significance in the diagnosis and differential diagnosis of sclerosing stromal tumors [5,7,11,14−16].
Because there is no abnormality of TFE3 gene in sclerosing stromal tumors, in order to explored the source of TFE3 positive cells, we analyzed the expression of TFE3 in normal ovaries. To our knowledge, this is the first study to demonstrate that TFE3 nuclei are expressed in the inner membrane cells of follicles, but not in the granulosa cell layer, outer membrane cell layer, or fibroblasts. However, it remains unclear whether the nuclear localization of TFE3 is involved in egg maturation and plays a role in intrathecal cells, which will be the focus of our next study.
In our study, seven out of eight cases of SSTs expressed luteinized cells with moderate-to-severe staining of TFE3, but it was not expressed in the ovarian granulosa, theca, or microcystic stromal tumor. Moreover, the FISH analysis revealed that the TFE3 gene was not broken, indicating that there was no possibility of TFE3 fusion with other genes. These results are consistent with those previously reported [22]. Combined with the results of Chamberlain et al. [17] and Schoolmeester et al. [18], these findings indicate that unlike ASPS, TFE3 overexpression in SST was not caused by genetic translocation, suggesting that other types of genetic alterations may be involved. Chamberlain et al. [21] proposed that the abnormal accumulation of TFE3 in the nucleus could be caused by the dysfunction of organelles or intracellular metabolic signalling pathways, thus leading to the accumulation of phagosomes typical of granulosa cell tumor of soft tissue (GrCTS) in the cytoplasm. Other studies have reported that TFE3 is involved in the regulation of lysosome/phagosome synthesis and the Golgi stress response [22–27]. Thus, aberrant TFE3 expression can result in degenerative changes due to its lysosomal or cytoplasmic accumulation in these tumours and may not be a unique event for SSTs.
Tumours with abnormal TFE3 expression and gene fusion have some common morphological characteristics, such as abundant cytoplasm and obvious nucleoli. However, SSTs, GrCTSs and other tumours that only express TFE3 without TFE3 gene abnormalities have abundant cytoplasm, but no obvious cell nucleoli. These results indicate that the phenotype of cells is not caused by TFE3 genetic abnormalities.
In conclusion, our results show that TFE3 is expressed in the inner theca cells of normal follicles. Meanwhile, this study also suggests that the immunohistochemical detection of TFE3 is helpful for the diagnosis of difficult cases of sclerosing stromal tumor (such as cystic SST). The Lipid-rich SST cells mimic the inner theca cells of normal ovary and express TFE3 without disrupting the gene structure.