Ovarian Granulosa Cell Tumors Research Articles

Ovarian sex cord stromal tumours: analysis of the clinical and sonographic characteristics of different histopathologic subtypes

BackgroundOvarian sex cord stromal tumours (OSCSTs) are rare ovarian tumours and include different histopathologic subtypes. This study aimed to analyse the clinical and sonographic characteristics of different histopathologic OSCST subtypes.MethodsA total of 63 patients with surgically proven OSCSTs were enrolled in this retrospective study to analyse their clinical and sonographic features. Ultrasound examinations and predictive models were performed before surgery. The clinical and sonographic findings were compared according to the type of OSCST based on the histopathological diagnosis.ResultsThe mean age of 63 patients was 52.17 years (range: 17–78 years). Eighteen patients experienced irregular vaginal bleeding (28.57% 18/63), 7 patients exhibited abnormal body hair (11.11%). 2 patients (3.17%) showed an increased level of CA125, and 25 patients (39.68%, 25/63) showed an increased level of testosterone. Forty-two patients had ovarian thecoma-fibroma groups (OTFGs). Six patients had Sertoli-Leydig cell tumours (S-LCTs), 4 patients had Leydig cell tumours (LCTs), 8 patients had ovarian granulosa cell tumours (OGCTs), 2 patients had ovarian steroid cell tumours, not otherwise specified (OSCTs-NOS), and one patient had sclerosing stromal tumours (SSTs). The mean diameter of the tumour was 47.9 mm (range: 10–258 mm). Forty-seven masses were hypoechoic (74.60%). Twenty-eight masses had posterior echo attenuation, 22 masses exhibited abundant Doppler flow signals (34.92%), and one patient had ascites (1.59%). The diagnostic accuracy of the Simple Rules (SR) and the Assessment of Different NEoplasias in the adneXa (ADNEX) model in distinguishing benign and malignant OSCSTs was 44% (30/63) and 84% (53/63), respectively. The diagnostic accuracy of the SR for OTFGs, S-LCTs & LCTs & OSCTs-NOS, OGCTs, and SSTs was 47.6% (20/42), 16.67% (2/12), 100% (8/8), and 0% (0/1), respectively. The diagnostic accuracy of the ADNEX model for OTFGs, S-LCTs & LCTs & OSCTs-NOS, OGCTs, and SSTs was 93% (31/42), 58.33% (7/12), 75% (6/8), and 100% (1/1), respectively.ConclusionsOSCSTs generally appear as a solid mass on ultrasound. Posterior echo attenuation indicates an OTFG. A solid mass with abundant Doppler flow signals indicates an S-LCT, LCT, OSCT-NOS or OGCT. Current predictive models are not very effective, but symptoms, sonographic features and serum hormones are helpful for diagnosis.

LncRNA gas5 regulates granulosa cell apoptosis and viability following radiation by X-ray through sponging miR-205-5p and Wnt/β-catenin signaling pathway ingranulosa cell tumor of ovary

Purpose: The study explored the role of lncRNA gas5 in ovarian granulosa cells exposed to X-ray in granulosa cell tumor of ovary(GCTO).
 Methods:Exposed the KGN cell line (KALANG, Beijing, China) to X-ray to mimic the radiotherapy for GCSO patients in vitro, cell viability was checked by CCK8 assays. RT-qPCR detected the RNA expression of apoptosis-related genes while Western Blot for biomarkers in wnt/β-catenin signaling. Differential expressions of lncRNA gas5 were examined after cells exposed to X ray for 0,24,48hs. We over expressed gas5 and assessed resultant cell viabilities, apoptosis and signaling. The sponging between gas5 and miR-205-5p was verified through Luciferase Assay. CCK8, RT-qPCR and Western Blot were applied for investigations into the correlation between miR-205-5p and cell viability and apoptosis after miR-205-5p augmentation. Similarly, the interactions between the gas5 and miR-205-5p were assessed after co-transfection of miR-205-5p mimics and oe-gas5. Last, wnt inhibitor was used to study the role of signaling pathway in KGN cells.
 Results: Exposure of KGN toX-ray reduced cell viabilities and increased apoptosis. Gas5 had reduced expression in cells while miR-205-5p increased. Gas5 upregulation could protect the cells from apoptosis and add to the cell viability and activation of wnt//β-catenin signaling. lncRNA gas5 targeted miR-205-5p and miR-205-5p mimics could counteract functions of up-regulated lncRNA gas5, regulating Wnt/β-catenin signaling pathway. Inactivation in Wnt/β-catenin could suppress cell viability.
 Conclusions: lncRNA gas5 regulated the cell apoptosis and viability after cellular radiation, which might be a potential therapeutic target to combine into radiotherapy for GCTO patients in clinical stage.
 Keywords: Ovary, proliferation, apoptosis, lncRNA gas5, x-ray

