RESUMEN
We report on the incidental finding of a FOXL2 mutated adult granulosa cell tumour of the ovary with thecoma-like foci, a rare entity recently described by Jennifer N. Stall and Robert H. Young in a series of sixteen cases in 2019, displaying features differing from conventional adult granulosa cell tumour. Our aim is to specify the morphologic and molecular particularities of this presumably underrecognized finding, with a short presentation of the typical clinical context. Awareness of this rare and challenging neoplasm with indeterminate clinical course is crucial in routine diagnostics.
Asunto(s)
Tumor de Células de la Granulosa , Neoplasias Ováricas , Neoplasia Tecoma , Adulto , Femenino , Humanos , Tumor de Células de la Granulosa/diagnóstico , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Neoplasia Tecoma/diagnóstico , Neoplasia Tecoma/genética , Neoplasia Tecoma/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína Forkhead Box L2/genética , Factores de Transcripción Forkhead/genéticaRESUMEN
Molecular profiling was performed in 50 problematic ovarian sex cord-stromal tumours (SCSTs) most of which were seen in consultation. Following analysis, 17 were classified as adult granulosa cell tumour (AGCT), 16 of which showed a FOXL2 sequence variant (mutation); the initial favoured diagnosis in five of the cases was benign thecoma/fibrothecoma. Thirteen tumours ultimately classified as cellular fibroma or thecoma were FOXL2 sequence variant negative which was helpful in excluding AGCT. All six Sertoli-Leydig cell tumours (SLCTs) demonstrated DICER1 'hot spot' sequence variants, and one case each of AGCT and SLCT showed high grade histological transformation associated with a concurrent TP53 sequence variant. All eight unclassified SCSTs were negative for FOXL2 mutations and the six tested cases were DICER1 wild type; however, three tumours demonstrated MET, CTNNB1 or TP53 sequence variants. Four cases were classified as juvenile granulosa cell tumour, and one of these harboured a GNAS sequence variant. The single gynandroblastoma and microcystic stromal tumours in the series demonstrated FOXL2 and CTNNB1 alterations, respectively. In summary, molecular analysis aids in accurate classification of challenging ovarian SCSTs and sometimes leads to revision of the favoured provisional diagnosis. TP53 sequence variants may be associated with dedifferentiation in both SLCTs and AGCTs.
Asunto(s)
Neoplasias Ováricas/clasificación , Tumores de los Cordones Sexuales y Estroma de las Gónadas/clasificación , Neoplasia Tecoma/clasificación , Proteína p53 Supresora de Tumor/genética , beta Catenina/genética , Desdiferenciación Celular , ARN Helicasas DEAD-box/genética , Femenino , Proteína Forkhead Box L2/genética , Humanos , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ovario/patología , Ribonucleasa III/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasia Tecoma/genética , Neoplasia Tecoma/patologíaRESUMEN
Correlation of FOXL2 mutation status with morphologic features and reticulin staining patterns was performed in a comprehensive single-institutional cohort of ovarian sex cord-stromal tumors. Fifty-one cases were included, 35 of which were morphologically diagnosed as adult granulosa cell tumor, 4 as Sertoli-Leydig cell tumor, 11 as fibroma/fibrothecoma and 1 as a thecoma. Of the adult granulosa cell tumors, 31 (88.6%) harbored FOXL2 mutation. Abundant pale cytoplasm was seen in 51.6% (16/31) of FOXL2 mutated tumors, compared with 6.7% (1/15) among FOXL2 wild type tumors (P=0.003). Nearly half of FOXL2 negative tumors showed individual pericellular reticulin staining pattern, while none of the FOXL2 positive cases demonstrated this feature (P=0.0001). Nested reticulin pattern was observed in 67.7% of FOXL2 positive tumors, compared with 20% of FOXL2 negative cases (P=0.004). Indeterminate reticulin staining pattern was seen in nearly one third of cases in both groups. Nested reticulin pattern was 87.5% specific and 67.7% sensitive for FOXL2 mutation, while individual reticulin pattern was 100% specific for absence of FOXL2 mutation. No statistical significance was observed between the 2 groups in tumor size, mitotic activity, nuclear atypia, and nuclear grooves. Follow-up was available for 44 patients ranging from 0.3 to 259 months (mean: 67.5 mo). Two patients developed recurrence, both of them harbored FOXL2 mutation. In conclusion, the pathology diagnosis of sex cord-stromal tumors continues to be difficult, and reticulin staining remains a valuable tool as an initial step in the diagnostic work-up. Individual pericellular reticulin pattern essentially rules out adult granulosa cell tumor, while cases with indeterminate or nested patterns can be subjected to FOXL2 mutation testing to aid the diagnosis.
