TFE3 nuclear expression as a novel biomarker of ovarian sclerosing stromal tumors and associated with its histological morphology.

Sclerosing stromal tumors of the ovary are benign and tend to occur in youthful women with lobular structures at low frequencies. Three types of cells, including luteinized cells, short spindle myoid cells, and intermediate cells, are found in the lobules which abundant in the blood vessels. Currently, immunohistochemistry is used to detect normal follicles, sclerosing stromal tumors, granulosa cell tumors, and fibromas/thecomas. Our research results showed that transcription factor enhancer 3 (TFE3) was moderate to strong positive in the theca interna layer of normal follicles. TFE3 was expressed in seven out of eight sclerosing stromal tumors, mainly in luteinized cells. It did not express in 20 granulosa cell tumors. Of the nine fibromas/thecomas, TFE3 was weakly staining in 2 cases and negative in the remaining 7 cases. The expression of TFE3 was also weak in only one microcystic stromal tumor. 8 cases of sclerosing stromal tumors were analyzed by FISH using a TFE3 separation probe, and the results were negative. In short, as a nuclear transcription protein, TFE3 specifically expressed in sclerosing stromal tumors and could serve as a new marker for the diagnosis and differential diagnosis of sclerosing stromal tumors. Moreover, we speculate that TFE3 will promotes the formation of the vascular plexus after entry into the nucleus, which can further explain why sclerosing stromal tumors are different from other ovary sex-cord stromal tumors.

A 17 year old male with a testicular fibrothecoma: a case report.

We herein report the case of a right-sided testicular fibrothecoma in a 17 year old male and review the pertinent literature relatable to this rare, benign lesion. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7738283021019280.

Testicular fibrothecoma: a morphologic and immunohistochemical study of 16 cases.

Benign intratesticular spindle cell lesions are rare. Herein, we report the morphology, immunohistochemical characteristics, and prognosis of 16 cases of testicular fibrothecoma. The mean age at diagnosis was 44 years (16 to 69 y). Of 15 patients with information, 14 presented with a palpable testicular mass and 1 with heaviness in the scrotum. Medical histories included bilateral orchidopexy as a child (n=1) and testicular atrophy receiving testosterone replacement (n=1). The average size was 1.8 cm (median 2 cm; range, 0.5 to 7.6 cm). All cases were intratesticular, although 13 were abutting the tunica albuginea with others centered on the rete testis (n=2), or were indeterminate on biopsy (n=1). Eleven cases were relatively well circumscribed, although not encapsulated, with 1 being infiltrative and 4 not evaluable. Four tumors showed entrapment of seminiferous tubules. Half of the fibrothecomas showed a mixed storiform pattern and short fascicles, with 6 storiform only and 2 short fascicles only. One half of the tumors were very hypercellular. Cases were equally split between having plumper ovoid as opposed to spindled pointed nuclei, with all cases lacking prominent nucleoli. Eleven cases had 0 to 2 mitoses per 10 HPF, 3 had 4 to 5 mitoses per 10 HPF, and 2 had 9 to 10 mitoses per 10 HPF. Collagen deposition either in bands or investing single cells ranged from none to extensive, with 10/16 cases having at least a moderate amount. Immunohistochemical positivity was as follows: inhibin (11/13, patchy to diffuse); calretinin (5/9); Melan-A (4/4); pan keratin (5/8); BCL2 (3/4); CD34 (3/8); S100 (4/8); muscle-specific actin (4/4); and desmin (5/8). Patients were followed up for a mean of 71.8 months (range, 3 to 144 mo). All were well with no evidence of disease. Of the 2 men with 9 to 10 mitoses per 10 HPF, 1 died of other causes 5 years and 8 months later, and the other had no evidence of disease at 4 years and 10 months after surgery. In summary, testicular fibrothecomas are rare with somewhat variable histology and can have worrisome histologic features such as minimal invasion into surrounding testis, high cellularity, and increased mitotic rate. Their immunoprofile is variable and typically not diagnostic. Despite some worrisome histologic features, they appear uniformly benign in their behavior.

Preliminary observations and diagnostic value of lipid peak in ovarian thecomas/fibrothecomas using in vivo proton MR spectroscopy at 3T.

