Novel mutation in FTHL17 gene in pedigree with 46,XY pure gonadal dysgenesis.

OBJECTIVE: To identify the genetic cause of a pedigree with four patients with 46,XY pure gonadal dysgenesis (PGD). DESIGN: Genetic mutation study. SETTING: Academic medical center. PATIENT(S): Four first cousins, from three households of a Chinese pedigree, affected by 46,XY PGD. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The patients were studied from clinical and genetic perspectives. Whole-genome sequencing was conducted in family members. RESULT(S): Four first cousins in the third generation were affected by 46,XY PGD. A specific familial characteristic was the prevalence of as high as 100% of gonadal tumors in patients. Whole-genome sequencing identified a new ferritin heavy chain-like 17 (FTHL17) mutation, c.GA442_443TT (p.E148L), which has the potential to interfere with protein function and cause 46,XY PGD. Moreover, the location (Xp21.2) of the FTHL17 gene proves that the family is X-linked recessive. In vitro functional study revealed that the perturbation of FTHL17 caused the decrease of protein expression and cell proliferation. CONCLUSION(S): We describe the first 46,XY PGD pedigree that may be attributed to mutations of the FTHL17 gene. We speculated that the FTHL17 gene is involved in the testis-determining pathway and tumorigenesis.

Activin-ßC modulates gonadal, but not adrenal tumorigenesis in the inhibin deficient mice.

Activins and inhibins are involved in the regulation of several biological processes, including reproduction, development and fertility. Deregulation of the inhibin/activin signaling pathway has been implicated in the progression of reproductive and adrenal cancers. Deletion of the inhibin α-subunit results in up-regulation of the circulating levels of activins and this leads to the development of sex-cord stromal tumors followed by a cancer associated-cachexia in mice. When gonadectomy is performed, development of adrenocortical carcinomas is observed. We previously showed that overexpression of activin-ßC modulates the development of sex-cord stromal tumors and reduces cancer-cachexia in the inhibin-deficient mice by antagonizing the activin signaling pathway. The adrenal cortex and gonads share in common a large subset of genes, consistent with their common embryonic lineage. Additionally, it has been shown that adrenocortical carcinomas adopt an altered cellular identity resembling the ovary. Therefore, a study to assess the impact of overexpression of activin-ßC on the onset of adrenocortical carcinoma in gonadectomized inhibin-deficient mice was warranted. Within the current study we evaluated markers of apoptosis, proliferation, tumor burden, survival analysis and serum levels of activin-A in gonadectomized mice versus sham operated controls. Results showed that overexpression of activin-ßC modulated the development of reproductive tumors but had no effect on adrenal tumorigenesis. Our data reinforces the importance of activin-ßC in reproductive biology and suggest that activin-ßC is a tumor modulator with gonadal specificity.

Myoid gonadal stromal tumor: a clinicopathologic study of three cases of a distinctive testicular tumor.

OBJECTIVES: To report three new cases of testicular myoid gonadal stromal tumor to better characterize its features. METHODS: The clinicopathologic findings (including follow-up) were evaluated and a review of the literature was performed. RESULTS: The patients were 38, 43, and 59 years old, and tumor sizes were 1.2, 1.3, and 3.2 cm. All were unilateral, well circumscribed, adjacent to the rete testis, and composed exclusively of spindled cells with elongated nuclei and occasional nuclear grooves arranged in fascicles with admixed variably ectatic blood vessels. Nucleoli were inconspicuous, and the cytoplasm was scant, ill-defined, and pale/lightly eosinophilic. No sex cord component was present. Mitotic figures ranged from zero to five per 10 high-power fields. Significant atypia, lymphovascular invasion, and necrosis were absent. All were consistently positive for smooth muscle actin, S100 protein, FOXL2, and steroidogenic factor 1 but negative for h-caldesmon, calretinin, and SOX9. Inhibin and calponin were focally positive. All patients were alive and well at 5, 31, and 58 months postorchiectomy. Combining our cases with those previously reported (n = 6) shows that this neoplasm occurs mostly in younger men (mean, 37 years), and all follow-up thus far (mean, 25 months) has been benign. CONCLUSIONS: Myoid gonadal stromal tumors are small (<4 cm) indolent testicular tumors distinctly different from other sex cord-stromal tumors and are adequately managed by orchiectomy.

