Ovarian Granulosa Cell Tumors Research Articles

A case series of non-small cell lung cancer patients with EGFR or HER2 exon 20 insertion in Li Fraumeni syndrome.

Germline pathogenic mutations in TP53 gene are associated with a cancer predisposition syndrome known as Li Fraumeni syndrome. Albeit infrequently, non-small cell lung cancer, especially as oncogene-addicted disease, may be diagnosed in young patients with Li Fraumeni syndrome. We report three cases of patients affected by Li Fraumeni syndrome who developed non-small cell lung cancer with EGFR or HER2 exon 20 insertions. The first patient suffered from liposarcoma and, then, brain metastases from HER2-mutated non-small cell lung cancer: after stereotactic radiotherapy, he benefited from enrollment in a clinical trial with a HER2-targeted therapy. The second young patient was a female with personal history of rhabdomyosarcoma, diagnosed with brain metastases from EGFR-mutated non-small cell lung cancer: enrollment in a clinical trial led to a temporary clinical benefit. The last case was a female diagnosed with breast carcinoma, ovarian granulosa cell tumor and advanced EGFR-mutated non-small cell lung cancer at a young age. Young patients affected by oncogene-addicted non-small cell lung cancer and with a positive familial cancer history should be referred for an accurate genetic counselling to look for Li Fraumeni syndrome. The underlying molecular connection between TP53 and HER family receptor tyrosine kinases remains unclear, but an extensive molecular characterization of tumors from patients with Li Fraumeni syndrome should always be performed, to offer patients a personalized therapeutic approach.

Determination of anti-Müllerian hormone levels in blood and urine in fertile cats

In recent years, blood anti-Müllerian hormone (AMH) levels have been investigated in female animals to diagnose many conditions, such as the presence of ovarian tissue, follicle reserve, and granulosa cell tumors. Since blood collection is an invasive method, diagnosis with a non-invasive method is important in terms of practicality and animal welfare. This study aimed to investigate the presence of AMH in cat urine and determine whether a correlation exists between blood and urine AMH levels. In addition, it was aimed at revealing whether there was a change in blood and urine AMH levels according to ovarian follicle distribution. Twenty-seven healthy, fertile female cats in the follicular phase were included. Following blood and urine sample collection, a routine ovariohysterectomy was performed. Histological analysis of the removed ovarian tissue was used to determine ovarian follicle types. While both AMH and estrogen levels were determined in blood samples, only AMH levels were investigated in urine samples. Blood AMH levels averaged 10.61 ± 0.75 ng/mL (range: 5–16 ng/mL), while urine AMH levels averaged 5.67 ± 0.91 ng/mL (range: 0.2–13 ng/mL). While urinary AMH level was <1 ng/mL in 7 cats, urinary AMH was >1 ng/mL in all remaining cats. While the study demonstrated AMH excretion in urine, no correlation was found between blood and urine AMH values. However, a significant positive correlation was observed between blood AMH levels and serum estrogen levels (P < 0.001). These findings suggest that urinary AMH may be a product of proteolytic degradation, potentially leading to inaccurate estimations of ovarian activity based solely on urine AMH levels.

Human mesenchymal stem cells derived exosomes improve ovarian function in chemotherapy-induced premature ovarian insufficiency mice by inhibiting ferroptosis through Nrf2/GPX4 pathway.

Chemotherapy exposure has become a main cause of premature ovarian insufficiency (POI). This study aimed to evaluate the role and molecular mechanism of human umbilical cord mesenchymal stem cell-derived exosomes (hUMSC-Exos) in ovarian function protection after chemotherapy. hUMSC-Exos were applied to cyclophosphamide-induced premature ovarian insufficiency mice and human ovarian granulosa tumor cells (KGN) to determine their effects on follicular development and granulosa cell apoptosis. Evaluation was done for iron ion and reactive oxygen species (ROS) production, lipid peroxidation levels, and changes in iron death-related molecules (nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Glutathione Peroxidase enzyme 4 (GPX4), and Solute carrier family 7 member 11 cystine glutamate transporter (SLC7A11; xCT)). Furthermore, rescue experiments using an Nrf2 inhibitor were performed to assess the therapeutic effects of hUMSC-Exos on granulosa cells. hUMSC-Exos promoted ovarian hormone levels and primary follicle development in POI mice and reduced granulosa cell apoptosis. After hUMSC-Exos treatment, the ROS production, free iron ions and lipid peroxidation levels of granulosa cells decreased, and the iron death marker proteins Nrf2, xCT and GPX4 also decreased. Furthermore, the Nrf2 inhibitor ML385 significantly attenuated the effects of hUMSC-Exos on granulosa cells. hUMSC-Exos inhibit ferroptosis and protect against CTX-induced ovarian damage and granulosa cell apoptosis through the Nrf2/GPX4 signaling pathway, revealing a novel mechanism of hUMSC-Exos in POI therapy.