PURPOSE: To retrospectively evaluate the significance of lipid peak in in vivo proton magnetic resonance (MR) spectroscopy for the diagnosis of ovarian thecomas/fibrothecomas in patients with solid gynecologic tumors exhibiting totally or partially low signal intensity on T2-weighted images. MATERIALS AND METHODS: MR spectroscopy was performed in patients with pathologically diagnosed gynecologic tumors at 3T MRI. Single-voxel MR spectroscopy data were collected from a single square volume of interest that encompassed the gynecologic masses. The lipid concentration level was classified into three classes (high; low; none). RESULTS: A total of 20 gynecologic tumors in 20 patients were evaluated in this study. High lipid peak was observed in all seven thecomas/fibrothecomas, whereas low lipid peak was observed in only one fibroma in 13 nonthecomatous tumors (six benign ovarian tumors and seven subserosal uterine leiomyomas). The presence of lipid peak for the diagnosis of thecomas/fibrothecomas had a sensitivity of 100%, specificity of 92%, positive predictive value of 88%, and negative predictive value of 100%. CONCLUSION: The high lipid peak reflecting abundant intracellular lipid contents is considered a specific metabolite concentration for thecomas/fibrothecomas. Demonstration of high lipid peak may contribute to the diagnosis of thecomas/fibrothecomas in distinguishing from other benign ovarian fibrous tumors or subserosal uterine leiomyomas.

Ovarian thecoma: clinicopathological analysis of 50 cases.

The clinicopathological findings of 50 thecoma cases were studied to establish the most useful diagnostic criteria helpful in characterizing this ovarian stromal tumor. Patient age ranged from 21 to 77 years (median, 57.5 years). In this study, thecoma appears to be associated with endometrial diseases (15 patients) as an incidental finding in a gynecologic routine examination (14 patients) and in a cesarean delivery (1 patient). Arteries, veins, lymphatics, and mast cells are normally present in the ovarian medulla and are absent in the cortical area. The 50 thecomas studied showed proliferation of stromal cells and presence of arteries, lymphatics, and mast cells. Thecoma tumoral growth appeared to cause atrophy or compression of the cortical area. These findings are significant for diagnosis; thus, thecoma is proposed as a tumor originating in the ovarian medulla. Fibroma and thecoma seem to be different neoplasms and should be considered distinct, separate entities because they have different origin, morphology, and potential functionality.

Adenocarcinoma arising from mature cystic teratoma of the ovary.

An extremely rare adenocarcinoma arising from a mature cystic teratoma is reported. A 58-year-old woman underwent bilateral salpingo-oophorectomy because of a tumor in each ovary. The right ovarian tumor (solid, 9.6 x 9.6 x 6.3 cm) was a benign thecoma. Histology revealed the left ovarian cystic tumor (multilocular, 6.4 x 4.8 x 2.8 cm) was a mature cystic teratoma containing skin, fatty tissue and respiratory epithelial tissue. In addition, there was a small focal adenocarcinomatous lesion contiguous to the teratomatous ciliated columnar epithelium without stromal invasion (so-called adenocarcinoma in situ) that was suggestive of respiratory epithelium origin. However, goblet cells were present in the glandular structures of the lesion and immunohistochemical staining was segmentally strongly positive for CK20 and uniformly negative for CK7. These results suggested that the adenocarcinomatous lesion had a mucin secretory gastrointestinal phenotype. Further investigation and the collection of more cases is necessary to determine the origin and growth mechanism of adenocarcinoma arising from mature cystic teratoma of the ovary.

Tetrasomy 12 in ovarian tumors of thecoma-fibroma group: A fluorescence in situ hybridization analysis using paraffin sections.

Recent cytogenetical studies have indicated that trisomy 12 is a feature of ovarian tumors in the thecoma-fibroma group. Ten cases of these ovarian tumors were studied in total, including two thecomas, two fibrothecomas, four fibromas, one cellular fibroma and one fibrosarcoma, to clarify the relationship between polysomy 12 and proliferative activity in these tumors. Each formalin-fixed, paraffin-embedded tumor tissue was examined by fluorescence in situ hybridization to determine copy numbers of chromosome 12 and by immunohistochemical staining of Ki-67 for evaluation of tumor cell proliferation. Gains of trisomy 12 were found in seven of the 10 cases, and the percentage of cells with tetrasomy 12, but not that of cells with trisomy 12, was significantly and positively correlated with percentage of Ki-67-positive cells, but significantly and inversely correlated with patient age. These findings suggest that tetrasomy 12 is an age-related aberration of chromosome 12 in ovarian tumors of the thecoma-fibroma group, and that such tumors exhibit more active proliferation in younger patients.

Malignant theca cell tumor of rat.

A large-sized ovarian tumor of theca cell origin was found in a female rat. The mass was located in the right ovary position. Histologically, the tumor was covered by thin fibrous capsule and consisted of a solid area and an abundant necrotic area. Tumor cells were arranged in a storiform or whorled pattern. Connective tissue elements occasionally presented as bundles of dense collagen fibers. Fusiform to elongated cells had oval- to spindle-shaped nuclei with indistinct nucleoli. Large round nuclei and mitotic figures were scattered throughout the tumor cells. These cells were stained positively with S-100 but negatively with vimentin and a-smooth muscle actin. Tumor cells with abundant cytoplasm sometimes contained multiple small-sized lipid vacuoles.

