Laparoscopic treatment of ovarian granulosa cells tumor developed in the pelvic anterior preperitoneal space 20 years after laparotomic salpingo-oophorectomy: case report and review of literature.

Granulosa cells (GC) tumors are rare tumors which account for approximately 2-3% of all ovarian malignancies with a favorable prognosis. We report a case of a 54-year-old postmenopausal woman who developed an ovarian GC tumor in the pelvic anterior preperitoneal space 20 years after laparotomic salpingo-oophorectomy due to small part of the cyst could drop or remain entrapped into the abdominal wound during the closure of laparotomy 20 years before. Then, the patient underwent a second laparoscopic procedure with peritoneal washing, a type A radical hysterectomy, omentectomy, appendectomy, and pelvic and para-aortic lymphadenectomy. This rare case of ovarian GC tumor developing in the site of previous laparotomy demonstrates the importance of a correct and clean surgical procedure to avoid the risk of leaving even small portions of the cyst exposing the patients to either the risk of malignancy or additional surgical procedures.Precis: This rare case of ovarian granulosa cells tumor developed from residual ovarian tissue intrapped into the abdominal wound 20 years after laparotomic ovariectomy.

APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression.

BACKGROUND: Canonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. METHODS: A detailed analysis of ovarian histology, gene expression, ovulation and hormone levels was carried out in 10 week old and in aged constitutive APC2-knockout (Apc2-/-) mice (mixed background). Statistical significance for qRT-PCR data was determined from 95% confidence intervals. Significance testing was performed using 2-tailed Student's t-test, when 2 experimental cohorts were compared. When more were compared, ANOVA test was used, followed by a post-hoc test (LSD or Games-Howell). P-values of < 0.05 were considered statistically significant. RESULTS: APC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphic Apc allele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs. CONCLUSIONS: Our work adds APC2 to the growing list of WNT-signalling members that regulate ovarian homeostasis, fertility and suppress GCT formation. Importantly, given that the APC2-deficient mouse develops tumours that recapitulate the molecular signature and histological features of human adult GCTs, this mouse has excellent potential as a pre-clinical model to study ovarian subfertility and transitioning to GCT, tumour biology and for therapeutic testing.

Comparative study of microRNA regulation on FOXL2 between adult-type and juvenile-type granulosa cell tumours in vitro.

OBJECTIVES: Despite their distinct biology, granulosa cell tumours (GCTs) are treated similarly to other ovarian tumours. Predominantly expressed in granulosa cells, the transcription factor Forkhead Box L2 (FOXL2) is near absent in juvenile-type GCTs. This research aimed to investigate miRNAs as a mechanism of suppression of FOXL2 expression in juvenile-type GCTs. METHODS: The miRNA abundance of two GCT cell lines COV434 and KGN was profiled using Affymetrix miRNA GeneChip arrays. Luciferase assays were used to confirm miRNA binding to the 3'UTR of FOXL2. Identified as promising candidates, the miR-17 miRNA family was targeted for knockdown with a miRNA sponge. Additionally, individual family members miR-17, miR-20b and miR-106a were knocked down using Anti-miR™ inhibitors. Subsequently, FOXL2 expression was analysed using RT-qPCR and Western blotting. RESULTS: The profiling of COV434 and KGN cells revealed unique miRNA signatures, with COV434 expressing miR-17 family miRNAs whilst KGN expressed members of the let-7 miRNA gene family. Luciferase assays confirmed miRNA binding to FOXL2's 3'UTR. Reduction of miR-17 family miRNAs increased FOXL2 mRNA expression, however luciferase assays performed in combination with the sponge suggested this is an indirect effect. As no changes in protein were observed, we propose another miRNA is repressing the translation of FOXL2 mRNA. CONCLUSION: Through miRNA profiling we have begun to unravel the profiles of GCTs, showing that juvenile and adult derived-cell lines are biologically distinct. By expanding on this discovery we may further elucidate the miRNA-mRNA pathways involved in GCT initiation and progression with potential for novel therapeutics for these cancers.

New targets for old hormones: inhibins clinical role revisited.