Granulosa Cells-Related MicroRNAs in Ovarian Diseases: Mechanism, Facts and Perspectives.

MicroRNAs (miRNAs) are a class of short single-stranded, noncoding RNAs that affect the translation of mRNAs by imperfectly binding to homologous 3'UTRs. Research on miRNAs in ovarian diseases is constantly expanding because miRNAs are powerful regulators of gene expression and cellular processes and are promising biomarkers. miRNA mimics, miRNA inhibitors and molecules targeting miRNAs (antimiRs) have shown promise as novel therapeutic agents in preclinical development. Granulosa cells (GCs) are supporting cells for developing oocytes in the ovary. GCs regulate female reproductive health by producing sex hormones and LH receptors. Increasing research has reported the relevance of miRNAs in GC pathophysiology. With in-depth studies of disease mechanisms, there are an increasing number of studies on the biomolecular pathways of miRNAs in gynecology and endocrinology. In the present review, we summarize the different functions of GC-related microRNAs in various ovarian disorders, such as polycystic ovary syndrome, premature ovarian insufficiency, premature ovarian failure and ovarian granulosa cell tumors.

Abstract CT109: Livmoniplimab and budigalimab combination therapy in treating patients with metastatic ovarian granulosa cell tumors: Results from dose escalation in a first-in-human study

Abstract Background: Ovarian granulosa cell tumors (OGC) are rare, accounting for 5-7% of all ovarian cancers and fatal when metastatic. There are no approved targeted therapies for metastatic OGC. Several agents with different targets, such as pembrolizumab, nirogacestat, orteronel, and STM 434, are being evaluated but to date have not shown clinical benefit. Most OGC carry a C134W mutation in the FOXL2 gene, which manifests its protumor effects via the transforming growth factor (TGF)-β signaling pathway. Livmoniplimab (livmo) is a monoclonal antibody (mAb) that specifically binds to the TGF-β1-glycoprotein-A repetitions predominant protein complex, blocking the release of active TGF-β1. Livmo has been assessed with or without budigalimab (budi), an anti-PD-1 mAb, in the dose escalation (ESC) part of a first-in-human study in patients (pts) with advanced solid tumors, including OGC. Herein, we report results of 4 pts with OGC enrolled into the combination ESC part of this phase 1 study (NCT03821935). Methods: Pts ≥18 years with ECOG PS 0-1 were enrolled in ESC, including pts with metastatic OGC refractory to/not eligible for standard therapies. The maximum tolerated dose was not reached, and pts received the maximum administered dose of 1500 mg livmo (Q2W IV) + 500 mg budi (Q4W IV). Safety and overall response rate (ORR) per RECIST v1.1 were assessed. Results: As of 28 Sep 2023, 57 pts were enrolled in ESC, including 4 with metastatic OGC aged 50-63 years who received 3-7 prior lines of systemic therapy. In total, 98% (n=56) pts in ESC experienced TEAEs, most commonly fatigue (42%), nausea (37%), and anemia (37%). One pt with OGC was enrolled in the study with metastatic target lesions in the lung, liver, and peritoneum at screening. She had received 7 prior lines of therapy including doxorubicin, bevacizumab, anastrozole, tamoxifen, and carboplatin + paclitaxel. Upon treatment with livmo + budi, she had a deep partial response (-92% from baseline) and a complete response in the target liver lesion. The pt stayed in response for ~2.5 years before death due to an event unrelated to study drugs. Furthermore, 2 other pts with metastatic OGC had a partial response (ORR=75%) and none of the 4 pts with OGC experienced disease progression (disease control rate=100%). Conclusions: Livmo + budi had promising antitumor efficacy and a tolerable safety profile in pts with metastatic OGC, a rare TGF-β signaling-dependent tumor. All enrolled pts with OGC showed tumor shrinkage and 1 pt had durable and near-complete response. Since single-agent pembrolizumab exhibited an ORR of 0% in pts with OGC (How et al. Invest New Drugs, 2021;39:829-835), we conclude that OGC is a proof-of-mechanism indication for livmo and that targeting TGF-β may represent an effective strategy for treating pts with OGC. Citation Format: Ildefonso Rodriguez Rivera, David Sommerhalder, Mohammad Sahtout, Cristiano Ferlini, Duyen Ngo, Sujata Jha, John Engelhardt, Anthony Tolcher. Livmoniplimab and budigalimab combination therapy in treating patients with metastatic ovarian granulosa cell tumors: Results from dose escalation in a first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT109.