Asunto(s)
Proteína Forkhead Box L2/genética , Neoplasias Ováricas/diagnóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Adulto , Estudios de Cohortes , Femenino , Fibroma/diagnóstico , Fibroma/genética , Fibroma/patología , Estudios de Seguimiento , Estudios de Asociación Genética , Tumor de Células de la Granulosa/diagnóstico , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Humanos , Mutación , Recurrencia Local de Neoplasia , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Estudios Retrospectivos , Tumor de Células de Sertoli-Leydig/diagnóstico , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasia Tecoma/diagnóstico , Neoplasia Tecoma/genética , Neoplasia Tecoma/patologíaRESUMEN
Ovarian sex-cord stromal tumors that have between 10% and 50% granulosa cells in a prominent fibrothecomatous background have been referred to as granulosa theca cell tumors or mixed granulosa theca cell tumors. The classification and prognosis of these tumors is not clear. Most adult granulosa cell tumors of the ovary harbor a mutation in the FOXL2 gene, whereas fibromas and thecomas lack this mutation. The aim of our study was to assess the FOXL2 mutation status of ovarian granulosa theca cell tumors and to correlate the mutation status with morphologic and clinical characteristics. A FOXL2 mutation was detected in 6 of 12 (50%) granulosa theca cell tumors. Tumors with higher cellularity of granulosa cells were more likely to harbor a FOXL2 mutation as were tumors in which the granulosa cells formed large lobules. No conclusions could be drawn regarding the clinical and prognostic significance of the presence of a mutation given the small number of cases and limited clinical follow-up. Our study shows that half of granulosa theca cell tumors harbor the same FOXL2 mutation that characterizes adult granulosa cell tumors but there is no outcome evidence to guide whether mutation status should alter the classification of the tumor or the management of the patient.
Asunto(s)
Proteína Forkhead Box L2/genética , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Neoplasias Ováricas/genética , Neoplasia Tecoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Tumor de Células de la Granulosa/diagnóstico , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Ovario/patología , Pronóstico , Neoplasia Tecoma/diagnóstico , Neoplasia Tecoma/patologíaRESUMEN
According to the World Health Organization (WHO) classification from 2004, sex cord gonadal stromal tumors are divided into Leydig cell tumors, Sertoli cell tumors, granulosa cell tumors, tumors of the thecoma-fibroma group, incompletely differentiated sex cord gonadal stromal tumors, mixed forms of sex cord gonadal stromal tumors and tumors containing both germ cell and sex cord gonadal stromal elements. These tumors can appear sporadically or in combination with hereditary syndromes. To diagnose these rare tumors the combination of characteristic morphological aspects and various immunohistochemical markers is useful. Latest investigations demonstrate the potential role of mutation analyses in the diagnosis of this heterogeneous group of tumors.
Asunto(s)
Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasias Testiculares/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Fibroma/genética , Fibroma/patología , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Humanos , Tumor de Células de Leydig/genética , Tumor de Células de Leydig/patología , Masculino , Pronóstico , Tumor de Células de Sertoli/genética , Tumor de Células de Sertoli/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Neoplasias Testiculares/genética , Testículo/patología , Neoplasia Tecoma/genética , Neoplasia Tecoma/patologíaRESUMEN
A missense somatic mutation in the FOXL2 gene affecting codon 134 has recently been reported in granulosa cell tumour (GCT) and thecoma of the ovary. Such a recurrent nature of the mutation strongly suggests that the FOXL2 mutation may play an important role in the development of ovarian sex cord-stromal tumours. The aim of this study was to characterize the FOXL2 mutation in human tumour tissues. We analysed 1353 tumour tissues from various origins, including ovarian tumours and other common cancers, by single-strand conformation polymorphism analysis. We found the FOXL2 codon 134 missense mutation in 53 of 56 adult GCTs (94.6%) and two of the 16 thecomas (12.5%), but none in other tumours. Histologically, FOXL2 mutation-negative adult GCT showed that GCT cells were admixed with fibrothecomatous cells, and FOXL2 mutation-positive thecomas showed that luteinized theca cells were predominant. However, immunostaining of either inhibin alpha or FOXL2 did not differentiate the FOXL2 mutation status of adult GCTs and thecomas. There was no FOXL1 mutation and no common oncogenic mutation in the adult GCTs and thecomas. Our data indicate that the FOXL2 codon 134 mutation occurs exclusively in GCT and thecoma, and suggest the possibility that the development of most GCTs and a fraction of thecomas may be dependent on this mutation. Our data also suggest that the FOXL2 mutation status, as well as some histological features, may be important in the diagnosis of ovarian sex cord-stromal tumours.