The therapeutic potential of blocking the activin signalling pathway.

Members of the transforming growth factor ß (TGF-ß) family regulate fundamental physiological process, such as cell growth, differentiation and apoptosis. As a result, defects in this pathway have been linked to uncontrolled proliferation and cancer progression. Here we explore the signal transduction mechanism of TGF-ß focusing on therapeutic intervention in human diseases. Like TGF-ß, another member of the TGF-ß superfamily, activin has been proven to play an important role in maintenance of tissue homeostasis and dysregulation leads to disease. Several studies showed elevated levels of activin are responsible for the development of gonadal tumours and a cachexia-like weight loss syndrome. Discussing the recent advances in approaches developed to antagonise the activin pathway and the encouraging results obtained in animal models, this review presents a therapeutic rationale for targeting the activin pathway in conditions such as cachexia, neuromuscular and/or musculoskeletal disorders.

Origin and identity of adrenocortical tumors in inhibin knockout mice: implications for cellular plasticity in the adrenal cortex.

Inhibin knockout (Inha-/-) mice develop gonadal sex-cord tumors and--when gonadectomized--adrenocortical tumors. Previous reports demonstrated that adrenocortical tumors from Inha-/- mice produce estrogen and depend on gonadotropin signaling for initiation. Here we show that, in addition to producing estrogen, the adrenocortical tumors display a global change in cellular identity, composed of two unique cell types expressing differing arrays of genes normally restricted to theca and granulosa cells of the ovary. Many of these genes are also induced in wild-type adrenals after gonadectomy or upon chronic gonadotropin stimulation, suggesting that the adrenal cortex normally contains a population of pluripotent cells that can be driven toward an adrenal or gonadal identity given the appropriate pituitary stimuli. A central feature of this altered cellular identity is the switch from predominant expression of Gata6 (endogenous to the adrenal cortex) to Gata4, which defines cellular identity in the ovary. We show that stable transfection of Gata4 in cultured adrenocortical cells is sufficient to activate ovarian-specific genes of both theca and granulose lineages. Spatial analysis of Gata4 expression reveals a distinct pattern of localization to the supcapsular region of the adrenal, which contains undifferentiated progenitor cells that continuously populate the adrenocortical zones. Although both wild-type and Inha-/- mice display this pattern, only Inha-/- mice produce tumors composed of these Gata4-positive cells. These data suggest that Inha-/- adrenocortical tumors cells are derived from pluripotent adrenocortical progenitor cells that adopt a gonadal fate due to the convergent loss of inhibin and chronic exposure to elevated gonadotropins.

Podoplanin: a novel diagnostic immunohistochemical marker.

Podoplanin is a transmembrane mucoprotein recognized by the recently commercially available D2-40 monoclonal antibody. Recent investigations have shown that podoplanin is selectively expressed in lymphatic endothelium as well as lymphangiomas, Kaposi sarcomas, and in a subset of angiosarcomas with probable lymphatic differentiation. Podoplanin has also been shown to be strongly expressed in seminomas, epithelioid mesotheliomas, and hemangioblastomas, and immunostaining for this marker can assist in the diagnosis of these tumors. This article reviews the current information on the applications of podoplanin immunostaining in surgical pathology.

A steroid cell tumor outside the ovary is a rare cause of virilization.