Clinicopathologic Characteristics of a Single-institution Cohort of Ovarian Adult Granulosa Cell Tumors, With Biomarker and Therapeutic Implications Utilizing the Detection of Androgen, Estrogen, and Progesterone Hormone Receptor Expression by Immunohistochemistry.

Adult granulosa cell tumors (AGCTs) are rare ovarian tumors with generally good prognosis after surgical resection; however, they do have recurrence potential. Therapeutic and management options for recurrences are currently limited, and the need for expanded adjuvant therapies is increasingly recognized. Anti-hormonal therapy is being explored as an option, which relies on the detection and assessment of hormone receptor expression (androgen, estrogen, and progesterone receptors) as a biomarker and therapeutic target. Our study identifies several clinicopathologic characteristics with significant associations for recurrence of AGCT, which were younger age, higher stage, and larger tumor size. Our study also demonstrates that androgen receptor (AR) expression may be utilized as a potential biomarker for hormonal therapy and that detection of AR expression in AGCT by immunohistochemistry (IHC) varies depending on the antibody clone used for testing. AR was detected in 95% of samples tested with antibodies derived from clone AR27. This detection rate is much higher than previously reported.

Juvenile granulosa cell ovarian tumors: Report of a case

Juvenile granulosa tumors of the ovary are rare tumors. We report the case of juvenile granulosa cell tumor affecting a 33-year-old woman operated on for pain pelvic, the tumor was located in the left ovary with moderate ascites. The purpose of this work is to present the anatomoclinical and radiological characteristics of this tumor in order to allow an early diagnosis and to improve its prognosis, to establish a therapeutic chronology for this tumor. Different prognostic factors for ovarian granulosa cell tumor are being studied; the treatment is surgical.

Abstract B057: Oncogenic Foxl2 directs enhancer reprogramming and changes in 3D genome structure in ovarian granulosa cell tumors