Inhibins are gonadal peptide hormones belonging to the transforming growth factor-ß (TGF-ß) superfamily that regulate the pituitary follicle stimulating hormone (FSH) secretion by negative feedback mechanisms. It is evident that the understanding of inhibins function in the hypothalamic-pituitary-gonadal axis will provide insights into physiology and pathology of the gonadal function. In recent years, a great deal of attention has been focussed on clinical relevance of measuring circulating inhibins in normal and disease state. The past few years also have witnessed the emergence and discovery of extra pituitary action of inhibins that might provide further insights into the underlying diseases like cancer especially in the reproductive axis and various other new endocrine target organs. In this review after systematic analysis of literature, we discuss briefly the known and recent advances in function of these hormones highlighting also its structure, production and mechanisms of signal transduction. Also this review discusses about the physiological relevance of inhibin association in the normal function to the development of reproductive cancers. Finally, we describe evidence from various emerging studies that inhibins make an important contribution to other physiological functions apart from reproduction which reveals new endocrine target organs of inhibins. The emerging view is inhibin participates in multiple ways to regulate the function in different cell types and still complete repertoire of its actions is under investigation.

Treating rare tumors with the assistance of the expert virtual consultation system: two cases of juvenile granulosa cell tumors.

BACKGROUND: The lack of internationally recognized guidelines for very rare tumors, such as juvenile granulosa cell tumors (JGCTs), which are nonepithelial, unusual ovarian tumors, is a challenge for pediatric oncologists, especially in developing countries with limited resources and experience in treating rare tumors. METHODS: We report clinical data of 2 girls with JGCTs treated at the Pediatric Cancer and Blood Disorders Center of Armenia with the assistance of the EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) international cooperation panel. CASE PRESENTATION: Two girls (16 and 15 years old) with JGCTs of the ovaries, stage Ic, underwent surgery and, with consultation through an online advisory board (http://vrt.cineca.it/), received 4 cycles of chemotherapy according to the PEI regimen (cisplatin, etoposide, ifosfamide). CONCLUSION: Very rare tumors, especially in advanced stages, have limited data and a low survival rate. International collaboration with the EXPeRT group is beneficial for physicians with limited experience and facilitates research in pediatric oncology.

Granulosa and theca cell tumor in rat's ovary after modified Biskind operation.

BACKGROUND: Earlier, we described morphological changes in rat ovaries in different terms after Biskind's operation elucidating the factors that affect the precancerous conditions and ovarian neoplasms appearance. The aim of the research was to identify tumor nature on the 120th day after modified Biskind's operation using immunohistochemical approach. RESULTS: We described morphological changes in rat ovaries on the 120th day after Biskind's operation, demonstrated development of theca-granulosa cell tumors, and differentiated between Sertoli-Leydig cell tumors and theca-granulosa cell tumors using monoclonal antibodies against Ingibin-alfa, Calretinin, Melan А. CONCLUSION: Modified Biskind's model could be used to study sex-cord tumors in rat ovaries.

Common variable immunodeficiency: a new look at an old disease.

Primary immunodeficiencies comprise many diseases caused by genetic defects primarily affecting the immune system. About 150 such diseases have been identified with more than 120 associated genetic defects. Although primary immunodeficiencies are quite rare in incidence, the prevalence can range from one in 500 to one in 500 000 in the general population, depending on the diagnostic skills and medical resources available in different countries. Common variable immunodeficiency (CVID) is the primary immunodeficiency most commonly encountered in clinical practice, and appropriate diagnosis and management of patients will have a significant effect on morbidity and mortality as well as financial aspects of health care. Advances in diagnostic laboratory methods, including B-cell subset analysis and genetic testing, coupled with new insights into the molecular basis of immune dysfunction in some patients with CVID, have enabled advances in the clinical classification of this heterogeneous disease.

Persistent endocrine-disrupting chemicals found in human follicular fluid stimulate the proliferation of granulosa tumor spheroids via GPR30 and IGF1R but not via the classic estrogen receptors.