Mixtures of persistent organic pollutants increase ovarian granulosa tumor cell line migration and spheroid invasion by upregulating MMP2 expression and activity via IGF1R

Granulosa cell tumors (GCT) of the ovary have a good prognosis. Recurrence tends to be late; however, > 66 % of patients with recurrent GCT die from the disease. Most recurrences are abdominopelvic, although distant metastases have been documented. Here, we tested the hypothesis that a mixture of persistent endocrine-disrupting chemicals (EDCs) stimulates the invasion of GCT cells. We selected perfluorooctanoate (PFOA, 2 ng/mL), perfluorooctanesulfonate (PFOS, 8 ng/mL), 2,2-dichlorodiphenyldichloroethylene (p,p’-DDE, 1 ng/mL), polychlorinated biphenyl 153 (PCB153, 100 pg/mL), and hexachlorobenzene (HCB, 50 pg/mL), which have the highest measured concentrations in follicular fluid of women undergoing treatment with assisted reproductive technology. The human GCT cell lines COV434 and KGN have been used as in vitro models of juvenile (JGCT) and adult (AGCT) GCT subtypes, respectively. Cells were treated with a mixture of the test compounds for 15 min prior to analysis of protein phosphorylation; for 4 h prior to analysis in a circular chemorepellent-induced defect assay; for 6 h prior to analysis of matrix metalloproteinase 2 (MMP2) activity; for 24 h prior to analysis of migration, invasion, and gene expression; and for 48 h prior to analysis of protein expression. First, we showed that KGN cells migrated and exhibited invasive behavior. By contrast, COV434 cells lacked migration and invasion potential. Moreover, expression of mesenchymal genes and the gene encoding MMP2 was higher in KGN cells, and that of epithelial genes lower, than that in COV434 cells. Treatment of KGN cells with the EDC mixture stimulated cell migration, invasion, and lymphatic dissemination. The results suggest that the role of the EDC mixture in AGCT invasion is not related to changes in expression of epithelial and mesenchymal genes; rather, it is related to increased expression and activity of MMP2. Additionally, silencing insulin-like growth factor 1 (IGF1R) in AGCT abolished the stimulatory effect of the EDC mixture on KGN spheroid invasion. These results demonstrate that the EDC mixture increased KGN spheroid invasion by stimulating expression and activity of MMP2 via IGF1R.

Resveratrol depolarizes the membrane potential in human granulosa cells and promotes mitochondrial biogenesis

To study the biological effects of resveratrol on the growth, electrophysiology, and mitochondrial function of human granulosa cells (h-GCs). Preclinical study. Electrophysiology laboratory and invitro fertilization unit. This study included h-GCs from seven infertile women undergoing assisted reproductive techniques. Human ovarian Granulosa Cell Tumor (GCT) cell line COV434 and h-GCs obtained after oocyte retrieval were cultured in the absence or presence of resveratrol. Granulosa cells were evaluated for cell viability and mitochondrial activity. Electrophysiological recordings and evaluation of potassium current (IKur) and Ca2+ concentration were also performed. Resveratrol induced mitochondrial activity in a bell-shaped, dose-effect-dependent manner. Specifically, resveratrol treatment (3 μM, 48 hours) increased ATP production and cell viability and promoted the induction of cellular differentiation. These biological changes were associated with mitochondrial biogenesis. Electrophysiological recordings showed that resveratrol reduced the functional expression of an ultra rapid activating, slow inactivating, delayed rectifier potassium current (IKur) that is associated with a plasma membrane depolarization and that promotes an increase in intracellular Ca2+. CONCLUSION(S): The effects of resveratrol on potassium current and mitochondrial biogenesis in h-GCs could explain the beneficial effects of this polyphenol on the physiology of the female reproductive system. These findings suggest there are therapeutic implications of resveratrol in a clinical setting.