Abstract Background: Adult-type granulosa cell tumors (aGCTs) are a rare monogenic disease. Nearly all aGCTs carry a missense point mutation in the Forkhead domain containing FOXL2 (Foxl2 p.C134W) transcription factor, but the oncogenic mechanism of this mutation is unknown. Other Forkhead family transcription factors have well-described “pioneer” activity, binding to compacted, nucleosome-bound DNA and increasing accessibility for other regulatory proteins. Objectives: To investigate if oncogenic Foxl2-C134W has pioneering activity and if mutant Foxl2 operates its oncogenic activity through enhancer reprogramming. Methods: CRISPR/Cas9 editing was used to generate isogenic granulosa cell tumor cells lacking either the FOXL2 wild-type allele (single knock-out; SKO) or both the mutant and wild-type FOXL2 alleles (double knock-out; DKO). ATAC-Seq and endogenous Foxl2 ChIP-Seq were performed on these isogenic lines to determine the differential chromatin accessibility at Foxl2-bound regulatory regions across genotypes. Promoter capture HiC was performed using a bespoke genome-wide hybrid capture probe set, CHiCAGO was used to identify significant HiC interactions, and an activity-by-contact model was constructed to identify enhancer elements bound by endogenous Foxl2-C134W and determine their target promoter contact frequency (promoter capture HiC) and enhancer activity (geometric mean of H3K27ac and ATACseq signal. Results: Endogenous ChIP-seq of Foxl2-C134W from the SKO cell line identified 1147 high-confidence peaks. De novo motif discovery identified the canonical Foxl2 binding motif (TGTTTACATT, P = 1.4 × 10−7) in 44.9% of peaks, as well as a novel variant motif (TGTTTTGTCT, P = 6.7 × 10−15) in 68.5% of peaks. Median chromatin accessibility at Foxl2-C134W peak regions, as measured by ATAC-seq, was significantly decreased in the DKO cells compared to either SKO or parental cell lines (P &amp;lt; 2 × 10-16 for both comparisons). Decreased chromatin accessibility at Foxl2-C134W ChIP-seq peaks in the DKO cells was driven by peaks containing the novel variant Foxl2 binding motif. Promoter capture HiC through activity-by-contact model identified promoter-enhancer interactions lost in the DKO cell line involving several genes, including ADAMTS5, FOXF2, and PRICKLE1 (adjusted P &amp;lt; 0.05). Conclusion: Foxl2-C134W exhibits “pioneering” activity, increasing chromatin accessibility at key gene regulatory elements with associated re-programming of promoter-enhancer interactions. The oncogenic mechanism of Foxl2-C134W in granulosa cell tumors may involve changes in DNA binding specificity, re-directing this pioneering function to sites containing a novel variant Foxl2 binding motif. Citation Format: Veena K. Vuttaradhi, Eleonora Khlebus, Thomas Welte, Barrett Lawson, Robert Tyler Hillman. Oncogenic Foxl2 directs enhancer reprogramming and changes in 3D genome structure in ovarian granulosa cell tumors [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B057.

Abstract A023: Pre-clinical evaluation of the gamma-secretase inhibitor nirogacestat in an adult-type ovarian granulosa cell tumor model

Abstract Introduction: Adult type ovarian granulosa cell tumors (GCTs) represent 5-7% of ovarian cancers and are the most common subtype of ovarian sex cord stromal tumors. Primarily driven by a C134W mutation in FOXL2 (present in ~97% of tumors), GCTs have a tendency for late recurrence without effective treatment options. Expression of mutant FOXL2 results in modified binding to transcription factors, including members of the SMAD family, and changes in apoptotic pathway signaling. Notch is an essential pathway for development of the ovary and plays important roles in the post-natal ovary including regulation of folliculogenesis, meiosis, vasculogenesis, and steroid hormone production. Notch signaling has been shown to promote FOXL2 expression, and cleavage of the Notch intracellular domain (NICD) by the enzyme gamma secretase (GS) can enhance SMAD signaling and promote interactions of SMADs with binding partners, including NICD. Emerging evidence suggests that Notch signaling, which is activated by GS-mediated cleavage, can promote tumor growth. Nirogacestat is an investigational, oral, small-molecule, selective gamma-secretase inhibitor (GSI) which, in a phase 3 study in patients with progressing desmoid tumors, significantly improved progression-free survival compared with placebo. Previous studies showed that inhibition of Notch signaling in a granulosa tumor cell line by the GSI “DAPT” could increase apoptosis and inhibit proliferation. Therefore, this study sought to evaluate effects of nirogacestat in FOXL2 C134W mutant granulosa cells. Methods: The effects of nirogacestat were evaluated in vitro using the “KGN” GCT cell line, which harbors a FOXL2 C134W mutation. Cell proliferation of KGN cells was analyzed by MTT assay, and clonogenic survival was analyzed using crystal violet staining in a dose-response assay. Furthermore, gene expression analysis of markers of cell cycle (TOP2A, CCNE2), epithelial to mesenchymal transition (SNAI2, MMP2), and apoptosis (CASP6) was performed by qPCR. Results: Nirogacestat significantly inhibited the proliferation of KGN cells in a dose-dependent manner. Similarly, clonogenic survival was significantly reduced after 10 days of treatment and correlated with administered concentration of nirogacestat treatment in vitro. We also observed a significant reduction in the expression of cell cycle markers TOP2A and CCNE2 by qPCR after 1 week of treatment with nirogacestat. Additionally, we found a significant induction of the apoptotic marker CASP6 and reductions of the EMT markers SNAI2 and MMP2 after high-dose treatment with nirogacestat. Conclusion: Treatment of the KGN GCT cell line with nirogacestat in vitro inhibited cell proliferation and growth in a concentration-dependent manner. Furthermore, nirogacestat markedly inhibited the expression of cell cycle markers, suggesting a cytostatic effect in granulosa cells which aligns with results from studies in desmoid tumor models. Collectively, these data suggest that nirogacestat represents a potential novel therapeutic agent for treatment of adult type GCTs. Citation Format: Maeva Y. Chauvin, David Pépin. Pre-clinical evaluation of the gamma-secretase inhibitor nirogacestat in an adult-type ovarian granulosa cell tumor model [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A023.