Asunto(s)
Factores de Transcripción Forkhead/genética , Tumor de Células de la Granulosa/genética , Mutación Missense/genética , Neoplasias Ováricas/genética , Neoplasia Tecoma/genética , Adulto , Niño , Codón/genética , Femenino , Proteína Forkhead Box L2 , Marcadores Genéticos/genética , Tumor de Células de la Granulosa/patología , Humanos , Corea (Geográfico) , Neoplasias/genética , Neoplasias/patología , Neoplasias Ováricas/patología , Análisis de Secuencia de ARN , Neoplasia Tecoma/patologíaRESUMEN
Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. More than half of female patients with Mulibrey nanism develop benign mesenchymal tumors of ovarian sex cord-stromal origin. In this work, we characterize the gynecological tumors of female patients with Mulibrey nanism in detail. In addition to tumors of the fibrothecoma group, 18% (4/22) of the patients were observed with epithelial neoplasias, including 2 ovarian adenofibromas, 1 ovarian poorly differentiated adenocarcinoma and 1 endometrial adenocarcinoma. To investigate the possible involvement of TRIM37 alterations in the pathogenesis of sporadic fibrothecomas, we analyzed the TRIM37 cDNA for mutations and alternatively spliced transcripts and TRIM37 expression in fibrothecomas of women without Mulibrey nanism. No mutations in the open-reading frame of TRIM37 were detected. Two alternatively spliced variants were found, one lacking exon 23 and one exon 2. TRIM37del2 was also found in normal ovary but in a proportion of sporadic fibrothecomas, the TRIM37del2:TRIM37 ratio was increased. In normal ovary, TRIM37 was localized in the cytoplasm of stromal cells, especially theca cells surrounding developing follicles. TRIM37 transcript was found in all sporadic fibrothecomas examined, but 80% (20/25) of the tumors showed reduced or absent expression of TRIM37 protein. Allelic loss at the TRIM37 locus (17q22-23) was observed in 6% of sporadic fibrothecomas. Nearly half of the sporadic fibrothecomas showed evidence of CpG promoter methylation, suggesting promoter downregulation as one mechanism of reduced TRIM37 expression. In conclusion, inherited biallelic inactivation of TRIM37 (Mulibrey nanism) predisposes to both mesenchymal and epithelial ovarian tumors and dysregulation of TRIM37 may also be involved in the pathogenesis of sporadic fibrothecomas.
Asunto(s)
Enanismo Mulibrey/complicaciones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/genética , Neoplasia Tecoma/genética , Islas de CpG/genética , Metilación de ADN , Análisis Mutacional de ADN , Femenino , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Enanismo Mulibrey/genética , Mutación , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Regiones Promotoras Genéticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Neoplasia Tecoma/metabolismo , Neoplasia Tecoma/patología , Análisis de Matrices Tisulares , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
Traditional cytogenetic studies of ovarian stromal tumors are few, although trisomy 12 has been frequently documented with fluorescence in situ hybridization (FISH). In the current study, karyotypic analysis of four ovarian stromal tumors and a review of the literature suggest that numerical abnormalities of chromosomes 4 and 9 might also be important, possibly as secondary changes. To determine the frequency of 4, 9, and 12 aneuploidy in a larger group of ovarian tumors, FISH studies were performed on eight fibromas, three thecomas, one fibrothecoma, and five cellular fibromas. Trisomy 12 was identified in all five cellular fibromas as well as in two fibromas and the fibrothecoma. Gain of chromosome 9 was confined to the cellular fibromas. Loss of chromosomes 4 and/or 9 was prominent in the fibromas. These findings confirm the presence of trisomy 12 as a nonrandom chromosomal abnormality in ovarian stromal tumors. Moreover, these conventional and molecular cytogenetic data indicate that gain of chromosome 9 in addition to gain of chromosome 12 is prominent in cellular fibroma. In contrast, loss of chromosomes 4 and/or 9 are recurrent in fibroma. In summary, imbalances of chromosomes 4 and 9 appear to represent important secondary abnormalities in the thecoma-fibroma ovarian tumor group.
