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

Ovarian sex cord-stromal tumors (SCST) represent approximately 8% of malignant ovarian tumors. The most common are granulosa cell tumors (GCT) which account for approximately 90% of malignant SCST. Recent studies have unraveled the key genomic and genetic events contributing to their pathogenesis. SCST are found in the hereditary syndromes: Peutz-Jeghers syndrome, Ollier disease and Maffucci syndrome, and DICER1 syndrome. Genomic studies have largely been limited to GCT where a number of recurring chromosomal abnormalities (monsomy and trisomy) have been identified although their contribution to pathogenesis remains unclear. In addition to the recurrent DICER1 mutations reported in non-hereditary cases of Sertoli cell and Sertoli-Leydig cell tumors, recurrent somatic mutations in both the juvenile (j) and adult (a) forms of GCT have been reported. Approximately 30% of jGCT contain a somatic mutation, the gsp oncogene, while a further 60% have an activating mutation in the AKT gene. In the case of aGCT, a well characterized mutation in the FOXL2 transcription factor (FOXL2 C134W) is found in almost all cases, which arguably defines the disease, although the molecular events that determine the stage, behavior and prognosis of aGCT remain to be determined.© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Adult granulosa cell tumor (aGCT), the most common malignant ovarian sex cord-stromal tumor, is characterized by the forkhead transcription factor FOXL2 p.C134W somatic mutation. Late recurrences are relatively common but the molecular mechanisms of relapse or aggressive behavior are not known. The mutational landscape of FOXL2 p.C134W mutation-positive tumors ( = 22) was determined using whole-exome sequencing (WES). An average of 64 coding and essential splice-site variants were identified per tumor. As the TERT promoter region is poorly covered by the WES, targeted sequencing identified the TERT -124C>T promoter mutation as the only recurrent mutation (∼40% of cases). Pathway analysis suggested an association with DNA replication/repair and the EGFR family canonical pathways. Copy number analysis confirmed that gains of chromosomes 12 and 14 occur in approximately 30% of aGCT and loss of chromosome 22 occurs in approximately 40% of cases. In summary, exome-wide analysis of the mutational landscape of aGCT revealed that, except for the TERT promoter mutation, recurrence and/or aggressive behavior is not defined by activation or loss of specific genes. IMPLICATIONS: This study found that although aGCTs are defined by the presence of a common gene mutation, recurrence and/or aggressive behavior cannot be attributed to subsequent mutation of specific gene(s) or pathways; however, there is a high frequency of the TERT -124C>T promoter mutation, which is associated with more aggressive disease.©2018 American Association for Cancer Research.

Background: Ovarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors. Several studies have shown that a somatic mutation leading to a C134W substitution in the transcription factor FOXL2 appears in more than 95% of adult-type GCTs. Its pervasive presence suggests that FOXL2 is the main cancer driver gene. However, other mutations and genomic changes might also contribute to tumor formation and/or progression. Methods: We have performed a combined comparative genomic hybridization and transcriptomic analyses of 10 adult-type GCTs to obtain a picture of the genomic landscape of this cancer type and to identify new candidate co-driver genes. Results: Our results, along with a review of previous molecular studies, show the existence of highly recurrent chromosomal imbalances (especially, trisomy 14 and monosomy 22) and preferential co-occurrences (i.e. trisomy 14/monosomy 22 and trisomy 7/monosomy 16q). In-depth analyses showed the presence of recurrently broken, amplified/duplicated or deleted genes. Many of these genes, such as AKT1, RUNX1 and LIMA1, are known to be involved in cancer and related processes. Further genomic explorations suggest that they are functionally related. Conclusions: Our combined analysis identifies potential candidate genes, whose alterations might contribute to adult-type GCT formation/progression together with the recurrent FOXL2 somatic mutation.