Sclerosing stromal tumors, thecomas, and fibromas of the ovary: an immunohistochemical profile.

The immunohistochemistry of 11 sclerosing stromal tumors (SSTs), 11 fibromas, and 5 thecomas was studied to determine criteria for the assessment of 5 densely sclerotic, calcified ovarian tumors of uncertain diagnosis occurring in young women. The results indicate that the staining pattern for alpha glutathione S-transferase can be used to distinguish SSTs, fibromas, and thecomas. CD34, by highlighting the vascular pattern and density, can be used to distinguish between SSTs and other tumors in the thecoma-fibroma group. Alpha-inhibin and calretinin mirrored the alpha glutathione S-transferase staining. Vimentin, smooth muscle actin, and muscle specific actin were generally positive, but desmin was negative in all but one tumor. These results suggest that at least four of the five tumors of uncertain diagnosis were SSTs that had undergone end-stage sclerosis and calcification.

E-cadherin expression in human epithelial ovarian cancer and normal ovary.

The ovarian surface epithelium (OSE) is the origin of the majority of human ovarian cancers. These adenocarcinomas are characterized by initial local growth followed by spreading into the peritoneal cavity at later stages of tumor progression. The cell-adhesion molecule E-cadherin (E-cad) plays an important role in maintaining tissue integrity. Disappearance or impaired function of E-cad have often been associated with tumor formation and invasion in vivo and in vitro. The cell-specific expression of E-cad was investigated in normal human ovaries (n = 12), in benign (n = 5) and borderline (n = 4) ovarian epithelial tumors and in adenocarcinomas of different stages and histological grades (n = 18), by immunohistochemistry and immunoblotting. An ovarian cancer cell line (NIH-OVCAR3) was used as a reference. The epithelial origin of the cells was confirmed with cytokeratin (AE1/AE3) staining. In normal ovaries, the expression of E-cad was limited to inclusion cysts or deep clefts lined with OSE, whereas no staining of the OSE could be demonstrated at the surface of the ovary. In contrast, benign and borderline tumors uniformly expressed E-cad. This was observed in malignant tumors of all stages despite their degree of differentiation. E-cad was also present in metastasis from such tumors. The cell-specific expression of E-cad in inclusion cysts of normal ovaries and in epithelial layers of borderline tumors indicates a role for E-cad in the early events of the progression to a malignant phenotype. E-cad was not downregulated in later stages of ovarian cancer progression.

Lipid cell (steroid cell) tumor of the ovary: immunophenotype with analysis of potential pitfall due to endogenous biotin-like activity.

Twenty-eight lipid cell (steroid cell) tumors of the ovary were studied by immunohistochemistry using an avidin-biotin complex detection system; 75% of tumors were vimentin positive, 46% were positive for cytokeratin (CAM5.2 antibody), 37% were positive with the cytokeratin cocktail AE1/AE3 and CK1, and 29% were positive for smooth muscle alpha-actin. Three tumors were positive for CD68 (KP-1), a histiocyte marker, and each of the following markers was positive in two cases: desmin, epithelial membrane antigen, neuron-specific enolase, and S-100 protein. All tumors tested were negative for chromogranin A, CD15 (Leu-M1), myoglobin, neurofilament protein, alpha-fetoprotein, carcinoembryonic antigen, and melanoma-associated antigen (HMB-45 antibody). Immunoreactivity for cytokeratins was usually focal, paranuclear, and globoid, while reactivity for actin and vimentin was diffuse and cytoplasmic. Based on these findings, melanomas and some carcinomas should be distinguishable from lipid cell tumors. However, the immunohistochemical profiles of smooth-muscle tumors, other gonadal stromal tumors (granulosa cell tumors, thecomas), and hepatocellular, renal cell, and adrenocortical carcinomas overlap with that of lipid cell tumors, and therefore these tumors may not be distinguishable from lipid cell tumors using this technique. In 10 cases (36%), negative controls exhibited weak to moderate nonspecific cytoplasmic staining. Evidence obtained using a biotin blocking kit, and a monoclonal antibody against biotin, suggests endogenous biotin-like reactivity as the source of the nonspecific staining.

Virilizing stromal Leydig cell tumor (Leydig cell-containing thecoma) of the ovary in pregnancy. A case report with extensive immunohistochemical investigation of the tumor cells.