Asunto(s)
Desequilibrio Alélico , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 9 , Fibroma/genética , Neoplasias Ováricas/genética , Neoplasia Tecoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , Femenino , Fibroma/patología , Humanos , Cariotipificación , Persona de Mediana Edad , Neoplasias Ováricas/patología , Recurrencia , Neoplasia Tecoma/patologíaRESUMEN
Some ovarian fibromas and rare fibrosarcomas are associated with Gorlin syndrome, which is caused by mutation in the human homologue of Drosophila patched gene (PTCH), localized on chromosome 9q22.3. The relationship between PTCH gene and sporadic ovarian tumors in the thecoma-fibroma group has not been well characterized. On the other hand, we have recently described loss of heterozygosity (LOH) at 19p13.3 in 2 sporadic fibromas with sex-cord elements. We have analyzed DNA from 8 fibromas, 6 cellular fibromas, 2 fibrothecomas, 9 luteinized thecomas, and 2 fibrosarcomas of the ovary for LOH at 9q22.3 and 19p13.3, using polymerase chain reaction amplification for 10 microsatellite markers. LOH at 9q22.3 was detected in 4 (67%) of 6 cellular fibromas, with the highest frequency at microsatellite marker D9S15, which localizes proximal to the PTCH gene. Of 9 luteinized thecomas, 2 (22%) also exhibited LOH at 9q22.3 with 3 microsatellite markers other than D9S15. Allelic losses were not detected in any fibroma, fibrothecoma, or fibrosarcoma. LOH at 19p13.3 was found in 2 (25%) of 8 fibromas, 3 (50%) of 6 cellular fibromas, and 1 (11%) of 9 luteinized thecomas. None of the 2 fibrothecomas or 2 fibrosarcomas showed LOH at 19p13.3. LOH at both 9p22.3 and 19p13.3 was observed in 3 (50%) of 6 cellular fibromas, but not in luteinized thecomas. The results indicate that (1) LOH at both PTCH gene and STK11 gene is relatively frequent in cellular fibromas; (2) approximately a quarter of luteinized thecomas exhibited LOH of the PTCH gene; in both neoplasms, cellular fibromas and luteinized thecomas, LOH may play a role in their pathogenesis; and (3) sporadic cellular fibromas may arise through similar genetic pathways as cases of Gorlin syndrome.
Asunto(s)
Cromosomas Humanos Par 19 , Cromosomas Humanos Par 9 , Fibroma/genética , Pérdida de Heterocigocidad/genética , Neoplasias Ováricas/genética , Receptores de Superficie Celular/genética , Neoplasia Tecoma/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Adulto , Anciano , Síndrome del Nevo Basocelular/genética , Síndrome del Nevo Basocelular/metabolismo , Síndrome del Nevo Basocelular/patología , Femenino , Fibroma/metabolismo , Fibroma/patología , Marcadores Genéticos/genética , Humanos , Células Lúteas/metabolismo , Células Lúteas/patología , Luteína/metabolismo , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Receptores Patched , Receptor Patched-1 , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Superficie Celular/metabolismo , Células del Estroma/metabolismo , Células del Estroma/patología , Neoplasia Tecoma/metabolismo , Neoplasia Tecoma/patologíaRESUMEN
Human CG is a pregnancy marker secreted by the placenta, and it utilizes the same receptors as does LH. Human CG is a heterodimer, and its subunits are expressed in tissues other than placenta. Similarly, LH/hCG receptors are also expressed in multiple tissues; however, the physiological significance of this expression is unknown. Free hCGbeta is efficiently secreted in vitro in transfected cells and is highly expressed in many human cancers; however, the biological effects of free hCGbeta in vivo are unknown. To study in vivo consequences of elevated levels of free hCGbeta and hCG dimer in both male and female reproductive physiology, we used mouse metallothionein 1 promoter to generate multiple lines of transgenic mice that overexpressed either one or both subunits of hCG. Although mice expressing the glycoprotein hormone alpha subunit are normal and fertile, both male and female transgenic mice overexpressing only the hormone-specific hCGbeta subunit are infertile. The hCGbeta subunit-expressing transgenic female mice progressively develop cystic ovaries, whereas the male transgenic mice are infertile but otherwise are not phenotypically discernible. In contrast, both the male and female transgenic mice coexpressing high levels of the hCG subunits (i.e., the hCG dimer) demonstrate multiple reproductive defects. The male transgenic mice have Leydig cell hyperplasia, very high levels of serum testosterone, reduced testis size, and dramatically enlarged seminal vesicles and are infertile and display overly aggressive behavior when caged with females. The female transgenic mice are also infertile, have elevated levels of serum estradiol, and progressively develop hemorrhagic and cystic ovaries with thecal layer enlargement and stromal cell proliferation and degenerating kidneys. These results suggest that the in vivo biological effects of ectopically expressed free hCGbeta subunit are distinct from those of the hCG dimer and are gender specific. These transgenic mice are useful models for studying the biology of free hCGbeta subunit, for further analyzing the gain of function effects of hCG during early Leydig cell development, and for studying the roles of hCG in ovarian and kidney pathophysiology and function.