Granulosa Cell Tumors of the Ovary: A Retrospective Tertiary Center Experience

Objective: Granulosa cell tumor (GCT) of the ovary is an uncommon neoplasm with good prognosis. GCT is a rare ovarian malignancy originating from sex cord-stromal cells. The only clinically proven prognostic factor regarding recurrence is stage. In this study, we aimed to analyze the detailed clinical and histopathological prognostic parameters of this rare malignancy, based on the cases we experienced in our own clinic. Material and Methods: Forty-six patients who were followed up and treated with the diagnosis of granulosa cell ovarian tumor between 2010 and 2020 were evaluated retrospectively by scanning the patient archive files. Results: The median follow-up period was 52 months. The mean patient age was 55 years. The most common symptom was abdominal pain. The most common surgical procedure was total abdominal hysterectomy+bilateral salpingo-oophorectomy+pelvic/paraaortic lymph node dissection with 60.9% (n=28). Fertility sparing surgery was performed for 5 (10.9%) patients. In this study, a significant relationship was found between the survival and FIGO stage, nuclear atypia, mitotic rate. The rate of metastatic lymph nodes is very low in primary surgery and therefore may not be performed. Conclusion: GCT is one of the rare diseases of ovary. Since recurrence may occur even after many years, the follow-up period should be kept long. Stage is still the most important prognostic factor and is directly related to survival. In addition, the mitotic rate and nuclear atypia of the tumor may also be prognostic factors and have an impact on survival.

MALIGNANT JUVENILE AND ADULT OVARIAN GRANULOSA CELL TUMORS IN PEDIATRIC PATIENTS - REPORT OF TWO CASES

Juvenile ovarian granulosa cell tumor is a sex chord stromal tumor derived from granulosa cells. It rarely occurs in children. Although it is usually classified as a benign tumor in children due to its good prognosis after surgical intervention, it is a malignant tumor and can be deadly, especially if recurrence occurs. We report two rare cases. The first one is a five-year-old girl with a malignant juvenile ovarian granulosa cell tumor stage 3 FIGO, presenting with abdominal pain in the inferior part of the abdomen and very early pubertal development. On physical examination, she was at stage two puberty. The second case is a 12 years old girl presenting with two periods monthly. An 8.3/5.4cm mass was found at the pelvic region on ultrasound examination. Exploratory laparoscopy with histological examination led to the diagnosis of stage 2A FIGO, combined juvenile and adult ovarian granulosa cell tumor. Conclusion: Precocious puberty accompanying abdominal pain or more than a period in a month is a pointer to juvenile and adult ovarian granulosa cell tumor requiring immediate investigations and patient management. Early diagnosis with the assistance of inhibin test and a FISH test of p53(17p13) aids better management of patients with Juvenile ovarian granulosa cell tumor, preventing tumor recurrence for a favorable outcome. Juvenile and adult ovarian granulosa cell tumors in pediatric female patients can present in different forms but gearing towards menstruation abnormalities.

Salvia miltiorrhiza solution and its active compounds ameliorate human granulosa cell damage induced by H2O2.

The dried roots or rhizomes of Salvia miltiorrhiza Bge are commonly used in Chinese medicine to promote blood circulation and regulate menstruation. Salvianic acid A and salvianolic acid B are the main active water-soluble compounds in Salvia miltiorrhiza solution. The present study investigated the protective effect of Salvia miltiorrhiza solution and its active compounds in H2O2-induced cell damage of the human ovarian granulosa tumor cell line (KGN) in vitro, as well as its underlying mechanism. Cell viability was detected using a Cell Counting Kit-8 assay. In addition, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and tumor necrosis factor-α (TNF-α) were measured. Western blotting was performed to detect the protein expression of cleaved caspase-3 and caspase-9. Furthermore, immunocytochemistry was used to detect the expression of TNF-α. It was demonstrated that Salvia miltiorrhiza solution, salvianic acid A and salvianolic acid B did not affect the viability of KGN cells. Additionally, salvianic acid A and salvianolic acid B significantly reduced the H2O2-induced increased MDA levels, and reversed the H2O2-induced suppression of SOD and GSH activities in KGN cells (P<0.05). Treatment with Salvia miltiorrhiza solution, salvianic acid A and salvianolic acid B significantly reduced the overexpression of cleaved caspase-3, cleaved caspase-9 and TNF-α compared with the H2O2-treated group (P<0.05). Therefore, the present results indicated that Salvia miltiorrhiza solution and its main water-soluble compounds, salvianic acid A and salvianolic acid B, ameliorated KGN cell damage induced by H2O2.