Epidemiological studies have found that women have detectable levels of organic pollutants such as hexachlorobenzene (HCB), 2,2-dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyl 153 (PCB153), perfluorooctanoate (PFOA), and perfluorooctane sulfonate (PFOS) in their follicular fluid. Thus, these compounds may directly affect the function of granulosa cells within the ovary and may promote granulosa cell tumor (GCT) progression. Two human GCT cell lines, COV434 and KGN, have been used as in vitro model systems to represent juvenile (JGCT) and adult (AGCT) GCT subtypes, respectively. In this study, we found that basal expression of estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and insulin-like growth factor 1 receptor (IGF1R) was higher in the AGCT subtype than in the JGCT subtype. All of the compounds acted as mitogenic factors at low nanomolar concentrations in the JGCT and AGCT forms of GCT. Interestingly, PFOA, PFOS, and HCB stimulated cell proliferation through IGF1R, whereas p,p'-DDE acted through GPR30. Moreover, a mixture of the five compounds also significantly stimulated granulosa cell proliferation; however, the observed effect was lower than predicted. Interestingly, the proliferative effect of a mixture of these compounds was dependent on IGF1R and GPR30 but independent of the classic estrogen receptors. Taken together, our results demonstrate for the first time that mixtures of persistent organic pollutants present in follicular fluids may induce granulosa tumor progression through IGF1R and GPR30 by acting as mitogenic factors in granulosa cells.

The molecular mechanism of ovarian granulosa cell tumors.

Over these years, more and more sex cord-stromal tumors have been reported. Granulosa cell tumor (GCT) is a rare tumor in ovaries, accounts for 2% to 5% of ovarian cancers. The main different feature of GCTs from other ovarian cancers is that GCTs can lead to abnormally secreted hormones (estrogen, inhibin and Müllerian inhibiting substance). The GCT is divided into two categories according to the age of patients, namely AGCT (adult granulosa cell tumor) and JGCT (Juvenile granulosa cell tumor). AGCT patients accounts for 95%. Although the pathogenesis is not clear, FOXL2 (Forkhead box L2) mutation was considered as the most critical factor in AGCT development. The current treatment is dominated by surgery. Target therapy remains in the adjuvant therapy stage, such as hormone therapy. During these years, other pathogenic factors were also explored, such as PI3K/AKT (phosphatidylinositol-3-kinase; serine/threonine kinase), TGF-ß (Transforming growth factor beta) signaling pathway, Notch signaling pathway, GATA4 and VEGF (vascular endothelial growth factor). These factors and signaling pathway play important roles in GCT cell proliferation, apoptosis, or angiogenesis. The purpose of this review is to summarize the possible pathogenic factors and signaling pathways, which may shed lights on developing potential therapeutic targets for GCT.

Spontaneous malignant granulosa cell tumors in ovaries of young SWR mice.

Granulosa cell tumors (GCT) of the ovary appear spontaneously at 4-6 weeks of age in SWR/J and in SWR/Bm inbred strain mice, with a maximum incidence reached by 10 weeks. Cancer was confirmed by metastasis to abdominal organs and by transplantability of primary tumors to histocompatible hosts. Results of genetic crosses showed that GCT appear in SWR X SJL F1 but not in SJL X SWR F1 nor in other F1 females derived from matings of SWR mice with A/HeJ, C57BL/6By, CBA/J, or DBA/2J mice. These findings suggest the maternal transmission of GCT susceptibility. Recombinant inbred strains SWXJ were produced from a progenitor mating of a SWR female to a SJL male. At F20, females in 3 of 14 SWXJ strains developed GCT, with one strain displaying a 5-fold increase in incidence. Embryo transfer studies with SWXJ-6 and -9 mice suggested that maternal transmission was most likely via the fertilized egg rather than through milk or placenta-uterine contact. Analysis of metaphase chromosomes indicated that the modal number in tumors and bone marrow was 40 (2n = 40) with 2 X chromosomes present. Gross chromosomal aberrations were not detected. A working hypothesis proposes that interaction of a unique SWR factor, perhaps cytoplasmic, with nuclear genomic material common to Swiss mouse stocks results in occurrence of GCT in young SWR and SWR-derived mice.

Granulosa cell tumorigenesis in genetically hypogonadal-immunodeficient mice grafted with ovaries from tumor-susceptible donors.

