The role of FOXL2, SOX9, and ß-catenin expression and DICER1 mutation in differentiating sex cord tumor with annular tubules from other sex cord tumors of the ovary.

Sex cord tumor with annular tubules (SCTAT) is a highly rare type of ovarian sex cord-stromal tumor (SCST), the diagnosis of which remains to be challenging. The aim of this study was to scrutinize the utility of three immunohistochemical markers including Forkhead box protein 2 (FOXL2), SOX9, and ß-catenin and DICER1 mutation status in distinguishing SCTATs from other ovarian SCSTs. Nine cases of SCTAT, 10 Sertoli-Leydig cell tumor (SCLT), 10 adult-type granulosa cell tumor (AGCT), and 8 juvenile-type granulosa cell tumor (JGCT) were included in the study. SCTATs were characterized by diffuse and strong expression of SOX9, focal and weak expression of FOXL2, and the absence of DICER1 mutation. However, AGCTs and JGCTs displayed strong and diffuse expression of FOXL2, focal/no immunoreaction for SOX9. SLCTs generally showed moderate intensity of FOXL2 and SOX9 expression. Nuclear ß-catenin expression was observed in none of SLCT, 1/9 of SCTAT, 6/8 JGCT, and 4/10 AGCT cases, respectively. DICER1 hotspot mutation was detected in only 3 cases of SLCT and 2 cases of JGCT. We conclude that in addition to strong and diffuse SOX9 expression, weak/absent expression of FOXL2 is suggestive for the diagnosis of SCTAT. Hence, we suggest that inclusion of these two markers, SOX-9 and FOXL2, to the immunohistochemical panel helps in differentiation of SCTAT from other SCSTs in addition to morphologic findings. We also conclude that SCTATs of the ovary do not harbor DICER1 hotspot mutation.

[Ovarian Sertoli-Leydig tumor: A tricky tumor]. / La tumeur de Sertoli-Leydig ovarienne : une tumeur qui peut être piégeuse.

We report the case of a 15 years old teenage girl presenting with a primary amenorrhea and hypervirilisation symptoms. The clinical assessement found a 16cm wide heterogenous ovarian mass testosteronemia and alpha-foeto protein levels were increased. On gross exam the tumor was solid and cystic, multilocular containing serous and mucinous liquids. Microscopically, there was a sertoli cells rich solid area in which the cells had a trabecular and nested organization with Leydig cells between them and there was also a cystic area made of glandular structures lined with an intestinal muco-secreting epithelium. Next to these area, there were Sertoli cells and an oedematous stroma. The immunostaining showed that the Sertoli cells expressed, among others, the inhibine and the glands expressed the cytokeratins 7 and 20. A Sertoli and Leydig cells tumor of intermediate differentiation with heterologous elements diagnostic was made. This is a rare tumor, representing less than 0.5% of ovary tumors. Well differentiated tumors are not frequent. In one third of the cases, there are hypervirilisation symptoms, the imaging exams will serve to narrow the diagnosis and to do a full work-up to establish an extension. There are several histologic sub types caracterised by the existence of retiforms structures or heterologous elements. There are no specific immunostainings, this will only help to narrow the diagnosis and rule out some hypothesis. There are no guidelines for the management of the patients, indeed each center has its own practices. Those tumors have quite a good prognosis thanks to their early diagnosis at a stade where they are still confined to the ovary.

Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations.