LncRNA gas5 regulates granulosa cell apoptosis and viability following radiation by x-ray via sponging miR-205- 5p and Wnt/β-catenin signaling pathway in granulosa cell tumor of ovary

Purpose: To investigate the role of lncRNA gas5 in ovarian granulosa cells exposed to x-ray in granulosa cell tumor of ovary (GCTO).&#x0D; Methods: KGN cell line was exposed to X-ray to mimic the radiotherapy for GCSO patients in vitro, cell viability was checked by CCK8 assays. RNA expression of apoptosis-related genes was determined by quantitative reverse transcriptase-polymerase reaction (qRT-PCR) while Western Blot for biomarkers in wnt/β-catenin signaling. Differential expressions of lncRNA gas5 were examined after cells were exposed to a ray for 0,24,48hs. We over expressed gas5 and assessed resultant cell viability, apoptosis and signaling. The sponging between gas5 and miR-205-5p was verified by luciferase assay. CCK8, qRT-PCR and Western blot were applied to investigate the correlation between miR-205-5p, cell viability, and apoptosis after miR-205-5p augmentation. Similarly, interaction between gas5 and miR-205-5p was assessed after co-transfection of miR-205-5p mimics and oe-gas5. Finally, wnt inhibitor was used to study the role of signaling pathway in KGN cells.&#x0D; Results: Exposure of KGN to x-ray reduced cell viability and increased apoptosis. Gas5showed reduced expression in the cells, while miR-205-5p expression increased. Gas5 upregulation protected the cells against apoptosis and contributed to cell viability and activation of wnt//β-catenin signaling. lncRNA gas5 targeted miR-205-5p and miR-205-5p mimics counteracted the functions of up-regulated lncRNA gas5, regulating Wnt/β-catenin signaling pathway. Inactivation of Wnt/β-catenin suppressed cell viability.&#x0D; Conclusions: lncRNA gas5 regulates cell apoptosis and viability following cellular radiation, thus presenting a potential therapeutic target for the application radiotherapy in GCTO patients.&#x0D; Keywords: Ovary, Proliferation, Apoptosis, lncRNA gas5, Radiotherapy, β-catenin signaling

Four and a Half LIM Domains 2 (FHL2) Contribute to the Epithelial Ovarian Cancer Carcinogenesis.

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies. To date, the etiology of this deadly disease remains elusive. FHL2, a member of the four and a half LIM domain family, has been shown to serve either as an oncoprotein or as a tumor suppressor in various cancers. Our previous study showed that FHL2 plays a critical role in the initiation and progression of ovarian granulosa cell tumor via regulating AKT1 transcription. However, direct and systematic evidence of FHL2 in the initiation and progression of EOC remains unclear. In the present study, immunohistochemical analysis from EOC patient tissues showed that positivity and intensity of FHL2 immunosignal were up-regulated in the EOC tissues compared with normal ovary tissues. Knockdown of FHL2 in SKOV-3 cell line reduced cell growth and cell viability, blocked cell cycle progression, and inhibited cell migration. Ectopic expression of FHL2 in IGROV-1 cells which have low endogenous FHL2, promoted cell growth, improved cell viability and enhanced cell migration. Additionally, knock down of FHL2 in the SKOV-3 cell line significantly inhibited anchorage-independent growth indicated by the soft agar assay. In comparison, overexpression of FHL2 in IGROV-1 cell improved the colonies growth in soft agar. Western blot data showed that knockdown of FHL2 downregulated AKT expression level, and upregulated apoptosis related proteins such as cleaved PARP, and cleaved-lamin A. Finally, by employing stable SKOV-3/FHL2 stable knock down cell line, our data clearly showed that knockdown of FHL2 inhibited EOC xenograft initiation in vivo. Taken together, our results showed that FHL2, via regulating cell proliferation, cell cycle, and adhesion, has a critical role in regulating EOC initiation and progression. These results indicate that FHL2 could be a potential target for the therapeutic drugs against EOC.