Asunto(s)
Gonadotropina Coriónica/genética , Reproducción/genética , Animales , Gonadotropina Coriónica/química , Gonadotropina Coriónica/fisiología , Gonadotropina Coriónica Humana de Subunidad beta/química , Gonadotropina Coriónica Humana de Subunidad beta/genética , Gonadotropina Coriónica Humana de Subunidad beta/fisiología , Dimerización , Femenino , Expresión Génica , Hormonas Glicoproteicas de Subunidad alfa/química , Hormonas Glicoproteicas de Subunidad alfa/genética , Hormonas Glicoproteicas de Subunidad alfa/fisiología , Humanos , Infertilidad/genética , Infertilidad/patología , Infertilidad/fisiopatología , Células Intersticiales del Testículo/patología , Masculino , Metalotioneína/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Transgénicos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ovario/anomalías , Fenotipo , Embarazo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reproducción/fisiología , Testículo/anomalías , Neoplasia Tecoma/genética , Neoplasia Tecoma/patologíaRESUMEN
Recent cytogenetical studies have indicated that trisomy 12 is a feature of ovarian tumors in the thecoma-fibroma group. Ten cases of these ovarian tumors were studied in total, including two thecomas, two fibrothecomas, four fibromas, one cellular fibroma and one fibrosarcoma, to clarify the relationship between polysomy 12 and proliferative activity in these tumors. Each formalin-fixed, paraffin-embedded tumor tissue was examined by fluorescence in situ hybridization to determine copy numbers of chromosome 12 and by immunohistochemical staining of Ki-67 for evaluation of tumor cell proliferation. Gains of trisomy 12 were found in seven of the 10 cases, and the percentage of cells with tetrasomy 12, but not that of cells with trisomy 12, was significantly and positively correlated with percentage of Ki-67-positive cells, but significantly and inversely correlated with patient age. These findings suggest that tetrasomy 12 is an age-related aberration of chromosome 12 in ovarian tumors of the thecoma-fibroma group, and that such tumors exhibit more active proliferation in younger patients.
Asunto(s)
Aneuploidia , Cromosomas Humanos Par 12 , Fibroma/genética , Neoplasias Ováricas/genética , Neoplasia Tecoma/genética , Adulto , Anciano , Bandeo Cromosómico , ADN de Neoplasias/análisis , Femenino , Fibroma/química , Fibroma/patología , Humanos , Inmunohistoquímica , Hibridación in Situ , Antígeno Ki-67/análisis , Persona de Mediana Edad , Neoplasias Ováricas/química , Neoplasias Ováricas/patología , Neoplasia Tecoma/química , Neoplasia Tecoma/patología , Células Tumorales CultivadasRESUMEN
Chromosomic aberrations play a major role in the initiation and the progression of benign as well as malignant tumors. In particular, trisomy 12 is frequently observed in female genitourinary tract tumors and constitutes a recurrent and often unique anomaly in stromal ovarian tumors such as fibrothecomas. Today, the genetic analysis of fresh or fixed solid tumors is enabled by the fluorescent in situ hybridization method (FISH). Using FISH and/or conventional cytogenetics, we analysed 12 ovarian stromal tumors (6 fibromas, 3 fibro thecomas and 3 thecomas). All of these tumors were benign and trisomy 12 was observed in all cases. Moreover, 3 cases presented trisomy and tetrasomy for chromosome 12 simultaneously. The high frequency of trisomy 12 in this tumor type suggests that this abnormality might be implicated in ovarian tumorigenesis.
