Fine needle aspiration cytology of a recurrent juvenile granulosa cell tumor

Fine needle aspiration biopsy was performed on a recurrent juvenile granulosa cell tumor of the ovary in a 24-year-old woman. The cytologic appearances and the results of histochemical, immunocytochemical and ultrastructural studies are described, and the differential diagnosis with other ovarian tumors is discussed.     

A late recurring and easily forgotten tumor: ovarian granulosa cell tumor

ABSTRACT: Ovarian granulosa cell tumor (GCT) is a malignant tumor with slow progression. The recurrence of granulosa cell tumor often happens after 5 years, leading to a 'forgotten tumor' by the patient. We present the case of a 64-year-old woman with a presentation of left flank pain. An initial computed tomography scan revealed a single tumor with multiple adjacent organ invasions. Surgical intervention was prescribed and the pathological results revealed a metastatic granulosa cell tumor. We also review the literature for the follow-up and further management of this tumor.     

Fine needle aspiration cytology of an ovarian luteinized follicular cyst mimicking a granulosa cell tumor. A case report

BACKGROUND: Fine needle aspiration is a valuable tool in the diagnosis of ovarian cysts, especially in the young and when a nonneoplastic cyst is suspected. High cellularity, epitheliallike clusters and cellular atypia in aspirates from functional cysts are known features that may lead to an erroneous diagnosis of malignancy. Granulosa cells in ovarian cystic fluids may originate in follicular cysts or cystic granulosa cell tumors. In luteinized follicular cysts the cells usually have ample cytoplasm and tend to form clusters. This report draws attention to a case where abundant, dispersed cells lacking cytoplasm led to the incorrect diagnosis of a granulosa cell tumor. CASE: In an ovarian cystic aspirate from a 34-year-old woman, the fluid was highly cellular, with a striking predominance of cells interpreted as granulosa cells. Granulosa cells are often found in aspirates from functional cysts, but striking cellularity, prominent nuclear grooves and lack of luteinization made us consider a granulosa cell tumor rather than a follicle-derived cyst. Surgery was performed, and histology revealed a benign serous cystadenoma but also numerous maturing follicles and follicular cysts with thick layers of granulosa cells. The aspirate obviously did not represent the cystadenoma but one of the prominent follicular cysts. CONCLUSION: An understanding of the cytologic features of functional ovarian cysts, including the pitfalls, is necessary to avoid a false diagnoses of a neoplastic lesion. For a correct interpretation of the cytologic findings, close communication with the clinician and with the radiologist performing the aspiration is of vital importance.     

Cytologic features of ovarian granulosa cell tumor metastatic to the lung. A case report

BACKGROUND: Granulosa cell tumor (GCT) of the ovary is an uncommon but not rare tumor, and the adult type usually affects postmenopausal women. The adult type of GCT has several characteristic clinicopathologic features, including a composition of small, uniform cells with Call-Exner bodies and an ability to metastasize to extrapelvic organs, even several decades after the initial operation. CASE: A 62-year-old female was incidentally found to have multiple shadows in the peripheral portions of both lung fields on roentgenography. She had a past history of oophorectomy for an ovarian carcinoma more than 20 years earlier. A transbronchial lung biopsy series was nondiagnostic. An aspirate obtained by transthoracic fine needle aspiration (FNA) biopsy revealed clusters of rather uniform, small cells with nuclear grooves, suggestive of a metastatic lung tumor. Histologic examination of the lung tissue in comparison with the previous oophorectomy specimen confirmed the impression of GCT metastatic to the lung. CONCLUSION: A preoperative diagnosis of metastatic lung tumor was established by transthoracic FNA cytology. The important cytologic criteria for the differential diagnosis are uniformity of tumor cells, coffee bean-like nuclear grooves and Call-Exner bodies. The possibility of late recurrence of this kind of tumor, even two or three decades after surgical resection, should be kept in mind.     

Establishment and characterization of a human ovarian granulosa tumor cell line (HSOGT)

We successfully established a novel ovarian granulosa tumor cell line (HSOGT). The tumor tissue of the ovary was derived from a 25 year-old Japanese woman under her consent. The cell line was maintained for over 14 months, subcultured more than 73 times, and had a population doubling time of 18.9 hours. Phase contrast microscopy displayed a pavement-like arrangement without contact inhibition. The chromosome number showed a wide distribution of aneuploidy and the mode was 83; many marker chromosomes were observed. The HSOGT was also successfully xenotransplanted into nude mice. The cell line produced estradiol and has preserved some characters of granulosa cells with stable growth in vitro. We firmly believe that this cell line will be a most useful tool for endocrinological investigation of human granulosa cells.     