Successfully completed pregnancy after conservative treatment of nonepithelial ovarian cancer

Introduction. Granulosa cell tumors are rare neoplasms of the ovary with low malignancy potential and late recurrence. They originate from the granulose of the ovary stromal cells and have the ability to produce estrogen. The main treatment is surgical and implies hysterectomy with bilateral salpingooophorectomy, omentectomy, taking peritoneal biopsies, and cytological analysis of the peritoneal washing. When found in young women who have not given birth, a conservative approach can be considered. Fertility sparing surgery is safe only for early FIGO (Federation Internationale de Gynecologie et d?Obstetrique) stages IA tumors ?? IC, where it is necessary to make unilateral salpingo-oophorectomy and complete staging. Case outline. We present a case of young woman with granulosa cell tumor who was accidentally discovered, and after an adequate surgery and chemotherapy she gave a birth to a healthy child. Conclusion. Young women who have not given birth and who have been diagnosed with granulosa cell ovarian tumor can be treated conservatively after adequate disease staging and confirmation that the disease is at an early stage.

S2447 Acute Abdominal Pain; The Answer Lies in the Remote History

INTRODUCTION: Granulosa cell tumors (GCT) encompass 2-3% of ovarian tumors characterized by low malignancy potential and late relapse, which rarely metastasize to the liver. We describe a patient with a recurrent ovarian GCT with liver and diaphragm metastasis 12 years after her initial diagnosis. CASE DESCRIPTION/METHODS: 51-year-old diabetic female with a history of cholecystectomy, and stage IA granulosa cell tumor status post total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-SBO) with post-procedure chemotherapy with carboplatin-taxol in 2008, currently in remission; presented with intermittent and sharp right upper quadrant abdominal pain for a week. Her liver chemistry showed ALT: 379; AST: 254; ALP: 171 U/l. Her viral markers were negative. Abdominal imaging showed a new subcapsular liver lesion involving the right hepatic lobe concerning for hematoma versus metastases. MRI showed a persistent hepatic subcapsular process of unclear etiology. Diagnostic laparotomy was performed which showed multiple implants of soft, removable tissue throughout the dome of the liver, and the diaphragm. Pathology revealed granulosa cells consistent with the recurrence of granulosa cells as liver metastasis. The patient was later discharged with multidisciplinary outpatient follow up. DISCUSSION: Granulosa cell tumors (GCT) are the most common type of sex cord-stromal tumors which represent 2–3 % of total ovarian tumors. GCT tends to bleed, often presenting with intrapelvic bleeding and lower abdominal pain. They are associated with a favorable prognosis, especially when they are detected in the early stages. Reported 5-year survival rates range from 55% to 97%. Several series have shown the recurrence rates range between 9 and 35%. GCTs are associated with a low incidence of hepatic metastasis (<5–6%). Call-Exner bodies are pathognomonic for its diagnosis with immunohistochemistry analysis positive for CD56, CD99, inhibin-alfa, and S-100. Long-term free disease periods can prolong in some cases to more than 20 years. Surgical resection of the liver lesion remains to be the most successful approach to provide a better percentage of remission, quality of life, and disease-free intervals despite its possible complications. It is usually followed by systemic chemotherapy to obtain better tumor control and an improved long-term survival rate.Figure 1.: Subcapsular process along the right lobe of the liver.Figure 2.: Lower and high magnification tumor cells consistent with granulosa cell tumor.Figure 3.: Call-exner body.

Clinical and histological criteria for sex cord ovarian stromal tumors

Aim: to identify clinical and histological criteria for sex cord ovarian stromal tumors (OSTs).Materials and Methods. The retrospective non-comparative study was based on the main inclusion such as histologically verified sex cord OSTs. A standard examination algorithm was analyzed (ultrasound, blood tests, CT or MRI of the abdominal and pelvic organs). All clinical data were obtained from patients treated and monitored in clinical units at the Blokhin National Medical Research Center of Oncology and the National Center of Oncology and Hematology of the Kyrgyz Republic.Results. Data were obtained on the frequency of necrobiotic changes, malignancy, disease stages and their impact on survival in 456 patients. The 10-year survival rate for OSTs patients with vs. without intra-tumor necrobiotic changes was significantly lower (17.2 % and 78.1 %, respectively).Conclusion. The main factors of unfavorable prognosis in patients with granulosa cell ovarian tumors were disease stage and intra-tumor necrobiotic changes.