The SWR and SWXJ recombinant inbred strains of mice develop heritable, pubertal onset ovarian granulosa cell (GC) tumors with characteristics similar to those observed for human juvenile GC tumors. We utilized this murine model to determine: (a) whether spontaneous tumorigenesis is an intrinsic property of the susceptible ovary; (b) whether pubertal developmental stage affects tumorigenesis; and (c) whether tumorigenesis depends on extraovarian regulation provided by an immune system or a hypothalamic-pituitary gonadotropin system. To test these questions, ovaries from tumor-susceptible donors were grafted beneath the kidney capsules of hosts with differing immunological and hormonal capabilities. Hosts for these ovarian grafts were: (a) immunologically intact, syngeneic mice; (b) immune-deficient, allogeneic mice homozygous for the severe combined immune deficiency (scid/scid) mutation; and (c) scid/scid mice segregating for the hypogonadal (hpg) mutation, yielding gonadotropin-deficient hpg/hpg scid/scid and gonadotropin replete +/? (hpg/+ or +/+) scid/scid littermates. Donors and hosts of differing ages were used to address questions of developmental effects on tumorigenesis. Grafts were examined 6 to 10 wk after implantation for ovarian morphology and tumor incidence. Results showed that ovary grafts from susceptible female mice formed spontaneous GC tumors equally well in both syngeneic and immune-deficient scid/scid hosts. In each type of host, the incidence of grafts exhibiting spontaneous tumor development declined significantly with increasing age of both donor and host. In addition, prepubertal ovary grafts formed spontaneous tumors in hormonally normal +/? scid/scid but not in hormonally deficient hpg/hpg scid/scid hosts. Finally, treatment of hpg/hpg scid/scid host mice with the androgenic steroid hormone precursor, dehydroepiandrosterone, resulted in GC tumor formation in the tumor-susceptible ovary grafts. We conclude that pubertal onset, spontaneous tumorigenesis in the susceptible ovaries is: (a) independent of an intact immune system; (b) terminated by completion of ovarian maturation as a cyclic organ; (c) not dependent on extraovarian factors unique to the genetically susceptible host; and (d) potentially initiated by androgenic steroids in the absence of an intact hypothalamic-pituitary gonadotropin axis. We hypothesize that ovarian androgens synthesized in response to normal gonadotropin stimulation initiate spontaneous tumorigenesis in the genetically susceptible ovary.

High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin-alpha-subunit promoter/Simian virus 40 T-antigen fusion gene.

Transgenic (TG) mice expressing the Simian virus 40 T-antigen under the control of the murine inhibin-alpha promoter (Inhalpha/Tag) develop granulosa and Leydig cell tumors at the age of 5-6 months, with 100% penetrance. When these mice are gonadectomized, they develop adrenocortical tumors. Suppression of gonadotropin secretion inhibits the tumorigenesis in the gonads of intact animals and in the adrenals after gonadectomy. To study further the role of luteinizing hormone (LH) in gonadal and adrenal tumorigenesis, a double TG mouse model was generated by crossing the Inhalpha/Tag mice with mice producing constitutively elevated levels of LH (bLHbeta-CTP mice). Our results show that in double TG mice (bLHbeta-CTP/Inhalpha/Tag), gonadal tumorigenesis starts earlier and progresses faster than in Inhalpha/Tag mice. Both ovarian and testicular tumors were histologically comparable with the tumors found in Inhalpha/Tag mice. In addition, adrenal tumorigenesis was found in intact double TG females, but not in Inhalpha/Tag females. Inhibin-alpha and LH receptor (LHR) were highly expressed in tumorigenic gonadal tissues, and the elevated LH levels were shown to be associated with ectopic LHR and high inhibin-alpha expression in the female adrenals. We conclude that in the Inhalpha/Tag tumor mouse model, elevated LH levels act as a tumor promoter, advancing gonadal and adrenal tumorigenesis.

Ectopic bioactive luteinizing hormone secretion by a pancreatic endocrine tumor, manifested as luteinized granulosa-thecal cell tumor of the ovaries.