Abstract A068: Dual multiplexing analysis of the tumor immune microenvironment of rare ovarian granulosa cell tumors identified predictors of recurrence and potential therapeutic targets

Abstract Ovarian granulosa cell tumors (GCT) are a rare neoplasm of the ovary representing 2-5% of all ovarian cancers. Although most women are diagnosed at an early stage, the slow pattern of progression combined with a high rate of recurrence leads to ~80% of women succumbing to the disease. Prevention of recurrence is of importance in GCT patients. Typically, recurrences occur within 5-10 years making reliable prognostic indicators or predictors of recurrence a challenge. Identification of the tumor immune profile could clarify how these factors facilitate the balance between pro-tumor and anti-tumor immunity and furthermore improve patient survival. As GCTs are rare tumors and tissue availability is very limited, we used a dual multiplexing approach in order to maximize the data output from a total of 14 FFPE tumor samples (6 primary tumors, and 8 recurrent tumors). With this approach we used a single 4μm section to detect 15 markers in an immunofluorescence multiplexing assay, and an adjacent 10μm section to analyze expression of 770 immuno-related cancer genes using the Nanostring nCounter assay PanCancer Immune Panel, with the aim to spatially profile immune cell subsets, angiogenic vessels, as well as markers differentially expressed between primary and recurrent tumors. On the protein level we confirmed previous findings that ovarian GCTs are “cold” tumors, with a very low density of T cell infiltration. Likewise, levels of CTLA-4, PD-1, and PD-L1 were very low in all GCTs. When we analyzed the presence of tumor associated macrophages (TAMs) in the tumor microenvironment (TME) however, we found a 113% increase in TAM density in recurrent tumors compared to primary tumors, corresponding to an increase in the macrophage score on the mRNA level. Furthermore, nearest neighbor analysis of the proximity between M2-type TAMs and angiogenic vessels in the TME, demonstrated M2 TAMS to be much closer associated with the vessels in recurrent tumors compared to primary tumors. We detected a differential gene expression for 66 genes in recurrent tumors compared to primary tumors. IDO1, a key regulator of immune tolerance, showed the highest differential with a significant 14-fold increase in recurrent tumors and thereby represents a therapeutic target within immuno-oncology beyond checkpoint blockade. Additionally, we found SPP1 (the gene coding for osteopontin) to have a 9-fold higher expression in recurrent versus primary GCT tumors, while VEGFA was found to have a 10-fold higher expression. As a pro-inflammatory cytokine osteopontin is thought to both facilitate the recruitment of TAMs and to stimulate angiogenesis by inducing VEGF expression in endothelial cells, suggesting that osteopontin could be a therapeutic target in patients with recurrent GCT. Taken together, these data support the utility of a dual multiplexing approach to immunoprofiling the TME of rare ovarian granulosa cell tumors to identify novel targets for further investigation. Citation Format: Tyvette S. Hilliard, Anna Juncker-Jensen. Dual multiplexing analysis of the tumor immune microenvironment of rare ovarian granulosa cell tumors identified predictors of recurrence and potential therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A068.

MiR-128-3p Regulates Follicular Granulosa Cell Proliferation and Apoptosis by Targeting the Growth Hormone Secretagogue Receptor.