Embryonal rhabdomyosarcoma of the uterine cervix is an uncommon presentation of the most common soft-tissue sarcoma in the first decades of life. Unlike embryonal rhabdomyosarcoma in other anatomic sites, in which 70-80% of cases present before 9 years of age, the average age in our series of 14 cervical cases was 12.4 years (median, 13 years), with an age range of 9 months to 32 years at diagnosis. Of the 14 cases, 12 presented as a polyp at the cervical os; two patients had an infiltrative mass in the cervix without a botryoid polyp. The polyps measured 1.5-5 cm and all had the histopathological pattern of the sarcoma botryoides variant of embryonal rhabdomyosarcoma, with condensations of primitive and differentiated rhabdomyoblasts beneath the surface epithelium and around endocervical glands. Nodules of benign-appearing cartilage were present in the stroma of six cases (43%). One of the embyronal rhabdomyosarcomas from the youngest patient, 9 months old, also had a distinctive microscopic focus of immature tubular profiles in a primitive stroma; these tubules expressed epithelial and neuroendocrine markers. Two patients had a pleuropulmonary blastoma, one diagnosed 9 years before the embryonal rhabdomyosarcoma of the cervix and the other recognized synchronously. This latter 9-year old had a DICER1 germline mutation. One patient presented with hirsutism and had a Sertoli-Leydig cell tumor, an incidentally detected cervical embryonal rhabdomyosarcoma, and nodular hyperplasia of the thyroid. Although a pleuropulmonary blastoma was not documented in the latter patient, ovarian sex-cord stromal tumors and nodular hyperplasia of the thyroid are manifestations of the pleuropulmonary blastoma family tumor and dysplasia syndrome (OMIM 601200). Embryonal rhabdomyosarcoma of the cervix must be distinguished from other rare entities, including adenosarcoma, malignant mixed Mullerian tumor and low-grade stromal sarcoma, as the former has a better prognosis; 12 of our 14 patients remain disease-free following conservative surgery and chemotherapy. Our study suggests that cervical embryonal rhabdomyosarcoma may be another pathological manifestation in the spectrum of extrapulmonary pathology in the setting of pleuropulmonary blastoma.

Ovarian Sertoli-Leydig cell tumor with heterologous gastrointestinal epithelium as a source of alpha-fetoprotein: a case report.

Ovarian Sertoli-Leydig cell tumors (SLCT) are rare sex cord stromal neoplasms. To date there have been approximately 25 case reports of ovarian SLCT expressing alpha-fetoprotein (AFP). In such cases, AFP was immunohistochemically detected in the Sertoli cells, Leydig cells, or hepatocytes. This case report confirms heterologous gastrointestinal epithelium expression of AFP. A 20-year-old woman presented with complaints of abdominal enlargement and irregular menstrual cycles over one year. A right ovarian tumor was detected and the patient's serum AFP was elevated. A right salpingo-oophorectomy was performed. On microscopic examination, the tumor was composed of a fibrosarcoma-like area and a poorly differentiated SLCT area with heterologous gastrointestinal epithelium. Immunohistochemical analysis detected AFP in the gastrointestinal epithelium only. Postoperatively, serum AFP levels fell to normal. A recurrent tumor was discovered in the omentum after adjuvant chemotherapy, but serum AFP remained normal. A second laparotomy was performed and the recurrent tumor showed only fibrosarcoma-like features. The patient received second line chemotherapy and is currently in remission. This is the first case of AFP production by heterologous gastrointestinal epithelium in SLCT.

[Ovarian tumors with endocrine function].

OBJECTIVE: To analyze the clinicopathological features of ovarian tumors with endocrine function. METHODS: Twenty-four cases of ovarian tumor with endocrine manifestation were collected from the hospital. Their clinical presentation and histopathologic features were reviewed, along with a panel immunohistochemistry stainings (EnVision method). The antibodies were AE1/AE3, epithelial membrane antibody (EMA), alpha-inhibin, calretini and smooth myoglobin (SMA). RESULTS: The main clinical endocrinological manifestations were related to an excess production of sex steroids. Histologically, the principle histological subtype of these tumors was ovarian sex cord-stroma tumors, including 13 cases ovarian type (8 granulosa cell tumors, 2 thecofibromas, 3 sclerosing stromal tumors), 7 cases testicular type (1 sertoli cell tumors, 5 sertoli-Leydig cell tumors, 1 Leydig cell tumor, and 2 cases of steroid cell tumor (NOS). Another 2 cases were ovarian epithelial tumors. Grossly, 50% (11/22) ovarian sex cord-stromal tumors were less than 5 cm in diameter. However, 4 tumors were quite larger, up to 18 cm in diameter. Most of these tumors were solid or solid-cystic and their cut surfaces were brown, pink, yellow or grey in color. The 2 primary ovarian epithelial tumors were larger, being 12 cm and 14 cm in diameter, respectively. Immunohistochemically, ovarian sex cord-stromal tumors showed positive staining for alpha-inhibin in all cases (22/22) and for calretinin in majority cases (18/22), and that the intensity of reactivity correlated with the degree of tumor differentiation. The non-neoplastic, luteinized stromal cells in 2 ovarian primary epithelial tumors also showed positive staining. Five cases of fibrothecomas and sclerosing stroma tumors were all positive for SMA. Although 6 of the 22 ovarian sex cord-stromal tumors were AE1/AE3 positive, all were EMA negative. CONCLUSIONS: Most endocrinological syndromes in ovarian neoplasia reflect an overproduction of sex steroids, but the clinical manifestations do not correlate with the tumor histological subtypes. Most functional ovarian tumors are sex cord-stromal tumors and are usually of small to medium in size, but few are larger or giant. The size of the tumor does not correlate with the duration and the degree of clinical manifestations. Ovarian tumors of non-sex cord-stromal type may also be clinically functional. The immunohistochemical results suggests that alpha-inhibin and/or calretinin expression are useful markers in support of a diagnosis of sex cord-stromal tumor of the ovary. Although some of these tumors are AE1/AE3 positive, EMA negativity may be useful for the differential diagnosis with epithelial ovarian tumors.