Ovarian granulosa cell tumors (GCTs) are divided into adult GCT (AGCT) and juvenile GCT (JGCT). The AGCT is more common type, conversely, less than 5% of tumors are the JGCT and occur in mainly premenarchal girls and in women younger than 30 years. Although JGCT have different histologic features compared to AGCT, the two types have similar imaging features because they have similar gross appearance. Therefore, it is difficult to distinguish two types by radiologic findings. In addition, it has not been described about the growth rate of JGCTs in past literatures. The aims of this report were to describe a case of rapidly growing JGCT arising in adult with difficulty in diagnosing and to review the literatures.A 38-year-old woman, presented with abdominal distension and frequent urination, was found to have a pelvic mass measuring approximately 12 cm on ultrasonography. On magnetic resonance imaging (MRI), right ovarian multiloculated cystic mass accompanied with hemorrhagic foci was demonstrated. Although the presumptive diagnosis of GCT was made based on MR findings, the intraoperative differential diagnoses included GCT, yolk sac tumor or malignant mucinous tumor due to cytologic atypia and lack of the typical findings for AGCT such as nuclear grooves and Call-Exner bodies. As a result, abdominal simple total hysterectomy, bilateral oophoro-salpingectomy, partial omentectomy and appendectomy were performed. Moreover, she had a history of laparoscopic uterine myomectomy about one year before, and during that surgery bilateral ovaries were found to be macrospically normal. Therefore, it was suspected the tumor became enlarged within the short period of time.Even though it is difficult to distinguish two types of GCT by imaging findings, in some cases without typical findings for AGCT pathologically, MRI could provide useful information in accurately diagnosing JGCT. Moreover, in this case, the tumor growth rate seemed to be rapid regardless of its borderline malignant potential. It may be related with nuclear atypia and high mitotic rate of the tumor.

Several biomarkers have been proposed for the detection of recurrences in adult-type granulosa cell tumors of the ovary. Here we validate the value of inhibin B in detecting recurrences and investigate its role in guiding follow-up examinations and treatment strategies in postmenopausal patients with ovarian adult-type granulosa cell tumors.Data from 140 patients with a diagnosis of adult-type granulosa cell tumor of the ovary referred to the European Institute of Oncology of Milan from January 1996 to March 2016 were retrospectively collected. Among these, we selected data from 47 postmenopausal women for whom serial inhibin B measurements and related imaging examinations were performed according to the follow-up program, with a total of 315 serum inhibin B samples, together with the corresponding clinical examination, and 180 imaging examinations, confirming the presence or absence of macroscopic disease.At a cut-off of 7 pg/mL, inhibin B levels were significantly correlated with the presence/absence of disease (p<0.01), with a sensitivity of 98.8% (95% confidence interval (CI) 95.8% to 99.9%) and a specificity of 88.9% (95% CI 82.6% to 93.5%). Further, inhibin B was positively correlated with the size of the lesion, and levels were significantly higher in patients with larger lesions also at a cut-off size of 3 cm (total diameter). Logistic regression showed that 15.6 pg/mL, 44.6 pg/mL, and 73.6 pg/mL inhibin B corresponded to 25%, 50%, and 75% probability of having an abnormal computer tomography scan, respectively.Our results confirmed that inhibin B is a sensitive and specific marker for adult-type granulosa cell tumors of the ovary that may be used during follow-up for detection of recurrences. Moreover, it could guide clinicians in the decision regarding when to perform imaging, avoiding redundant interventional tests in the absence of clinical suspicion.© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Ovarian sex cord-stromal tumors are uncommon tumors and clinically differ from epithelial tumors. They occur across a wide age range and patients often present with hormone-related symptoms. Most are associated with an indolent clinical course. Sex cord-stromal tumors are classified into 3 main categories: pure stromal tumors, pure sex cord tumors, and mixed sex cord-stromal tumors. The rarity, overlapping histomorphology and immunoprofile of various sex cord-stromal tumors often contributes to diagnostic difficulties. This article describes the various types of ovarian sex cord-stromal tumors and includes practical approaches to differential diagnoses and updates in classification.Copyright © 2019 Elsevier Inc. All rights reserved.

Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord-stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli-Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord-stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.© 2019 John Wiley & Sons Ltd.

