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Gynandroblastoma: its ultrastructure.

Gynandroblastoma is a rare, sex-cord stromal tumor of the ovary that shows morphologic evidence of female and male differentiation. Such a tumor produced masculinization in a 24-year-old woman, whose symptoms disappeared following removal of the tumor. By electron microscopy, the granulosa cell nests displayed Call-Exner (CE) bodies of the hyaline type composed of multiple layers of basal lamina resembling CE bodies of the normal graafian follicle. In contrast, CE bodies of a classic granulosa theca cell tumor were of the spongiform type, consisting of a space limited by a single basal lamina containing altered granulosa cells and cell processes. Both types of CE bodies are believed to arise following secretion by and/or degeneration of granulosa cells, the variation in morphology between the two resulting from differences in amounts of basal lamina deposited. The tubular components of the tumor resembled more closely the rete ovarii than did Sertoli cells, and its proposed that such structures be called by the alternate and less specific term "androblastoma." The identity of Leydig cells was established by demonstrated of intracytoplasmic Reinke crystals. Despite a difference in architectural pattern, there was a close ultrastructural resemblance between the different sex-cord components of the gynandroblastoma.

Adult↗

[Granulosa cell and thecacell tumors in 25 cases (author's transl)].

Granulosa cell tumors are derived from specific ovarion stroma and have the ability to produce hormones. In the 25 cases of granulosa cell tumors no concommitant endometrial carcinoma was found. Because of the varying degree of malignancy tumors which contain granulosa cells must be differentiated from pure theca cell tumors. Granulosa cell tumors are frequently malignant. Theca cell tumors are benign. The treatment of granulosa cell tumors is fundamentally the same as that of epithelial cancers of the ovary. The treatment of theca cell tumors is conservative.

Adult↗

Lectin histochemistry of sex cord-stromal tumors and small cell carcinoma of the ovaries.

Binding sites of peanut agglutinin (PNA), Ulex europaeus (UEA-1), concanavalin A (Con A), and wheat germ agglutinin (WGA) were localized in 10 granulosa cell tumors, 10 Sertoli-Leydig cell tumors, 4 theca cell tumors, and 5 small cell carcinomas. Con A and WGA reacted positively with the majority of the studied neoplasms. PNA and UEA-1 were persistently negative in the sex cord-stromal tumors (SCST) but showed focal positivity in small cell carcinomas. Negative reactions of SCST with PNA and UEA-1 may serve for differentiation between them and common epithelial tumors that are usually PNA and UEA-1 positive.

Binding Sites↗

Hormonal function of a granulosa cell tumor.

Granulosa and theca cell tumors are rather common gonadal stromal tumors. A postmenopausal patient with a granulosa cell tumor, who complained chiefly of breast tenderness and enlarging, abdomen, is presented. Preoperative and postoperative studies including serum estrone, estradiol, prolactin, FSH, and LH,as well as urinary estrogens, 17-ketosteroids, and 17-hydroxysteroids are reported. A plan of treatment and followup is suggested. It is recommended that survival data on patients with such slow-growing tumors be adjusted to reflect the true incidence of death from the specific tumor in question.

Aged↗

Localization of gonadotropin binding sites in human ovarian neoplasms.

The binding of human luteinizing hormone and human follicle-stimulating hormone to ovarian tumor biopsy specimens from 29 patients was analyzed. The binding sites for human luteinizing hormone were demonstrated in one tumor of epithelial origin (mucinous cystadenoma) and in one of sex cord-stromal origin (theca cell tumor). The binding sites for human follicle-stimulating hormone were found in three tumors of epithelial origin (serous cystadenoma and mucinous cystadenoma) and in two of sex cord-stromal origin (theca cell tumor and theca-granulosa cell tumor). The surface-binding autoradiographic study revealed that the binding sites for gonadotropins were localized in the stromal tissue. The results suggest that gonadotropic hormones may play a role in the growth and differentiation of a certain type of human ovarian neoplasms.

Adolescent↗

Regression of subcutaneous lymphoma following removal of an ovarian granulosatheca cell tumor in a horse.