The proliferation and apoptosis of granulosa cells (GCs) affect follicle development and reproductive disorders, with microRNAs playing a crucial regulatory role. Previous studies have shown the differential expression of miR-128-3p at different stages of goat follicle development, which suggests its potential regulatory role in follicle development. In this study, through the Cell Counting Kit-8 assay, the EDU assay, flow cytometry, quantitative real-time polymerase chain reaction, Western blot, and the dual-luciferase reporter assay, we used immortal human ovarian granulosa tumor cell line (KGN) cells as materials to investigate the effects of miR-128-3p and its predicted target gene growth hormone secretagogue receptor (GHSR) on GC proliferation and apoptosis. The results show that overexpression of miR-128-3p inhibited the proliferation of KGN cells, promoted cell apoptosis, and suppressed the expression of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma-2 (BCL2) while promoting that of Bcl-2 associated X protein (BAX). The dual-luciferase reporter assay revealed that miR-128-3p bound to the 3' untranslated region sequence of GHSR, which resulted in the inhibited expression of GHSR protein. Investigation of the effects of GHSR on GC proliferation and apoptosis revealed that GHSR overexpression promoted the expression of PCNA and BCL2, enhanced GC proliferation, and inhibited cell apoptosis, whereas the opposite effects were observed when GHSR expression was inhibited. In addition, miR-128-3p and GHSR can influence the expression of extracellular signal-regulated kinase 1/2 protein. In conclusion, miR-128-3p inhibits KGN cell proliferation and promotes cell apoptosis by downregulating the expression of the GHSR gene.

Novel FOXL2 Mutation in an Ovarian Adult Granulosa Cell Tumor: Report of a Case With Diagnostic and Clinicopathologic Implications.

Adult granulosa cell tumor, the most common malignant ovarian sex cord-stromal tumor, harbors the characteristic mutation c.402C>G (p.C134W) in the FOXL2 gene in ~90% to 95% of cases. To date, no other variants of FOXL2 mutations have been identified in these tumors. Here we report the first case of an adult granulosa cell tumor with a novel FOXL2 point mutation c.398C>T (p.A133V) presenting in a 64-year-old postmenopausal woman. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy for atypical endometrial hyperplasia and gross examination revealed an incidental 3.2cm right ovarian mass with a solid, bright yellow, homogeneous cut surface. Microscopically, ~30% of the tumor showed a nested growth pattern composed of uniform tumor cells with oval nuclei and a moderate amount of pale cytoplasm, while the remaining areas consisted of a bland storiform fibromatous stroma. Reticulin stain demonstrated loss of the individual pericellular network within the nested areas, while the pericellular staining pattern was retained in the background stromal component. FOXL2 sequencing analysis was performed in both components and revealed a c.398C>T (p.A133V) mutation in the nested component, whereas wild-type FOXL2 sequence was identified in the fibromatous stroma. Sections from the uterus showed a low-grade endometrioid endometrial adenocarcinoma with superficial myometrial invasion. The patient underwent adjuvant vaginal cuff brachytherapy for the endometrial carcinoma and is alive and well at 8 months follow-up. This case illustrates that new FOXL2 mutations may be detected in ovarian sex cord-stromal tumors with increasing use of routine molecular testing, adding to the complexity of the pathologic diagnosis. In the right morphologic and clinical context, a FOXL2 mutation-even if it is different from the dominant hotspot mutation c.402C>G (p.C134W)-can support the diagnosis of adult granulosa cell tumor.

Adult-type granulosa cell tumor associated with elevated luteinizing hormone: Two rare case reports.

Adult-type granulosa cell tumors (AGCTs), which account for 2% to 5% of all malignant ovarian tumors, are rare sex cord-stromal tumors that usually secrete excess estrogens, but they can also secrete androgens. We report 2 patients of childbearing age with AGCT who presented with the complaint of abnormal menstruation and elevated luteinizing hormone (LH), and mildly elevated testosterone. The ovarian tumors had hormonal activity. The 2 patients underwent laparoscopic left adnexectomy. The second patient underwent 4 cycles of chemotherapy with paclitaxel and carboplatin as adjuvant treatments. Their postoperative pathology confirmed AGCTs. Also, their menstrual cycle returned to normal, with normal serum LH and testosterone levels. There was no sign of recurrence. The cases suggest that elevated serum LH levels may be a sign of unknown tumors in cases of oligomenorrhea or secondary amenorrhea. It is useful to evaluate the serum levels of inhibin B and anti-Müllerian hormone to improve the early recognition of ovarian granulosa cell tumors.