To evaluate the role of laparoscopic (LPS) and laparotomic (LPT) re-staging in patients with incompletely surgically staged ovarian granulosa cell tumors (OGCT).We conducted a medical chart retrospective analysis of all patients with sex cord stromal tumors (SCSTs) who were managed in our division between March 1994 and March 2017. After a complete review of surgical and pathological notes, patients with incomplete staging were restaged according to the FIGO guidelines. Statistical analysis was conducted using Statistical Package version 20.0 for Windows (SPSS, Inc., Chicago, Illinois).Out of a total of 170 patients SCSTs, 84 patients (49,5%) received primary surgery that included a hysterectomy; 86 patients (50,5%) underwent fertility-sparing surgery. Eighty-one patients (48%) with diagnosis of OGCT were incompletely surgically staged at another institution. We evaluated our results in terms of laparoscopic approach (56 patients) and open treatment (25 patients). Among the IA patient's group, 1 was upstaged to IIB stage and 2 to IIIB; among patients with IC stage, 1 was upstaged to IIA, 2 to IIB and 1 to IIIB stage. Adjuvant chemotherapy was given to the upstaged patients with final stage IIB-IIIC. No statistically significant difference between laparoscopy and open-surgery was detected in terms of upstaged patients after second surgery (p = 0,36).According to our series, laparoscopic restaging compared to the open approach seems to be a feasible and efficient technique to complete surgical staging in patients with GCTs incorrectly staged. Surgical restaging seems to upstage a considerable number of OGCT, mainly in the initial stage IC group of patients. However, the impact of restaging on final outcome and survival remains to be demonstrated.Copyright © 2019 Elsevier Inc. All rights reserved.

The aim of this retrospective population-based study was to investigate the prevalence of lymph node metastasis in patients with apparent early stage malignant sex cord-stromal tumors (SCSTs) and the effect of regional lymph node sampling/lymphadenectomy (LND) on their survival.A cohort of patients diagnosed with malignant SCSTs between 1988 and 2012 was drawn from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Overall and Cancer Specific Survival, stratified by performance of LND, were calculated following generation of Kaplan-Meier curves. Comparisons were made using the log-rank and Breslow tests. A multivariate Cox proportional analysis was performed to determine the effect of LND on overall mortality.A total of 1156 patients with SCST met the inclusion criteria; 1000 (86.5%) and 156 (13.5%) patients had apparent stage I and II disease, respectively. LND was performed in 572 (49.5%) patients. Lymph node metastases were pathologically confirmed in 19 patients (3.3%). Five-year cancer specific survival (CSS) was similar, 92.7% and 94.7%, for patients who did or did not undergo LND, respectively. According to multivariate analysis overall mortality did not differ between the two groups after controlling for age, histology and apparent stage.Regional lymphatic mode metastasis in patients with apparent early stage SCSTs is uncommon and lymphadenectomy did not confer a survival benefit in this cohort.Copyright © 2017 Elsevier Inc. All rights reserved.

The aim of this study was to elucidate the clinicopathological features of ovarian granulosa cell tumors (GCTs) and to identify the prognostic factors.The Japanese Society of Gynecologic Oncology (JSGO) conducted an observational retrospective cohort study of women with GCTs enrolled in the Gynecological Tumor Registry of the Japan Society of Obstetrics and Gynecology (JSOG) between 2002 and 2015. Clinicopathological features, including lymph node metastasis, were evaluated. In addition, we performed a prognostic analysis of patients between 2002 and 2011 for whom survival data were available. Kaplan-Meier and multivariate Cox proportional hazards analyses were performed.We identified 1426 patients with GCTs. Of the 222 patients who underwent lymph node dissection, 10 (4.5%) had lymph node metastasis. The incidence of lymph node metastasis in patients with pT1, pT2, and pT3 was 2.1%, 13.3%, and 26.7%, respectively (p < 0.001). Prognostic analysis was performed on 674 patients. In the multivariate Cox regression analysis, residual disease after initial surgery (hazard ratio (HR) = 10.39, 95% confidence interval (CI) = 3.15-34.29) and lymph node metastasis (HR = 5.58, 95% CI = 1.62-19.19) were independent risk factors for cancer-specific survival.In the initial surgery for GCTs, lymph node dissection can be omitted if the operative finding is pT1. In cases of pT2 or higher, lymph node dissection should be considered. Debulking is critical for achieving no gross residual tumor at the end of the surgery.Copyright © 2021 Elsevier Inc. All rights reserved.