Asunto(s)
Cromosomas Humanos Par 12 , Hibridación Fluorescente in Situ , Neoplasias Ováricas/genética , Trisomía , Adulto , Anciano , Femenino , Fibroma/genética , Humanos , Cariotipificación , Persona de Mediana Edad , Neoplasia Tecoma/genéticaRESUMEN
OBJECTIVE: To search for somatic activating mutations of gonadotropin receptor (FSH-R and LH/chorionic gonadotropin receptor [CG-R]) genes as a cause of sex cord stromal tumors. DESIGN: Molecular studies in human tissue. SETTING: University hospital. SPECIMEN(S): Eight granulosa cell tumors collected from paraffin-embedded tissue, eight Leydig cell tumors, and three thecomas collected from fresh-frozen or paraffin-embedded tissue. INTERVENTION(S): Tumor samples were used for DNA extraction. The entire exon 11 of the LH/CG-R gene and a hot spot for gonadotropin receptor activating mutations on exon 10 of the FSH-R gene were amplified by polymerase chain reaction. The former was analyzed by denaturing gradient gel electrophoresis and automatic direct sequencing, and the latter by automatic direct sequencing. MAIN OUTCOME MEASURE(S): Results of denaturing gradient gel electrophoresis and automatic direct sequencing. RESULT(S): No somatic activating mutation was detected in exon 11 of the LH/CG-R gene in eight Leydig cell tumors and three thecomas. In addition, no mutations were detected in eight granulosa cell tumors in the hot spot for activating mutations in exon 10 of the FSH-R gene. CONCLUSION(S): Somatic activating mutations of gonadotropin receptors seem to play no relevant role in the development of sex cord stromal tumors.
Asunto(s)
Mutación/fisiología , Neoplasias Ováricas/genética , Receptores de HFE/genética , Receptores de HL/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Neoplasias Testiculares/genética , Exones/genética , Femenino , Tumor de Células de la Granulosa/genética , Humanos , Tumor de Células de Leydig/genética , Masculino , Neoplasia Tecoma/genéticaRESUMEN
Transgenic (TG) mice, expressing the Simian Virus 40 T-antigen (Tag) under a 6-kb fragment of the murine inhibin alpha-subunit promoter (inh alpha p), develop gonadal tumors of granulosa/theca or Leydig cell origin. We showed previously that adrenocortical tumors develop if the TG mice are gonadectomized but never develop in intact animals. However, if functional gonadectomy was induced by GnRH antagonist treatment or by cross-breeding the TG mice into the hypogonadotropic hpg genetic background, neither gonadal nor adrenal tumors appeared. Since the most obvious difference between the gonadectomized and GnRH-antagonist-treated or Tag/hpg double mutant mice is the elevated gonadotropin secretion in the first group, we examined whether the adrenal tumorigenesis would be gonadotropin-dependent. Surprisingly, both the adrenal tumors and a cell line (C alpha 1) derived from one of them expressed highly functional LH receptors (LHR), as assessed by Northern hybridization, immunocytochemistry, ligand binding, and human CG (hCG)-stimulated cAMP and steroid production. No FSH receptor expression was found in the adrenal tumors by RT-PCR. hCG treatment of the C alpha 1 cells stimulated their proliferation, as measured by [3H]thymidine incorporation. This effect was related to hCG-stimulated steroidogenesis since progesterone, testosterone, and estradiol, at physiological concentrations, also stimulated the C alpha 1 cell proliferation. Different adrenocortical cells expressed initially LHR and Tag, whereas both were highly expressed in the tumor cells. In conclusion, the high level of functional LHR in the adrenal tumors indicates that this receptor can function as tumor promoter when ectopically expressed and stimulated by the ligand hormone.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Antígenos Transformadores de Poliomavirus/fisiología , Tumor de Células de la Granulosa/genética , Inhibinas , Tumor de Células de Leydig/genética , Hormona Luteinizante , Hormona Luteinizante/farmacología , Neoplasias Hormono-Dependientes/genética , Neoplasias Ováricas/genética , Péptidos/fisiología , Regiones Promotoras Genéticas , Neoplasias Testiculares/genética , Neoplasia Tecoma/genética , Neoplasias de la Corteza Suprarrenal/fisiopatología , Animales , Antígenos Transformadores de Poliomavirus/genética , Castración , Transformación Celular Neoplásica/genética , Gonadotropina Coriónica/farmacología , Cruzamientos Genéticos , Replicación del ADN/efectos de los fármacos , Femenino , Hormonas Esteroides Gonadales/farmacología , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/toxicidad , Gonadotropinas Hipofisarias/deficiencia , Tumor de Células de la Granulosa/fisiopatología , Humanos , Tumor de Células de Leydig/fisiopatología , Hormona Luteinizante/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Mutantes , Ratones Transgénicos , Neoplasias Hormono-Dependientes/fisiopatología , Especificidad de Órganos , Neoplasias Ováricas/fisiopatología , Péptidos/genética , Receptores de HFE/análisis , Receptores de HL/biosíntesis , Receptores de HL/fisiología , Proteínas Recombinantes de Fusión/fisiología , Virus 40 de los Simios/fisiología , Neoplasias Testiculares/fisiopatología , Neoplasia Tecoma/fisiopatología , Células Tumorales CultivadasRESUMEN