Fine mapping of the NRC-1 tumor suppressor locus within chromosome 3p12

Identification of tumor suppressor genes based on physical mapping exercises has proven to be a challenging endeavor, due to the difficulty of narrowing regions of loss of heterozygosity (LOH), infrequency of homozygous deletions, and the labor-intensive characterization process for screening candidates in a given genomic interval. We previously defined a chromosome 3p12 tumor suppressor locus NRC-1 (Nonpapillary Renal Carcinoma-1) by functional complementation experiments in which renal cell carcinoma microcell hybrids containing introduced normal chromosome 3p fragments were either suppressed or unsuppressed for tumorigenicity following injection into athymic nude mice. We now present the fine-scale physical mapping of NRC-1 using a QPCR-based approach for measuring copy number at sequence tagged sites (STS) which allowed a sub-exon mapping resolution. Using STS-QPCR and a novel statistical algorithm, the NRC-1 locus was narrowed to 4.615-Mb with the distal boundary mapping within a 38-Kb interval between exon 3 and exon 4 of the DUTT1/Robo1 gene, currently the only candidate tumor suppressor gene in the interval. Further mutational screening and gene expression analyses indicate that DUTT1/ROBO1 is not involved in the tumor suppressor activity of NRC-1, suggesting that there are at least two important tumor suppressor genes within the chromosome 3p12 interval.     

Fine needle aspiration cytologic features of hepatic metastasis of granulosa cell tumor of the ovary. Differential diagnosis

The cytologic findings from a fine needle aspiration biopsy of hepatic metastases of a granulosa cell tumor are described. While the cytologic features of the tumor were characteristic, the early recurrence in an unusual site makes this case noteworthy. The differential diagnosis of granulosa cell tumors from other metastatic and primary liver tumors is discussed.     

Ginsenoside Rb1 inhibits oxidative stress-induced ovarian granulosa cell injury through Akt-FoxO1 interaction

Ginsenoside Rb1 shows a strong antioxidant effect and has potential activation effects on Akt. The aim of the present study was to investigate the protective effect of Rb1 on age-related ovarian granulosa cell injury. Ovarian granulosa cells(GCs) were obtained from 50 young women(≤30 years) and 50 aged women(≥38 years) at an IVF center. Young and aged ICR mice were administered with or without Rb1(10 mg kg^-1, i.p.) for 2 weeks. The protective effects of Rb1 were investigated and the r...     

Incipient spontaneous granulosa cell tumour in the gerbil, Meriones unguiculatus

In 167 cases of granulosa cell tumour (GCT) in the gerbil, Meriones unguiculatus, 42.5% (71 cases) were in the ovaries, with no evidence of macroscopic lesion. In this paper, we describe the common findings in the incipient--microscopic--type of this spontaneous ovarian tumour occurring in gerbils younger than two years of age.     

Fine mapping of the NRG1 Hirschsprung's disease locus

The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ～350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR.     

Cystic adult ovarian granulosa cell tumor as a potential source of false negative diagnosis in ovarian cytology. A case report

BACKGROUND: Adult granulosa cell tumors (AGCT), unilocular or multilocular, with thin-walled cysts, are extremely rare. They can be erroneously diagnosed as follicular cysts by sonography and fine needle aspiration and therefore may be a source of false negative results. CASE: Laparoscopy was performed on a 29-year-old woman in whom a cystic ovarian mass, probably benign, was diagnosed by transvaginal sonography. The smears obtained from the cyst revealed a moderate amount of regular, small cells with scant cytoplasm and round to oval nuclei with finely granular chromatin without longitudinal grooves. These granulosa cells were arranged singly and in small groups. Very scarce cellular aggregates, microfollicular or rosettelike, some containing amorphous material and resembling Call-Exner bodies, were identified. Histologic study of the cystic wall confirmed the diagnosis of multilocular cystic AGCT with a microfollicular pattern. CONCLUSION: The finding of a moderate to abundant amount of regular granulosa cells, with or without nuclear longitudinal grooves, during cytologic examination of ovarian cysts considered benign by ultrasonography requires a careful search for microfollicular differentiation and Call-Exner bodies due to the rare but possible occurrence of cystic AGCT.     

Complementation between alleles at the ovarian tumor locus of Drosophila melanogaster

The (ovarian tumor) otu gene resides at 23.2 on the genetic map of the X chromosome and near 7F1 on the cytological map. This germ line-expressed locus behaves as if it encodes a gene product which is required during certain steps in the transformation of oogonia into functional oocytes. On the basis of their ovarian morphologies 17 ethyl methane sulfonate (EMS)-induced mutants have been distributed among three developmental classes as follows: quiescent (eight), oncogenic (four), and differentiated (five). The otu13 and otu14 alleles interact to yield fertile females, and many other heteroallelic combinations show partial complementation. Since many mutant alleles interact beneficially, the functional product of the otu gene may be a multimer. We conclude, from an analysis of heteroallelic interactions and dosage effects, that the abnormal phenotypes observed are graded consequences of reduced levels of functional gene product and that the minimum concentration required for development increases as oogenesis proceeds.     