To analyze the clinical characteristics, diagnosis, and treatment of ovarian juvenile granulosa cell tumor.The clinical and pathological data of six patients with ovarian juvenile granulosa cell tumor was collected.The mean age of disease onset was 20.5 years (range 12 to 33). All six patients had an adnexal mass located laterally in the pelvis, and two developed ascites. All patients had fertility-sparing surgery with complete staging. The mean size of the tumors was 15.3 cm (range 5 to 35). Ovarian sex cord stromal tumors were diagnosed or highly suspected from the frozen sections for all patients. Five patients received three to six courses of postoperative adjuvant chemotherapy, with three receiving a bleomycin/etoposide/cisplatin regimen and two receiving a paclitaxel/carboplatin regimen. The five stage I patients had no recurrence with 52 to 155 months of follow-up. The patient with stage IIIB disease had a recurrence 55 months' later and underwent reoperation and chemotherapy. This patient remained disease-free 30 months after the reoperation.Fertility-sparing surgery is the treatment of choice for ovarian juvenile granulosa cell tumor and the overall prognosis is good.© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.

We evaluated the oncological and reproductive outcomes after fertility-sparing surgery (FSS) in patients with a stage I adult ovarian granulosa cell tumor (AGCT).The medical records of patients aged <50 years with a stage I AGCT who underwent surgery between January 1983 and April 2017 were reviewed. Fertility-sparing surgery was defined as the preservation of the uterus and at least one adnexa. Outcomes were compared between groups who underwent FSS or radical surgery. Patients who had undergone FSS were contacted to gather reproductive outcomes and menstrual histories.A total of 113 patients who met the inclusion criteria were included: 61 had FSS while 52 underwent radical surgery. After a median follow-up of 99.2 months (range 20.2-394.3 months), 30 patients had recurrent disease (17 in the FSS group and 13 in the radical surgery group). Multivariate analysis showed no difference in disease-free survival between the groups who underwent FSS or radical surgery (P = 0.550). In patients who underwent FSS, incomplete staging was significantly associated with the risk of recurrence (P = 0.024). Of the 22 patients desiring pregnancy, 19 achieved 20 singleton pregnancies. The pregnancy rate was 86.4% and the live birth rate was 95%.FSS is an acceptable option for young patients who wish to preserve their fertility. Secondary surgical staging is an important treatment in patients with an unstaged AGCT. Reproductive outcomes are promising. Radical surgery might be delayed until recurrence, provided they are willing to undergo a prolonged follow-up.Copyright © 2018 Elsevier Inc. All rights reserved.

Background: To evaluate the association between adjuvant chemotherapy and clinical outcomes in patients with stage IC adult granulosa cell tumor (AGCT).Methods: We performed a retrospective study of patients with stage IC AGCT diagnosed at our hospital from January 1985 to September 2015. We analyzed descriptive statistics, and performed univariate and multivariate and Kaplan-Meier survival analyses.Results: Sixty stage IC AGCT patients were identified, including 28 in the no adjuvant chemotherapy group (NACG) and 32 in the adjuvant chemotherapy group (ACG). The median follow-up time was 88 months (range: 9-334 months). Sixteen patients developed recurrences, including nine in the NACG and seven in the ACG groups. Univariate analysis identified incomplete surgical staging and initial treatment place as associated with disease-free survival (DFS) (P = 0.003 and 0.038, respectively). Incomplete surgical staging remained a risk factor for recurrence in multivariate analysis (hazard ratio (HR) = 3.883, 95% confidence interval (CI): 1.123-13.430, P = 0.032). The 5-year DFS rates in the NACG and ACG groups were 76.3% and 87.5% respectively (P = 0.197). Adjuvant chemotherapy was thus not associated with improved DFS. Furthermore, the number of chemotherapy cycles was not associated with recurrence rate (<= 3 cycles vs. > 3 cycles, HR = 0.613, 95% CI: 0.112-3.351, P = 0.572).Conclusion: Administration of adjuvant chemotherapy does not improve DFS in patients with stage IC AGCT. Further studies with larger samples involving multi-institutional collaboration are needed to validate new treatment regimens for this disease.