Relaxin-like factor expression in a human ovarian Sertoli-Leydig cell tumor.

Relaxin-like factor (RLF), a new member of the insulin-like growth factor family, is a reliable marker for normal Leydig cells in the human postpubertal testis (1). Expression of the RLF gene appears to be developmentally regulated, given that only during puberty is RLF expression up-regulated. We recently demonstrated down-regulation of the human RLF gene in testicular Leydig cell tumors indicating dedifferentiation of the Leydig cells within the tumor (2). Ovarian Sertoli-Leydig cell tumors (SLCTs), histologically typed as androblastomas, are rare, potentially malignant sex-cord stromal tumors exhibiting testicular-like structure and differentiation of various degrees. In the present study, we investigated the expression of RLF, 17alpha-hydroxylase, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), Ki-67, and cytokeratin 18 in a human ovarian SLCT of low differentiation.

Ovarian Sertoli-Leydig cell tumor: a SRY gene-independent pathway of pseudomale gonadal differentiation.

Sertoli-Leydig cell tumors (SLCT) are rare sex-cord stromal tumors of the ovary composed of undifferentiated gonadal stromal cells, Leydig cells (LC), and Sertoli cells (SC), with the latter forming structures resembling fetal testicular tubules. The histogenetic basis of morphological male differentiation patterns in females is controversial. Here, we report a SLCT with intermediate differentiation in a 23-year-old woman investigated by light microscopy, immunohistochemistry for intermediate filaments, and sex steroid hormone receptors (SSHR), as well as by polymerase chain reaction (PCR) for the presence of the sex-determining region Y gene (SRY). Our investigation shows that the SCs of SLCT express progesterone and androgen receptors as well as cytokeratins and vimentin. By PCR, SLCT-derived genomic DNA lacked the SRY gene, indicating that the SLCT results from a SRY gene-independent pathway of pseudomale gonadal differentiation. The expression of progesterone receptors (PRs) in the SCs of the SLCT is in contrast to their absence in testicular SCs, but in line with their presence in ovarian granulosa and surface epithelial cells. Thus, our results provide strong evidence for a close histogenetic relationship between the SLCT and the female gonocyte-supporting cell, the granulosa cell (GC).

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)

[A clinical, histological, and biochemical study of ovarian arrhenoblastomas: with reference to one case]. / Etude clinique, histologique et biochimique de l'arrhénoblastome de l'ovaire. A propos d'un cas.

The authors review the literature in relation to a detailed study of an ovarian arrhenoblastoma operated on in a young patient who subsequently became pregnant twice, one of these pregnancies developing to full term. This review makes it possible to formulate certain anatomopathological ideas, and above all makes it clear that complete endocrine studies are infrequently carried out. It has been shown in cases of arrhenoblastoma that some of the anomalies of steroidogenesis are secondary to the enzyme disorders, the impression being that, with this kind of tumour, the tumour parenchyma begins to secrete like a normal testicle.