Anti-apoptotic activity of porcine cFLIP in ovarian granulosa cell lines

In mammalian ovaries, more than 99% of follicles undergo atresia during growth and development. Recently, we found that the expression of cellular FLICE-like inhibitory protein long form (cFLIP(L)) decreased during follicular atresia in granulosa cells of porcine ovaries. In humans and other species, both the short (cFLIP(S)) and long (cFLIP(L)) forms of cFLIP are considered to function as cell survival factors that inhibit death ligand receptor-mediated apoptosis. Since the anti-apoptotic activity of porcine cFLIP (pcFLIP) in granulosa cells had not been determined, we examined the effect of pcFLIP on survival using granulosa-derived cell lines. A human cervix adenocarcinoma cell line, HeLa, human ovarian granulosa tumor cell line, KGN, and porcine granulosa-derived cell line, JC-410, were used. By Western blotting, internal cFLIP(L) was detected in all cell lines, but only trace levels of cFLIP(S) were found in HeLa and KGN cells. To examine the anti-apoptotic activity, pcFLIP(S) or pcFLIP(L) was overexpressed in HeLa and KGN cells. Transfected cells in which pcFLIP(S) or pcFLIP(L) was overexpressed, survived the induction of Fas-mediated apoptosis, while almost all of the cells transfected with empty vector died. Then, we suppressed the expression of porcine cFLIP(S) and/or cFLIP(L) in JC-410 cells using small interfering RNA (siRNA). When both cFLIP(S) and cFLIP(L), or only cFLIP(L) was suppressed, cell viability declined significantly. From the results, we conclude that porcine cFLIP(S) and cFLIP(L) exhibit anti-apoptotic activity in granulosa-derived cells. It was strongly suggested that pcFLIP acts as a survival-promoting factor in granulosa cells and determines whether porcine ovarian follicles survive or undergo atresia.     

mTOR controls ovarian follicle growth by regulating granulosa cell proliferation

We have shown that inhibition of mTOR in granulosa cells and ovarian follicles results in compromised granulosa proliferation and reduced follicle growth. Further analysis here using spontaneously immortalized rat granulosa cells has revealed that mTOR pathway activity is enhanced during M-phase of the cell cycle. mTOR specific phosphorylation of p70S6 kinase and 4E-BP, and expression of Raptor are all enhanced during M-phase. The predominant effect of mTOR inhibition by the specific inhibitor Rapamycin (RAP) was a dose-responsive arrest in the G1 cell cycle stage. The fraction of granulosa cells that continued to divide in the presence of RAP exhibited a dose-dependent increase in aberrant mitotic figures known as anaphase bridges. Strikingly, estradiol consistently decreased the incidence of aberrant mitotic figures. In mice treated with RAP, the mitotic index was reduced compared to controls, and a similar increase in aberrant mitotic events was noted. RAP injected during a superovulation regime resulted in a dose-dependent reduction in the numbers of eggs ovulated. Implications for the real-time regulation of follicle growth and dominance, including the consequences of increased numbers of aneuploid granulosa cells, are discussed.     

Testicular juvenile granulosa cell tumor: a case report

BACKGROUND: Juvenile granulosa cell tumors of the testis are rare gonadal stromal tumors of the pediatric age. They represent the most common neoplasms of the testis in the first 6 months of life. A testicular cystic mass is detected, or it can appear as an abdominal or inguinal mass. Differential diagnosis for testicular tumors at this age includes teratoma, simple cyst, epidermoid cyst, lymphangioma and testicular torsion. Association with ambiguous genitalia and sex chromosome abnormalities has been reported. Orchiectomy alone is recommended, because no case of metastasis or recurrence has been reported. CASE: We report a case of a 3-month-old male infant with a testicular juvenile granulosa cell tumor mass initially evaluated by fine needle biopsy, which disclosed single or cohesive groups of vimentin, alpha-inhibin and S-100-positive spindle cells with regular nuclei and fine chromatin and inconspicuous nucleoli. Orchiectomy was performed, and histology revealed a juvenile granulosa cell tumor. CONCLUSION: Even though juvenile granulosa cell tumor is the most common neoplasm of the testis in the first 6 months of life, we found no reports describing its cytologic features. In this setting, fine needle aspiration cytology is a useful tool for initial and therapeutic management.     

Hormonally induced cell shape changes in cultured rat ovarian granulosa cells

Cultured rat ovarian granulosa cells undergo a dramatic morphological change when exposed to follicle-stimulating hormone (FSH). Exposure to FSH causes the flattened epithelioid granulosa cells to assume a nearly spherical shape while retaining cytoplasmic processes which contact the substrate as well as adjacent cells. This effect of FSH is preceded by a dose-dependent increase in intracellular cAMP, is potentiated by cyclic nucleotide phosphodiesterase inhibitors, and is mimicked by dibutyryl cAMP. Prostaglandins E1 or E2 and cholera enterotoxin also cause the cells to change shape. A subpopulation of the cells responds to luteinizing hormone. These morphological changes, which are blocked by 2,4-dinitrophenol, resemble those produced by treating cultures with cytochalasin B. Electron microscopy shows that the unstimulated, flattened cells contain bundles of microfilaments particularly in the cortical and basal regions. After FSH stimulation, microfilament bundles are not found in the rounded granulosa cell bodies but they are present in the thin cytoplasmic processes. These data suggest that the morphological change results from a cAMP-mediated, energy-dependent mechanism that may involve the alteration of microfilaments in these cells.