This study was designed to measure the multi-drug resistance gene (MDR1) mRNA content and analyze clinical relationship between MDR1 expression and drug resistance in primary ovarian cancer. Reverse transcription PCR (RT-PCR) was used to measure MDR1 mRNA content in biopsy sample of 31 primary ovarian cancers (experimental group) and 30 gynecological tumors (control group). The level of 95.2% (20/21) MDR1 expression was relatively low, and the detected rate of MDR1 expression was 67.7% (21/31) in experimental group, which was higher than that in control group (40.0%, P < 0.05). The differences of MDR1 expression between the effective group and no effect group after combined chemotherapy was significant (P < 0.05). No significant relationship was found between MDR1 expression and clinical stage or histological classification or grade of differentiation in experimental group. We are led to concluded that primary ovarian cancers have drug-resistance clones which might express MDR1 spontaneously and expression of MDR1 may be used as a prognostic and predictive indicator for clinical response of ovarian cancers to combined chemotherapy.
Asunto(s)
Cistadenocarcinoma Mucinoso/genética , Cistadenocarcinoma Seroso/genética , Genes MDR/genética , Neoplasias Ováricas/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Expresión Génica , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Pronóstico , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Neoplasia Tecoma/genéticaRESUMEN
To define the involvement of p16/CDKN2 and p15/MTS2 inactivation in ovarian tumorigenesis and the association of these inactivation events with histological types and clinical stages of ovarian tumors, we analyzed homozygous deletion and somatic mutation of p16/CDKN2 and p15/MTS2 genes, as well as hypermethylation of the 5'-CpG island of the p16/CDKN2 gene, in 49 primary ovarian tumors and 6 ovarian carcinoma cell lines. We found homozygous deletions of p16/CDKN2 and p15/MTS2 in 6 (12%) and 5 (10%) primary tumors, respectively. Somatic mutation of p16/CDKN2 was found in only 1 primary tumor, but mutation of p15/MTS2 was not detected in any sample. None of the 28 primary tumors or 6 cell lines was hypermethylated at the 5'-CpG island of p16/CDKN2. The incidence of inactivation of p16/CDKN2 in primary tumors was significantly higher in the advanced stages (7 of 29) than in the early stages (0 of 14). Seven of 9 alterations in p16/CDKN2 and p15/MTS2 were observed in serous (3 of 12), endometrioid (3 of 9) and clear-cell (1 of 4) carcinomas. However, only normal sequences of these genes were detected in mucinous carcinomas. Loss of heterozygosity (LOH) at the IFNA locus was detected in 1 of 19 (5%) tumors, but no change at the D9S171 locus was observed in 17 tumors. These results suggest that: (i) homozygous deletion is the main mechanism of inactivation of p16/CDKN2 and p15/MTS2 in ovarian tumorigenesis; (ii) inactivation of p16/CDKN2 and p15/MTS2 may be the histological type-specific events involved in ovarian tumorigenesis; and (iii) inactivation of p16/CDKN2 is potentially involved in the progression of ovarian tumors in advanced stages.
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Carcinoma/genética , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Inhibidores Enzimáticos/metabolismo , Neoplasias Ováricas/genética , Proteínas Supresoras de Tumor , Carcinoma/patología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Progresión de la Enfermedad , Femenino , Heterocigoto , Humanos , Mutación , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/patología , Neoplasia Tecoma/genética , Neoplasia Tecoma/patología , Células Tumorales CultivadasRESUMEN
Cytogenetic analysis of a fibrothecoma of ovary revealed numerical and structural chromosome abnormalities, i.e., 44,XX, dup(1)(p13p31),del(3)(p14) add (10p), -16, -22. This is the first report of numerical and structural abnormalities in a fibrothecoma of the ovary.