Magnetic Resonance Imaging of Recurrent Adult Granulosa Cell Tumor of the Ovary: A Retrospective Analysis of 11 Cases.

ObjectiveThe aim of the study was to characterize magnetic resonance imaging findings in patients with recurrent ovarian adult granulosa cell tumors (AGCTs).MethodsClinical and magnetic resonance imaging manifestations of recurrent AGCTs were evaluated in 11 patients.ResultsInitial recurrences of AGCT were diagnosed between 13 months and 30 years (mean, 11.3 years). Recurrent tumors were located in the pelvic peritoneum, the abdominal peritoneum, the retroperitoneum, and bone. The number of recurrent tumors varied from 1 to 5. Tumors varied in morphology and all margins were well circumscribed. The internal structures noted were as follows: multilocular cystic and solid and cystic. Furthermore, internal hemorrhage and sponge-like multicystic components were identified.ConclusionsOvarian AGCTs recurred in the pelvic peritoneum, abdominal peritoneum, and the retroperitoneal lymph nodes. Large recurrent AGCTs were commonly well circumscribed, round or lobulated, and multilocular cystic or solid and cystic. Moreover, they frequently included internal hemorrhage and sponge-like multicystic components.

Rare DICER1 and Absent FOXL2 Mutations Characterize Ovarian Juvenile Granulosa Cell Tumors.

FOXL2 somatic mutation occurs in a high percentage of ovarian adult granulosa cell tumors and DICER1 mutations in a high proportion of Sertoli-Leydig cell tumors. These mutations have only been studied in a limited number of juvenile granulosa cell tumors (JGCTs), and their occurrence and frequency in these neoplasms is controversial. We aimed to determine the frequency of FOXL2 and DICER1 mutations in a large cohort of 50 JGCTs, and to evaluate the prognostic impact of these mutations. A FOXL2 hotspot mutation was found in 2/50 JGCTs. Review of these 2 cases reclassified them as adult granulosa cell tumors. Thus, FOXL2 mutation was absent from our large cohort of JGCTs. DICER1 mutations in the RNase IIIb domain were found in 4 cases. After review of the mutated cases, 1 was reclassified as a gynandroblastoma with a prominent JGCT component. Thus, DICER1 mutations were detected in 3/47 (6%) of pathologically confirmed JGCTs. Our results show that FOXL2 mutations are not present in JGCT, whereas a small percentage of these neoplasms exhibit DICER1 mutations.

Mutant FOXL2C134W Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors.

The mutant protein FOXL2C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2C134W contributes to tumorigenesis is not known. Here, we show that mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2C134W also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2C134W binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2C134W. Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2C134W and its interaction with SMAD4 as potential therapeutic targets to this condition. SIGNIFICANCE: FOXL2C134W hijacks SMAD4 and leads to the expression of genes involved in EMT, stemness, and oncogenesis in AGCT, making FOXL2C134W and the TGFβ pathway therapeutic targets in this condition. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3466/F1.large.jpg.

Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target

Granulosa cell tumors (GCT) are rare ovarian malignancies. Due to the lack of effective treatment in late relapse, there is a clear unmet need for novel therapies. Forkhead Box L2 (FOXL2) is a protein mainly expressed in granulosa cells (GC) and therefore is a rational therapeutic target. Since we identified tumor infiltrating lymphocytes (TILs) as the main immune population within GCT, TILs from 11 GCT patients were expanded, and their phenotypes were interrogated to determine that T cells acquired late antigen-experienced phenotypes and lower levels of PD1 expression. Importantly, TILs maintained their functionality after ex vivo expansion as they vigorously reacted against autologous tumors (100% of patients) and against FOXL2 peptides (57.1% of patients). To validate the relevance of FOXL2 as a target for immune therapy, we developed a plasmid DNA vaccine (FoxL2–tetanus toxin; FoxL2-TT) by fusing Foxl2 cDNA with the immune-enhancing domain of TT. Mice immunization with FoxL2-TT controlled growth of FOXL2-expressing ovarian (BR5) and breast (4T1) cancers in a T cell–mediated manner. Combination of anti–PD-L1 with FoxL2-TT vaccination further reduced tumor progression and improved mouse survival without affecting the female reproductive system and pregnancy. Together, our results suggest that FOXL2 immune targeting can produce substantial long-term clinical benefits. Our study can serve as a foundation for trials testing immunotherapeutic approaches in patients with ovarian GCT.