Defining the relationship between ovarian adult granulosa cell tumors and synchronous endometrial pathology: Does ovarian tumor size correlate with endometrial cancer?

The main feature of adult granulosa cell tumors (AGCT) is their capacity to secrete hormones, with nearly all of them capable of synthesizing oestradiol. The primary goal of this study is to identify synchronized endometrial pathologies, particularly endometrial cancer, in AGCT patients who had undergone a hysterectomy. The study cohort comprised retrospectively of 316 AGCT patients from 10 tertiary gynecological oncology centers. AGCT surgery consisted of bilateral salpingo-oophorectomy, hysterectomy, peritoneal cytology, omentectomy, and the excision of any suspicious lesion. The median tumor size value was used to define the relationship between tumor size and endometrial cancer. The relationship between each value and endometrial cancer was evaluated. Endometrial intraepithelial neoplasia, or hyperplasia with complex atypia, was detected in 7.3% of patients, and endometrial cancer in 3.1% of patients. Age, menopausal status, tumor size, International Federation of Gynecology and Obstetrics stage, ascites, and CA-125 level were not statistically significant factors to predict endometrial cancer. There was no endometrial cancer under the age of 40, and 97.8% of women diagnosed with endometrial hyperplasia were over the age of 40. During the menopausal period, the endometrial cancer risk was 4.5%. Developing endometrial cancer increased to 12.1% from 3.2% when the size of the tumor was >150 mm in menopausal patients (p = 0.036). Endometrial hyperplasia, or cancer, occurs in approximately 30% of AGCT patients. Patients diagnosed with AGCT, especially those older than 40 years, should be evaluated for endometrial pathologies. There may be a relationship between tumor size and endometrial cancer, especially in menopausal patients.

Juvenile granulosa cell tumor of the ovary: A rare cause of precocious puberty in a toddler

Ovarian tumors are a rare cause of sexual precocity in female children. Functional neoplasms of the ovary are relatively infrequent, and only 5% occur before puberty. Although ovarian juvenile granulosa cell tumor (GCT) is a rare tumor described infrequently in pediatrics, the most common presentation of this tumor is precocious puberty. We report a 1⅟2 year-old girl with isosexual precocious puberty, who presented with a rapid onset of premature menarche, pubic hair, and vaginal bleeding, with an abdominal mass on clinical examination. Ultrasonography of the pelvis and abdomen showed a heterogeneously hypoechoic solid mass with cystic areas and internal vascularity. The child underwent a left oophorectomy. Microscopic features of the resected mass were characteristic of juvenile GCTs. Even though the most common cause of precocious puberty in girls is idiopathic, functional ovarian tumors must be considered, especially when the onset is at an early age and puberty is rapidly progressive. Early-stage disease has a good prognosis, and adjuvant chemotherapy is not indicated.

Serial cytoreductive surgery and survival outcomes in recurrent adult-type ovarian granulosa cell tumors

BackgroundFew studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared to systemic therapy alone following the first recurrence and subsequent disease progressions. ObjectiveTo determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. Study DesignThis is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumor of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least one documented recurrence, and treatment/treatment planning at MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and Clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier and were modeled via cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. ResultsAmong the 369 patients with adult granulosa cell tumors of the ovary in the registry, there were 149 patients who met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (HR 0.37, 95% CI 0.17 – 0.81, p = 0.01) and multivariable analyses (HR 0.42, 95% CI 0.19 – 0.92, p = 0.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared to those who did not undergo cytoreductive surgery (181.92 months vs 61.56 months, respectively; p = 0.002). Overall survival benefit remained statistically significant on multivariable analysis (HR 0.28, 95% CI 0.11 – 0.67, p = 0.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (HR 0.43, 95% CI 0.26 – 0.70, p = 0.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (HR 0.74, 95% CI 0.42 – 1.26, p = 0.27). ConclusionsAmong those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may offer a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumor of the ovary.

Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors.

MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling, and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in 2 siblings with microcephaly, epileptic encephalopathy, and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13, Mad2, and Rev7 binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated an identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early-deceased patient with low-level aneuploidy, severe epileptic encephalopathy, and frequent blood glucose elevations, likely corresponds to complete loss of function, as in Mad2l1bp-/- mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.

Rapidly Growing Ovarian Granulosa Cell Tumor Following Complete Debulking for Suspected Ovarian Cancer with Histopathology Result of Benign Ovarian Cyst

Ovarian granulosa cell tumor (GCT) is a rare low-grade malignancy condition. One type of GCT is adult GCT (AGCT), which has the tendency for late recurrence. AGCT is clinically palpable and focally cystic and solid. In this case report, a condition of recurrent ovarian cancer after laparotomy debulking surgery was reported. A 57-year-old woman, who was diagnosed with AGCT, had a history of laparotomy debulking three months prior and complained of abdominal pain and enlargement, along with significant weight loss. Ultrasound examination revealed a solid cyst, raising suspicion of recurrent ovarian cancer. Laboratory results indicated elevated CA-125 levels. Histopathology results confirmed metastasis of AGCT, after the second laparotomy debulking was done. Recurrence of GCT is uncommon within three months of debulking. In this rare condition, we suggested a laparotomy debulking and adjuvant chemotherapy as a treatment. Effectiveness of treatment of recurrent disease is an independent risk factor to reduce the risk of another relapse and increase the survival rate.Keywords: granulosa cell tumor, ovarian cancer, debulking

Clinical differentiation between ovarian granulosa cell tumor and ovarian cancer: a review

Differentiation of granulosa cell tumor and ovarian cancer doesn’t seem to cause much trouble in everyday clinical work. Despite quite easy distinction, within the researches discussed within this review, findings were suggesting less obvious results. There was a huge urge to take into consideration immunohistochemical differentiation. Common symptoms of many gynecological tumors are very similar, studies investigated that GCT and ovarian cancer frequently overlap. Symptoms, method of treatment and prevalence rate (at some point) are often shared between these neoplasms. Fortunately, great distinction was provided by immunohistochemical findings.

Clinical Observation of Acute Intestinal Obstruction Caused by Giant Granulosa Cell Tumour of the Ovary

Ovarian granulosa cell tumours (OGCT) are non-epithelial neoplasms of the ovaries and belong to the group of granulosa-stromal tumours. The most likely source of these tumours’ development is granulosis of the primordial follicles of the ovary as a result of hormonal imbalance.&#x0D; The aim of the study is to represent a clinical observation of acute intestinal obstruction caused by a giant ovarian granulosa cell macrofollicular tumour.&#x0D; A woman, aged 52 years, medical history № 2579, was admitted to the surgical department of Communal Non-Profit Enterprise (CNPE) City Clinical Hospital (CCH) № 1 in Ivano-Frankivsk as an urgent patient with complaints of nausea, vomiting, delayed passage of flatus and defecation, general malaise, abdominal distention. During the laboratory and instrumental examination, a giant tumour of the abdominal cavity was revealed; it has led to the compression of internal organs and the development of small- and large-intestinal obstruction. The operation was performed: middle-median laparoscopy, removal of a giant cyst of the right ovary. Complete hysterectomy with appendages, drainage of the abdominal cavity were also performed.&#x0D; During the operation, a giant tumour with dimensions of 65x70x50 cm, of dense but elastic consistency, pale-pink in color, with multiple chambers of different diameters filled with cloudy, yellow liquid was revealed. The removed uterus with appendages and a large omentum were also given for pathological examination. Pathohistological examination results included: 15824-8- granulosa-cell ovarian tumour; 15815-7- uterus - plethora; 15818-20-ovary - white bodies, fallopian tube - chronic salpingitis; 15812-4- omentum - focal hemorrhages. The postoperative period was uneventful, the patient was referred to a gynecologist-oncologist for consultation and treatment.