The rare case of a stromal Leydig cell tumor of the ovary occurring in a 21-year-old woman who developed signs of virilization during pregnancy is reported. Serum androgen levels were markedly elevated. At cesarean section, a slightly hypotrophic, but otherwise normal, female infant was delivered and a tumor of the right ovary measuring 12 cm in maximum diameter was resected. Histologic examination revealed a sex cord-stromal tumor consisting of spindle-shaped, thecomatous cells and a large number of loosely scattered clusters of large polygonal cells with abundant eosinophilic cytoplasm. Both types of tumor cells were strongly immunoreactive for vimentin, but exhibited no proliferative activity and no overexpression of p53 protein. A few of the polygonal cells contained typical crystalloids of Reinke. Cellular atypia was not a prominent feature, and a diagnosis of benign stromal Leydig cell tumor was established. As expected, 20 months after diagnosis the patient exhibits no signs of recurrence or dissemination. To the best of our knowledge this is only the second case of a stromal Leydig cell tumor occurring in pregnancy to be described.

Histogenetic consideration of ovarian sex cord-stromal tumors analyzed by expression pattern of cytokeratins, vimentin, and laminin. Correlation studies with human gonads.

A total of 30 sex cord-stromal tumors including 9 adult type and 5 juvenile type granulosa cell tumors (GCTs), 4 Sertoli-Leydig cell tumors (SLTs), 1 gynandroblastoma, 5 thecomas, 2 fibromas and 3 sclerosing stromal tumors were immunohistochemically evaluated by means of cytokeratins of different molecular weight, vimentin and laminin with regard to the histogenesis of these tumors and to the embryogenesis of the sex cord and stroma of developing gonads. For comparison, 7 embryonic gonads, 9 fetal and 9 adult ovaries, 14 fetal and 5 postnatal testes, and 1 gonadoblastoma were also examined. The coelomic epithelium of all gonads were positive for both cytokeratins (CAM 5.2 and AE1) and vimentin. In fetal ovaries, the granulosa cells of primordial follicles express low molecular weight cytokeratins only and those cells of more maturing follicles did not express any cytokeratin or vimentin. In adult ovaries, the granulosa cells of primordial follicles coexpressed low molecular weight cytokeratins and vimentin, but those cells of more maturing follicles expressed vimentin only. In fetal testes before 20 weeks gestational age, the Sertoli and Leydig cells did not express any cytokeratins and vimentin. After that time, both cells expressed vimentin only throughout life. The rete ovarii and rete testis from fetal to adult life coexpressed both low molecular weight cytokeratins and vimentin. The rete ovarii in all ages and rete testis in prenatal and childhood ages were surrounded by the laminin-positive basement membrane, however, the rete testis in adult were not. In neoplasia, the GCTs, thecomas, fibromas, and sclerosing stromal tumors expressed vimentin only.(ABSTRACT TRUNCATED AT 250 WORDS)

Histologic and immunohistochemical evidence for considering ovarian myxoma as a variant of the thecoma-fibroma group of ovarian stromal tumors.

Ovarian myxomas recently have been reported as new, distinct pathologic entities that show a myxoid, moderately cellular proliferation of spindle and stellate cells interspersed with areas of fibrosis, hemorrhage, and delicate vascular spaces. These histologic features are frequently seen in the thecoma-fibroma group of ovarian stromal tumors. For this reason, we propose that ovarian myxomas are part of the spectrum of differentiation in thecomas-fibromas of the ovary. To provide histologic and immunohistochemical evidence for this proposal, four ovarian myxomas were compared with 48 primary ovarian stromal tumors in the thecoma-fibroma group from 46 patients. The thecoma-fibroma group of stromal tumors included 23 thecomas, 23 fibromas, and two sclerosing stromal tumors. We found significant (> 25% of histologic appearance) myxoid change in six thecomas and one sclerosing stromal tumor. This myxoid change resembled the histologic appearance of an ovarian myxoma. Immunohistochemical studies on paraffin-embedded material showed vimentin immunostaining in all tumors. Smooth-muscle actin was present in all of the myxomas, in two of the two sclerosing stromal tumors, and in 20 (90%) of the 23 thecomas, but it was present in only 11 (48%) of the 23 fibromas. Desmin staining was not present in any of the four ovarian myxomas or in the two sclerosing stromal tumors, and only three (13%) of the 23 thecomas showed focal staining for desmin. Nine (39%) of the 23 fibromas expressed desmin. S100 protein was expressed in one fibroma and one thecoma, weakly. None of the ovarian myxomas or the thecoma-fibroma group of stromal tumors expressed cytokeratins as detected by three different monoclonal antibody cocktails, ie, cytokeratin AE1/AE3, cytokeratin CAM 5.2, or cytokeratin MAK-6. The ovarian thecoma-fibroma group of stromal tumors form a histologic spectrum of lesions in which clear-cut distinguishing points between various entities are difficult to define. The myxoid change, present in the thecoma-fibroma group of tumors, was indistinguishable histologically and immunohistochemically from ovarian myxoma. For this reason, we propose that ovarian myxomas may be at one end of the spectrum of differentiation in the thecoma-fibroma group of tumors, in which no remaining stromal tumor is detectable.