OBJECTIVE: To report the case of a female who presented in childhood with symptoms and signs of hyperandrogenism secondary to an extraovarian steroid cell tumor. DESIGN: Case report. SETTING: Endocrine investigation unit of a university teaching hospital. PATIENT(S): An 11-year-old female presented with symptoms and signs of hyperandrogenism. INTERVENTION(S): Ultrasonography, MRI imaging, bilateral adrenal and ovarian venous sampling, laparoscopy, and laparotomy. MAIN OUTCOME MEASURE(S): Ultrasonography, laboratory tests. RESULT(S): Hyperandrogenism was due to an extraovarian steroid cell tumor located in the broad ligament. The tumor was successfully removed at laparotomy with biochemical and clinical resolution of the hyperandrogenism. CONCLUSION(S): Extraovarian steroid cell tumor is a rare cause of hyperandrogenism.

[Severe postmenopausal hyperandrogenism due to an ovarian lipoid cell tumor: a case report]. / Descrizione di un caso clinico di severo iper-androgenismo postmenopausale dovuto a un tumore ovarico a cellule lipidiche.

The case of a 62-year-old woman with severe post-menopausal hirsutism is described. Her clinical history revealed regular menstrual periods until menopause at the age of 50, hysterectomy for fibromatosis at 58 years, non-insulin dependent diabetes mellitus, hypertension, obesity, severe hirsutism, which had developed in the previous 3 years, with a deeping of the voice. Examination showed android obesity, hypertension and severe hirsutism involving the face and the trunk. Endocrine evaluation pointed out regular adrenal function, serum total and free-testosterone in the adult male range, with normal androstenedione, DHEAS and 17OHP levels. Estradiol was slightly increased and LH and FSH were inappropriately low for her post-menopausal age. Computed tomography of the abdomen showed regular adrenal glands, and a radio-labeled cholesterol scan was negative. A further pelvic transvaginal ultrasonography revealed a small cystic formation near the right ovary and a slight increase in the size of the left ovary. The patient underwent bilateral ovariectomy. Histological examination showed a lipoid cell tumor within the left ovary. Immunohistochemical studies were positive for inhibin and cytokeratin. After surgery, serum testosterone fell to normal levels, gonadotropins increased to menopausal levels, confirming that the tumor was able to produce both LH, and FSH-inhibiting factors, and hirsutism greatly improved. Periodic hormonal tests remained normal and CT of the abdomen and pelvic ultrasonography did not show alterations at a 3 years follow-up.

Neuropeptide Y receptor expression in human primary ovarian neoplasms.

Peptide hormone receptors overexpressed in human malignant neoplasms are potential targets for diagnostic scintigraphy and radiotherapy. One such receptor is the neuropeptide Y (NPY) receptor, mediating primarily feeding behavior in the brain but shown recently to play a role in breast cancer. In this study, the presence of NPY receptors was evaluated in another group of gynecological tumors, namely ovarian tumors, using in vitro receptor autoradiography with (125)I-labeled peptide YY and receptor subtype selective analogs. Remarkably, all 10 investigated inhibin-expressing granulosa cell tumors, Leydig cell tumors, and Sertoli-Leydig cell tumors expressed NPY receptors. In contrast, receptors were found in only seven of 22 ovarian adenocarcinomas (32%). Pharmacological characterization of the expressed NPY receptor subtypes in the various tumors revealed the presence of Y1, Y2, or both. In addition, Y1 receptors were observed in intra- and peritumoral blood vessels as well. NPY receptors were not expressed in three ovarian adenomas, three borderline tumors, four fibromas and fibrothecomas, and one dysgerminoma. This is the first time that NPY receptors are described in human ovarian tissue. They may play a role in the pathogenesis and also in the pathophysiology of ovarian malignancies. Moreover, the high incidence and density of NPY receptors in sex cord-stromal tumors suggest that these receptors represent a new potential target for the diagnostic and therapeutic administration of NPY analogs in these tumors.

Inhibin immunohistochemistry applied to ovarian neoplasms: a novel, effective, diagnostic tool.