The aim of this study was to explore the clinicopathological characteristics of recurrent adult-type granulosa cell tumor of the ovary (AGCOT) and evaluated the treatment results to define the prognostic parameters for survival after recurrence.A retrospective review of 40 patients with recurrent AGCOT, who were treated in the Cancer Hospital at the Chinese Academy of Medical Sciences from 2000 to 2015 was conducted. The impact of clinical and pathological characteristics, progression-free survival (PFS), and post-recurrence therapeutic approaches on prognosis were analyzed. Among the 40 recurrent patients, there were 10 cases where the relapse was uncontrolled, 24 cases had second relapses, and 6 cases without further relapses at the time of our follow-up. The median PFS was 61 months (range, 7-408 months), and the median time interval between the first and the second relapses (R-PFS) was 25 months (range, 0-94 months). The median time interval between the first relapse and death (R-OS) was 90 months (range, 2-216 months). PFS ≥ 61 months (P = 0.004) and post-recurrence therapeutic approach (P < 0.001) were independent risk factors for repeated recurrences. The age at recurrence (P = 0.031) and post-recurrence therapeutic approach (P = 0.001) were independent risk factors for death after recurrence.Among patients with recurrent AGCOT, those with long PFS had good prognoses. Maximal cytoreductive effort should be made after recurrence. Complete resection and postoperative adjuvant chemotherapy may improve the prognosis of patients with recurrent AGCOT.

Although the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches.Immunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence.59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation.Biomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.

The objective of this study was to determine the prevalence of predictive biomarkers associated with FDA-approved therapies in molecularly defined adult-type ovarian granulosa cell tumors (aGCTs).We performed a retrospective cross-sectional cohort study of tumor profiles using the inclusion criteria of molecularly defined (FOXL2 c.C402G positive) aGCTs previously sequenced at Foundation Medicine, Inc. The dataset included coding variants for up to 406 genes, microsatellite instability, tumor mutational burden, and genomic loss of heterozygosity (gLOH). PD-L1 expression was determined using the tumor proportion score, as measured using the DAKO 22C3 immunohistochemistry assay.423 tumor profiles met inclusion criteria. The median age at the time of sample submission was 57 years (interquartile range 48-65). The mean tumor mutational burden was 1.8 mutations per megabase (range 0-8.8). No tumors exhibited microsatellite instability, and none were gLOH-High (≥16%). Sixty-seven tumors had PD-L1 expression measurement, and 94% were negative. Potentially actionable variants including MTAP deletion (12/173, 5.8%) and activating PIK3CA mutations (23/423, 5.4%) were identified. TP53-mutated aGCT had a higher tumor mutational burden (mean 2.4 mut/Mb, 95% CI 1.7-3.0 mut/Mb vs mean 1.7 mut/Mb, 95% CI 1.5-1.9 mut/Mb; P =.02) and higher gLOH score (mean 4.4%, 95% CI 2.7-6.1% vs mean 1.4%, 95% CI 1.2-1.6%; P =.002) than TP53 non-mutated tumors.No women with molecularly defined aGCT in this large cohort would be eligible for FDA-approved pembrolizumab based on either microsatellite instability or high tumor mutational burden. TP53 mutation identified a subset of this tumor type with distinct molecular features. The development of precision treatment options remains a critical unmet need for this rare disease.Copyright © 2021 Elsevier Inc. All rights reserved.