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Aberraciones Cromosómicas/genética , Fibroma/genética , Neoplasias Ováricas/genética , Neoplasia Tecoma/genética , Anciano , Anciano de 80 o más Años , Trastornos de los Cromosomas , Femenino , Fibroma/patología , Humanos , Cariotipificación , Neoplasias Ováricas/patología , Neoplasia Tecoma/patologíaRESUMEN
Trisomy 12 is a nonrandom chromosomal abnormality found in a large proportion of ovarian sex cord-stromal tumors (OSCTs), including thecoma-fibromas (TFs) and granulosa cell tumors (GCTs). The prognostic significance of trisomy 12 in these tumors, however, is unknown. A series of 16 OSCTs, obtained from patients with long-term follow-up, was analyzed for the presence of trisomy 12 by interphase fluorescence in situ hybridization on paraffin-embedded sections. Sections of the contralateral nonneoplastic ovary were available in five cases and utilized as controls. Evidence of trisomy 12 was detected in 9 of 10 TFs, and contrary to previous reports, in only one of six GCTs. One TF with trisomy 12 was a malignant variant that resulted in the death of the patient in 5 months, but the remaining TFs with trisomy 12 were cytologically and clinically benign in those with follow-up available. The single GCT with trisomy 12 was a nonaggressive, stage 1 lesion without evidence of recurrence after 264 months, whereas those GCTs without trisomy 12 included one stage 2 tumor and a cytologically atypical GCT with tumor necrosis and an elevated number of mitotic figures. The evidence suggests that the great majority of OSCTs with trisomy 12 is clinically benign, but not all benign OSCTs have trisomy 12. We conclude that the presence of trisomy 12 is of limited prognostic usefulness in OSCTs.
Asunto(s)
Cromosomas Humanos Par 12 , Neoplasias Ováricas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Trisomía , Adulto , Anciano , Femenino , Estudios de Seguimiento , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Humanos , Hibridación Fluorescente in Situ , Interfase , Persona de Mediana Edad , Neoplasias Ováricas/patología , Pronóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasia Tecoma/genética , Neoplasia Tecoma/patologíaRESUMEN
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)
Asunto(s)
Queratinas/análisis , Laminina/análisis , Neoplasias Ováricas/química , Neoplasias Ováricas/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/química , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Vimentina/análisis , Adulto , Membrana Basal/química , Membrana Basal/ultraestructura , Preescolar , Femenino , Feto/química , Fibroma/química , Fibroma/patología , Gonadoblastoma/química , Gonadoblastoma/genética , Gonadoblastoma/patología , Humanos , Inmunohistoquímica , Lactante , Masculino , Peso Molecular , Neoplasias de Tejido Gonadal/química , Neoplasias de Tejido Gonadal/genética , Neoplasias de Tejido Gonadal/patología , Neoplasias Ováricas/genética , Ovario/química , Ovario/embriología , Ovario/patología , Tumor de Células de Sertoli-Leydig/química , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Testículo/química , Testículo/embriología , Testículo/patología , Neoplasia Tecoma/química , Neoplasia Tecoma/genética , Neoplasia Tecoma/patologíaRESUMEN
BACKGROUND: It is difficult to determine the prognosis of granulosa cell tumors (GCT) at the time of diagnosis. METHODS: The nuclear DNA content of 17 patients with ovarian GCT was investigated by flow cytometry using paraffin-embedded tissue. Nuclear area (NA), nuclear perimeter (NP), and nuclear shape factor (NSF) were measured by an image analyzer using hematoxylin- and-eosin-stained sections. RESULTS: The follow-up period of the patients ranged from 2 months to 11 years. Thirteen tumors were diploid or near diploid, whereas one was tetraploid, and three were aneuploid. Two tumors had varying degrees of DNA content heterogeneity. Crude survival of the patients with an euploid tumor (13 diploid, 1 tetraploid) was more favorable than that of the patients with an aneuploid tumor. Patients with S-phase fraction (SPF) greater than 10% or DNA content heterogeneity experienced disease recurrence or metastasis. A significant difference was observed in NA and NP between those with and without metastasis. CONCLUSIONS: Our results indicate that DNA aneuploidy, large SPF, DNA content heterogeneity, and large NA and NP are adverse prognostic factors in GCT. Thus, flow cytometric and morphometric measurement may provide a rapid and valuable method to predict the biologic behavior of GCT.