Immunohistochemistry using monoclonal antibodies against human inhibin, a peptide hormone produced by ovarian granulosa cells to inhibit follicle-stimulating hormone (FSH), has been recently applied to diagnostic anatomic pathology. This investigation hypothesizes that inhibin immunohistochemistry will aid in the crucial clinical distinction between sex cord-stromal and other primary ovarian neoplasms. Available H&E slides and clinical information from a retrospective surgical series of 186 primary ovarian tumors were reviewed to verify diagnoses, and representative paraffin sections were immunostained with anti-inhibin (R1 monoclonal, Serotec, Kidlington, Oxford, UK). Immunoreactivity was graded as weak/strong (W/S), and the proportion of strong staining cells was coded as follows: S1 = <10%, S2 = 10%-50%, S3 = >50%, respectively. Inhibin immunoreactivity for 137 sex cord-stromal lesions was as follows: 100% of 66 granulosa cell tumors: 80% S3, 20% S2; 100% of 17 Sertoli-stromal tumors: 90% S3, 10% S2; 100% of 13 hyperplastic follicular/stromal lesions: 90% S3, 10% S2; 100% of six steroid cell tumors: 100% S3; 90% of 18 thecomas: 40% S3, 10% S2, 10% S1, 30% W; 0% of 12 fibromas, three myxomas, and two sclerosing stromal tumors. None (0 of 49) of the other ovarian neoplasms exhibited inhibin: 22 carcinomas, 12 carcinosarcomas, seven small cell carcinomas, six germ cell tumors, and two lymphomas. In the typical case, the distinction between sex cord-stromal and other ovarian neoplasms requires nothing more than routine pathological examination. In diagnostically challenging cases, our data indicate that inhibin immunohistochemistry is a very useful adjunct because granulosa and sertoli-stromal tumors are positive whereas other potential mimickers have been negative thus far.

Gynandroblastoma of the ovary having a typical morphological appearance: a case study.

A rare gynandroblastoma of the right ovary with a typical morphological appearance in a 65-year-old woman is reported. The tumor comprised both a granulosa cell element with a Call-Exner body and a Sertoli cell element. Pathologically, this case could be the most typical of all the world's established cases. Clinically, there were feminizing symptoms such as post-menopausal genital bleeding and endometrial cystic hyperplasia. Pre-operative serum hormonal assays indicated elevated levels of estrone, estradiol and testosterone, and low levels of gonadotropins. These returned to normal after surgery.

Granulosa cell tumor of the ovary with Sertoli-Leydig cell tumor components (gynandroblastoma).

A rare granulosa cell tumor with Sertoli-Leydig cell tumor components (gynandroblastoma) arising in the left ovary was reported in a 63-year-old female. Microscopically, the tumor was composed predominantly of granulosa cells arranged mainly in a diffuse solid pattern, but in some areas there were a trabecular pattern and thecofibromatous stromal components. Also, well-differentiated Sertoli-Leydig cell tumor elements were present as a minor component. The tumor produced, endocrinologically, a large amount of estradiol, some androstenedione and a small amount of testosterone. The possibility that estradiol in the present tumor was produced predominantly from androstenedione via estrone was suggested by the results of an in vitro biosynthetic study.

The steroid profile of a virilizing ovarian tumor.

A case report of a 25-year-old female with a sex cord stromal virilizing ovarian tumor is presented. The pathway of ovarian steroid secretion in this tumor is elucidated with the dominant elements being pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, androstenedione, and testosterone. The tumor primarily made testosterone (T) with lesser elevations of androstenedione (A), dehydroepiandrosterone (DHEA), and dihydrotestosterone (DHT). Expert pathologic opinions differed whether this neoplasm was a Sertoli-Leydig tumor or a virilizing granulosa tumor; therefore, it was probably a gynandroblastoma. A unilateral salpingo-oophorectomy was performed and the patient promptly resumed normal ovarian function with ovulation.