A 9-year-old Arabian mare was admitted for evaluation of multiple subcutaneous nodules and infertility. Fine-needle aspiration of one of the subcutaneous nodules resulted in a cytologic diagnosis of histiolymphocytic lymphoma. Palpation per rectum and transrectal ultrasonography revealed a mass associated with the left ovary. Excision of the ovarian tumor was performed, and a histopathologic diagnosis of granulosa-theca cell tumor was made. After removal of the granulosa-theca cell tumor, subcutaneous nodules regressed. The referring veterinarian reported that the nodules had also disappeared and then recurred after administration of a synthetic progestin. To further characterize the lymphoma and investigate this possible hormonal relationship, immunophenotyping and estrogen and progesterone receptor assays were performed. The subcutaneous lymphoma was classified as a T-cell rich B-cell lymphoma, results of estrogen receptor assays were negative, and results of progesterone receptor assays were positive. Clinical observations of subcutaneous lymphoma in horses indicate that the waxing and waning nature of these tumors may be associated with the estrous cycle, pregnancy, foaling, and lactation. Clinical observations and identification of progesterone receptors suggest that a relationship between serum steroid hormone concentrations, such as estrogen and progesterone, and subcutaneous lymphoma may exists.

Animals↗

Induction of ovarian tumors by endogenous gonadotropins in rats bearing intrasplenic ovarian grafts.

In this study the role of gonadotropins for the induction of ovarian tumors in rats was examined. The rats were castrated and one ovary was transplanted under the splenic capsule. Rats remained untreated or received a GnRH analog for gonadotropin suppression either immediately, 90 or 180 days after castration. Under these conditions the untreated rats developed ovarian tumors while the treated rats only developed tumors when the stimulation of gonadotropins lasted for more than 90 days. The first appearing tumors were theca cell tumors while during the further course of the experiment the granulosa cell compartment increased; however, no histological signs of malignancy could be detected in these tumors. GnRH analogs could block the induction of granulosa cell tumors when administered 150 days after transplantation. After a period of 210-240 days the tumors grew independently of elevated LH and FSH levels. The causes of this growth autonomy need to be studied further.

Animals↗

Stimulation of nitric oxide-cyclic guanosine monophosphate pathway in bovine ovarian theca cells by tumor necrosis factor alpha (TNF alpha). Is this pathway implicated in the TNF alpha-induced inhibition of luteinizing hormone-stimulated prorenin production?

Gonadal function is known to be controlled by many factors, including locally acting cytokines like tumor necrosis factor alpha (TNF alpha). One of the ways this cytokine acts is via the nitric oxide (NO)-cGMP pathway. Since we have shown that in the ovary theca cells are a target of TNF alpha's action, it was of interest to determine whether TNF alpha stimulates the NO-cGMP pathway in these cells and whether such a mechanism can be implicated in the observed TNF alpha-mediated inhibition of LH-stimulated prorenin synthesis and secretion. Treatment of isolated theca cells with TNF alpha resulted in a dose- and time-dependent increase in cGMP production. This increase was not detectable until 6 h after the addition of TNF alpha and was totally abolished by the protein synthesis inhibitor cycloheximide. Addition of either L-N6-nitroarginine methyl ester (L-NAME), an inhibitor of all three NO synthase (NOS) isoforms or 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific inhibitor of the inducible isoform of the enzyme, likewise reversed the action of TNF alpha on cGMP formation. Finally, addition of 1H-[1,2,4]oxadiazolo [4,3-a] quinoxalin 1-one (ODQ), an inhibitor of NO-sensitive soluble guanylate cyclase, resulted in a concentration-dependent reduction of TNF alpha-stimulated cGMP formation. In contrast, the TNF alpha-mediated inhibition of LH-stimulated prorenin secretion was not affected by either L-NAME, AMT, or ODQ. Also the addition of stimulators of soluble guanylate cyclase, sodium nitroprusside, and S-nitroso-N-acetylpenicillamine, or 8 bromo-cGMP had no effect on the action of LH on theca cells. We conclude that although TNF alpha is able to stimulate cGMP formation in theca cells by inducing the expression of inducible NOS, the mechanism underlying the TNF alpha-mediated inhibition of LH-stimulated prorenin production is independent of its ability to induce cGMP formation.