Endocrine pancreatic tumors are rare neoplasms consisting of multipotent cells capable of secreting various bioactive substances causing characteristic clinical syndromes. Ovarian stromal hyperthecosis is characterized by varying degrees of luteinized stromal cell proliferation after sustained LH and/or human chorionic gonadotropin stimulation, clinically manifested by symptoms/signs of virilization resembling the polycystic ovary syndrome (PCOS). We report a case of ectopic bioactive LH production from a pancreatic endocrine tumor in a 33-yr-old woman with rapidly developing symptoms/signs of hyperandrogenism and markedly elevated serum androgen and LH levels leading to hyperthecosis and bilateral luteinized granulosa-thecal cell tumors of the ovaries. Although the patient was initially thought to have either severe PCOS or an LH-secreting pituitary tumor, an LH-producing pancreatic endocrine tumor bearing somatostatin receptors was demonstrated on scintigraphy with [111In]octreotide and abdominal imaging. Symptoms and signs of hyperandrogenism resolved after the resection of the tumor. Immunohistochemistry, in situ hybridization, and electron microscopy studies confirmed LH synthesis by the tumor cell. Although extremely rare, ectopic LH production from nonpituitary endocrine tumors should be considered in the differential diagnosis of hyperandrogenism, particularly when associated with highly elevated serum LH levels.

The inhibins and ovarian cancer.

Interest in inhibin as a marker of ovarian malignancy was stimulated by the description of elevated immunoreactive inhibin levels in the sera of patients with granulosa cell tumours. Several groups have confirmed the value of serum inhibin in the diagnosis and follow-up of patients with this uncommon malignancy. Immunoreactive inhibin levels are also frequently elevated in patients with mucinous cystadenocarcinoma and less frequently in other forms of ovarian tumour. Assay of sera using the specific dimeric inhibin assays has shown that ovarian tumours are able to secrete dimeric inhibin particularly inhibin B. The less specific alpha-subunit directed assays, however, most frequently show elevated concentrations. Used in combination with CA125 as a dual tumour marker, it appears in principle that inhibin can be a useful diagnostic agent. Immunohistochemistry for the inhibin subunits has been reported with increasing frequency as a helpful method to assess suspected ovarian stromal cell tumours. Its diagnostic accuracy for other types of ovarian adenocarcinoma appears less reliable. Expression of the inhibin subunit mRNAs has been demonstrated in a variety of ovarian malignancies. The observation that inhibin levels are elevated in ovarian cancer has stimulated studies of their relevance to the molecular pathogenesis of these malignancies. Findings to date have been largely negative with no evidence for activating mutations of the FSH receptor or of the post-receptor signalling pathway proteins.

Tumorigenesis in infant C3H/HeN mice exposed to tritiated water (HTO).

The purpose of this study was to determine the carcinogenicity and retention of tritiated water (HTO) in mice. A two-part study was undertaken. In an HTO-incorporation study, both sexes of 12-day old C3H/HeN mice were i.p. injected with 3.70 MBq/pup of HTO and sacrificed 3 hr and 1, 3, 7, 14 days after HTO administration; in a carcinogenicity study, pups were given a single i.p. injection of HTO at doses of 0, 0.23, 0.92 and 3.70 MBq/mouse, and then observed for 14 months. The survival rates of both sexes slightly decreased upon increasing the HTO administered doses. The results indicated that the administration of HTO to infants led to a significant increase of liver tumors in male mice, but not in females. In female mice, ovarian tumors were observed for the high-dose group of injected HTO.

[The role of the system of proteolytic enzymes and their inhibitors in the pathogenesis of ovarian tumors in Wistar rats and the possibilities for correcting the disorders detected]. / Rol' sistemy proteoliticheskikh fermentov i ikh ingibitorov v patogeneze opukholei iaichnika u krys Wistar i vozmozhnosti korrektsii vyiavlennykh narushenii.

The system of proteolytic enzymes and their inhibitors was studied in tissues of ovarian tumours of Wistar rats. It has been revealed that activation of proteolysis enzymes is observed in the genesis of tumour growth against a background of the absence of protease inhibitors. The correction of revealed disturbances by introducing the inhibitors of proteolytic enzymes and hormone preparations has shown that contrical and norcolute are the most effective. The results obtained suggest the further search of preparation normalizing the condition of the given system.

Granulosa cell tumor in an ovariohysterectomized dog.

A granulosa cell tumor was found in a dog with clinical signs of persistent estrus that began 6 years after ovariohysterectomy had been performed. The tumor was diagnosed by use of ultrasonography, provocative testing with human chorionic gonadotropin, and exploratory laparotomy. Hyperestrogenism from functional tumor cells caused bone marrow suppression and endocrine alopecia. Successful treatment included tumor removal, blood transfusions, and antibiotic administration.

Ovarian torsion associated with granulosa-theca cell tumor in a mare.