Application of molecular analysis in differential diagnosis of ovarian adult granulosa cell tumors

Objective: To investigate the application value of molecular detection in the differential diagnosis of ovarian adult granulosa cell tumors (AGCT) by analyzing FOXL2, AKT1 and DICER1 mutations in these tumors. Methods: A total of 48 cases of ovarian sex cord-stromal tumor (SCST) were selected from July 2012 to June 2019 in Beijing Obstetrics and Gynecology Hospital, including 21 adult granulosa cell tumors (AGCT), 15 fibromas/fibrothecomas, 8 Sertoli-Leydig cell tumors (SLCT) and 4 other types of ovarian SCST. Genomic DNA was extracted from the formalin-fixed paraffin-embedded tissue sections. Polymerase chain reaction amplification for FOXL2, AKT1 and DICER1 genes was performed, followed by sequencing using capillary electrophoresis. Fisher exact test was used to compare the prevalence difference of FOXL2, AKT1 and DICER1 mutations among the groups. P<0.05 was considered significant. Results: Eighteen of the 21 (85.7%) AGCT harbored FOXL2 mutation. Compared with other SCST (13.0%, 3 of 23; including fibromas/fibrothecomas and SLCT), FOXL2 mutation was significantly higher in AGCT (P<0.001). In addition, FOXL2 mutation was also detected in one fibrothecoma, two SLCT and two gynandroblastomas. DICER1 mutation was identified in four of eight SLCT, and these cases were moderately to poorly differentiated. FOXL2 mutation was found in one SLCT with DICER1 mutation. There was no DICER1 mutation in other ovarian SCST. No AKT1 mutation was detected in all the patients. Conclusions: FOXL2 mutation is a highly specific biomarker for adult AGCT and may be helpful to resolve problematic cases. Diagnosis should also be taken into consideration of the clinical and histological features as FOXL2 mutation is also found in other SCST. The detection of DICER1 mutation is helpful for the differential diagnosis of ovarian SLCT. Synchronous DICER1 and FOXL2 mutation in the SLCT has been observed, and its significance needs to be further studied.

Inhibin B in diagnosis and monitoring of granulosa-cell tumors of ovary

Introduction. Granulosa cell tumors of ovary (GCTO) rare type of malignant ovarian neoplasms formed from granulosa cells of the follicles capable to produce biologically active substances, including inhibin B. The purpose of this study is evaluation of clinical significance of inhibin B analysis in blood serum of patients with adult type of GCTO primary disease, relapse and during remission after treatment.&#x0D; Materials and methods. The study included 134 patients with GCTO, 15 patients with benign ovarian tumors and 82 healthy women. Inhibin B was determined in blood serum with standard enzyme-linked immunosorbent assay Inhibin B Gen II ELISA (Beckman Coulter, USA) in the microplate format.&#x0D; Results. The analysis data indicates a high sensitivity of inhibin B in the diagnosis of primary GCTO (92.3%) and in relapse (92.7%) with a specificity 100%. An increase of inhibin B before the clinical manifestation of relapse (for 212 months) confirms its significance as an effective biochemical marker for GCTO monitoring.&#x0D; Conclusion. Inhibin B can be used as effective biochemical marker of primary and GCTO and its relapses.

Endometrial mineralisation in a bitch with ovarian granulosa cell tumour and cystic endometrial hyperplasia-pyometra complex

Granulosa cell tumour is a common ovarian pathology in bitches. Depending on its hormonal production, this tumour often induces persistent oestrus signs and uterine disorders. Chronic treatment with progesterone contraceptives...

"Coffe Bean" Nucleic in a Rare Case of Ovarian Adult Granulosa Cell Tumor

Granulosa cell tumors represent only 1% of the total number of ovarian tumors. “Coffee bean” nuclei represent an extremely rare feature of these tumors. We presented the case of a 66-year-old patient that was hospitalized for abdominopelvic pain, lately to be diagnosticated with an Adult Granulosa Cell Tumor. The histopathological analysis revealed Call-Exner corpuscles and Coffee Bean” nuclei. A positive S100 marker was a particular finding in the immunohistochemical profile. Treatment strategy for this kind of case should include surgery and adjuvant treatment and a strict follow-up of the patient for at least 5-10 years.