Animals↗

Transcription factors GATA-4 and GATA-6 and a GATA family cofactor, FOG-2, are expressed in human ovary and sex cord-derived ovarian tumors.

Previous studies have implicated transcription factors GATA-4 and GATA-6 in the regulation of murine ovarian development and function. In rodents, GATA-4 is expressed in granulosa cells of primary and early antral follicles, whereas GATA-6 is expressed in granulosa cells of late antral follicles and luteal glands. Both transcription factors can be detected in lesser amounts in theca cells and interstitial cells. We have now examined the expression of GATA-4 and GATA-6 in human ovaries, human granulosa-luteal (GL) cells and sex cord-derived tumors. We show by in situ hybridization and immunohistochemistry that GATA-4 and GATA-6 messenger RNA (mRNA) and GATA-4 protein are present in granulosa and theca cells in both preantral and antral follicles. Both human ovarian tissue samples and freshly isolated GL cells derived from preovulatory follicles of gonadotropin-treated women express GATA-4, GATA-6, and FOG-2 transcripts, and GATA-6 mRNA expression in GL cell cultures is stimulated by human CG and 8-bromo-cAMP. The vast majority of granulosa and theca cell tumors examined expressed GATA-4 and GATA-6. We also found that mRNA for FOG-2, a recently discovered regulator of GATA-4, is coexpressed with GATA-4 in human ovary samples, normal granulosa cells, and in sex cord-derived tumors. Our results demonstrate that GATA-4, GATA-6, and FOG-2 are expressed in human ovary and in granulosa and theca cell tumors. Our findings support a role for GATA-binding proteins in human ovarian folliculogenesis. Moreover, these data suggest that GATA factors may contribute to the phenotypes of sex cord-derived ovarian tumors.

Adult↗

Establishment and characterization of an estrogen-producing human ovarian granulosa tumor cell line.

Cells designated HTOG and HTOT were established by long-term culture from a human ovarian granulosa cell and a theca cell tumor, respectively. The HTOG line grew well forming colonies and multilayered rapidly without contact inhibition; serial passages of HTOG were performed over 100 times successively within 25 months. HTOG were spindle cells, polygonal or spherical in shape, revealed neoplastic and pleomorphic features, and produced estrone (E1) and 17 beta-estradiol (E2). The chromosome number varied considerably and showed hyperploidy; the modal chromosome number was in the hypertriploid-tetraploid range. When HTOG cells were heterotransplanted into the subcutis of BALB/c nude mice, they produced a sarcomatous diffuse type of granulosa cell tumors. In contrast, HTOT cells grew slowly while forming monolayers and underwent five successive passages in about 100 days, but a theca cell tumor line could not be established. HTOT cells were fibroblastic in shape and also produced E1 and E2. The majority of the cells showed diploidy and karyologic normality.

Animals↗

[Clinico-morphological signs of hormone-producing ovarian tumors].

Apparent signs of hormonal activity were observed in 65.3% of patients with hormone-producing ovarian tumors of different histology. Feminization was evident in 69.1% of cases of granulosa-stromal cell tumors: it was most often seen in patients with mixed theca-granulosa cell tumors (86.2%) but was least frequent in those with Brenner's tumor (22.2%). The occurrence of proliferative lesions of the uterus such as hyperplasia of the endometrium, cervical canal polyps and uterine myoma (81.8%) was higher in patients with granulosa-stromal cell tumors, too, the highest rate being observed for cases of mixed theca-granulosa cell tumors (93.1%) whereas the lowest--for patients with Brenner's tumor (27.8%). Various clinical signs of masculinization were most often seen in cases of androblastoma (79.2%) whereas the proliferative disorders in that group were rare (12.5%). As a result, the authors placed mixed theca-granulosa cell, theca cell, granulosa cell tumors and Brenner's tumor in the order of decreasing feminizing activity. In the granulosa-stromal cell tumor subgroup, masculinization was most often observed in granulosa cell tumor patients (12.1%).

Brenner Tumor↗