A 12-year-old Morgan mare was examined because of stallion-like behavior of 45 days' duration. Palpation per rectum and transrectal ultrasonographic examination revealed a large left ovary with multiple cystic areas and crepitus. A granulosa-theca cell tumor was suspected. During hospitalization for further evaluation of the affected ovary, the mare developed signs of abdominal pain. Exploratory surgery revealed a large left ovary, which was black with a necrotic and friable surface, and a 720 degrees clock-wise torsion of the ovarian pedicle. Torsion was corrected, and oophorectomy was performed. The mare recovered satisfactorily from surgery. Histologic diagnosis was granulosatheca cell tumor with marked diffuse necrosis. To our knowledge, torsion of the ovarian pedicle has not been reported in the veterinary literature. However, it is not uncommon in women. Ovarian torsion seems to develop in association with neoplasia, cysts, and ovarian hyperstimulation syndrome. Ovarian torsion should be considered as a differential diagnosis for mares with a known ovarian pathologic change such as neoplasia or abscess if signs of abdominal pain are evident.

[Ovulation induction therapy and malignant ovarian cancer]. / Az ovuláció-indukciós kezelés és a petefészek rosszindulatú daganatos megbetegedése.

In the authors' institute 1097 patients received treatment for ovarian cancer between the 1st of January, 1960 and the 31st of December, 1997. 92 of them had malignant granulosa cell tumor. In this study the link between ovulation induction therapy and ovarian cancer was analyzed with retrospective questionnaire. 236 questionnaires were shared out among patients with malignant ovarian tumor, who were treated between 1990 and 1997. 7 of 113 patients, who gave correct answers to the questions (6.2%) received ovulation induction therapy. Epithelial ovarian cancer developed in 2 of the cases during, and in 5 cases just 6-16 years after the clomiphene-citrate treatment. None of the 45 patients with granulosa cell tumors received induction therapy. The number of patients admitted because of malignant ovarian tumor before and after the induction therapy was also compared. There was no significant increase in the occurrence of the malignancy. Since 1986 in the in vitro fertilization program of the clinic nearly 1,500 patients were treated with effected ovulation induction drugs causing superovulation. The authors don't know of any development of malignant ovarian tumor, and 732 woman have confirmed this fact. The number of patients deceased in consequence of ovarian cancer in different age groups, and the distribution of the women population in every age group in Hungary, from the year of 1979 was also analyzed. There was no significant increase found in the number of deceased among the studied age groups, moreover a significant decrease among them could be observed. The link between ovulation induction therapy and ovarian cancer can neither be strengthen, nor deny by the result of the study, however the close relationship which seemed to be logical can be queried. To give an exact answer for the question a vast, long-term, prospective of retrospective follow-up case-control study is needed.

Molecular pathogenesis of granulosa cell tumors of the ovary.

Granulosa cell tumors of the ovary (GCT) comprise a distinct subset of ovarian cancers that account for approximately 5% of all ovarian malignancies. They are thought to arise from normal proliferating granulosa cells of the late preovulatory follicle and exhibit many morphological and biochemical features of these cells. GCT are distinct from other ovarian carcinomas in their hormonal activity; their ability to secrete estrogen, inhibin, and Müllerian inhibiting substance accounts for some of the clinical manifestations of the disease and also provides useful tumor markers for disease surveillance. Although considered to be of low malignant potential, GCT are commonly associated with slow, indolent disease progression, and frequent yet long delays to tumor recurrence are characteristic of this disease. Unlike the more intensely investigated epithelial ovarian tumors, relatively little is known about the molecular and genetic changes that give rise to GCT. To date, many investigations have centered around pathways known to be involved in normal granulosa cell proliferation, including those activated by FSH receptor stimulation. Most recently, the finding that approximately 97% of adult GCT harbor a somatic missense mutation in the FOXL2 gene (c.402C→G; p.C134W) represents an exciting advancement in the field of GCT research. The high frequency with which the mutation occurs in adult GCT, along with its absence from juvenile GCT and other human malignancies is suggestive of an oncogenic or gain-of-function mutation and, indeed, that the mutation is pathognomonic for adult GCT. In this review, we explore the implications of this finding and the most recent work characterizing molecular pathways of potential pathogenetic significance in GCT.