Adult Granulosa Cell Tumor Research Articles

A Case of Adult Granulosa Cell Tumour of the Testis Masquerading as Hernia with Hydrocele

Granulosa cell tumours are extremely rare and very few cases of adult type have been reported till date . Granulosa cell tumours can broadly classified into juvenile and adult types. They are known to occur more commonly occurs in females (in ovaries) than in males (in testis) . We here reported here a case of 39 year old man who was diagnosed with testicular adult granulose cell tumour with no metastasis . A High Inguinal radical Orchidectomy was performed with histology demonstrating no invasion of the tunica albuginea , epididymis , spermatic cord and no lymphovascular invasion . The aim of the present report is to document another case of AGCT to summarize the knowledge regarding this rare tumour.

Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch

Alterations in the metabolism of cancer cells are crucial for tumor growth and progression. However, the mechanism whereby environmental pollutants such as bisphenols F (BPF) and S (BPS) affect glucose metabolism through the glycolytic pathway, and therefore influence tumor progression, are unclear. Both bisphenols are endocrine-disrupting molecules that are used in plastics. As a consequence of their widespread use, these compounds have been detected in various human body fluids. Thus, hormone-sensitive cancers, such as ovarian cancers, are exposed to these compounds. In the present study, we aimed to determine the effects of the concentrations of BPS and BPF found in body fluids on the cell viability, glucose uptake, glycolysis, oxygen consumption, and invasion by the adult ovarian granulosa cell tumor (AGCT) cell line. We found that BPS and BPF increased the glucose uptake, hexokinase activity, proliferation, and invasion of the cells at environmentally relevant concentrations. Furthermore, we identified an inhibition of glycolysis in parallel with an increase in oxygen consumption, suggesting a BPS/BPF-induced switch from aerobic glycolysis to mitochondrial respiration. In summary, these findings demonstrate a new mechanism through which BPS and BPF promote ovarian granulosa cell tumor progression by increasing energy production through mitochondrial respiration. Thus, both bisphenols induced a metabolic switch that appears to be a stimulus for AGCT progression.

Pathological Features of Ovarian Tumors, Diagnosed at a Tertiary Care Hospital in Afghanistan: A Cross-sectional Study.

In Afghanistan, research work is still in its infancy and there is no national level tumor registry at the moment in the country that could elaborate the histopathological features of ovarian tumors in the country. The current study was conducted with the aim to describe pathological characteristics of ovarian tumors diagnosed at tertiary level in Afghanistan. A descriptive cross-sectional study was conducted, including 198 cases diagnosed with ovarian tumors, that were consecutively included in the study from July 2017 to August 2020. All the cases were diagnosed at the Department of Pathology, French Medical Institute for Mothers and Children, Kabul, Afghanistan, that receives biopsy samples from all of the tertiary care institutions in Kabul. In the current study, majority of the ovarian tumors were benign and presented with nonspecific symptoms. The mean age at diagnosis was 34.4 (SD ±13.4). Benign tumors comprised 81.8%, borderline 1.5% and malignant 16.7% of the cases. Majority of the diagnosed tumors were from surface epithelium in origin, followed by germ cell tumors, sex cord stromal tumors, and a single metastatic tumor. The most common benign neoplasm was mature cystic teratoma, followed by benign serous cystadenoma. Considering the malignant tumors, serous cystadenocarcinoma and adult granulosa cell tumors were predominant, followed by endometrioid adenocarcinoma and mucinous cystadenocarcinoma. More than half of the ovarian tumors occurred between 21 and 40 years of age. In the current study, the proportion of malignant ovarian neoplasms was significantly less than benign lesions. Although, many of the pathological features related to ovarian neoplasms were similar to the features demonstrated in other regions of the world, there were important findings that were exclusively noted in the cases diagnosed in Afghanistan.

PMON225 Androgen excess in pre-menopausal women due to Granulosa Cell tumor: A case report.

Abstract A 23-year-old nulliparous female without any significant past medical history presented for irregular menstrual cycles, amenorrhea, hirsutism and 25-pound weight loss in one year. Excessive hair growth was found on the face and chest. Prior to endocrinology visit she was started on oral contraceptives without any improvements. Of importance, she had a negative progesterone challenge test (no withdrawal bleeding). On examination in the Endocrinology clinic, she was a class II morbidly obese female, with coarse terminal hair on her chin and chest and no cushingoid features. Intra-vaginal ultrasound revealed large bilateral multi cystic masses in the ovaries. Her laboratory work up was significant for elevated DHEA-S at 826.6 ng/dl (134-407), Total testosterone 144 ng/dl(0-60) and free testosterone 4.75 ng/dl (0.06-1.08). Her 17-OH pregnenolone was also elevated at 539 ng/dl (31- 455), Inhibin B was elevated at 374 pg/ml (<139 premenopausal). 17 - OH progesterone was normal. Estradiol, inhibin A and FSH/LH were normal. ACTH, AM cortisol, TSH and prolactin were normal. Beta HCG and Cancer markers CA 19-9, CA 125, and CEA were negative. CT scan of the abdomen showed a right ovarian mass measuring 10.7×9.6×9.2 cm. Adrenal glands were normal. Patient subsequently underwent a laparoscopic diagnostic right salpingo-oophorectomy. Pathology was reported as an adult granulosa cell tumor (9.5 cm) of the ovary with an intact capsule. After surgery Inhibin B level decreased from 374 to 10 (normal <139), Total testosterone decreased from 144 to 36 ng/dl (0-60), Free testosterone decreased from 4.75 to 1.22 ng/dl (0.06-1.08) and DHEA-S from 826.60 to 687.40 ng/dl (134-407) however remained elevated. Moreover, after surgery irregular menses resolved and she noted some improvement in hirsutism. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Prolonged Disease-Free Survival in a Relapsed Adult Granulosa Cell Tumor of the Ovary Treated by Combined Leuprolide and Letrozole: Case Report

Relapsing ovarian granulosa-cell tumor (GCT) is a challenge for physicians due to the lack of effective therapy. Current strategies did not improve the 80% death rate of recurrent disease. GCTs synthesize estrogens and express follicle-stimulating hormone, gonadotropin-releasing hormone, and estrogen and progesterone receptors. The FOXL2-C134W mutation is shared in all GCTs, and its downregulation of hormone-related apoptosis appears causal in induction of tumor phenotype. On these assumptions, hormone anti-estrogenic therapies have been proposed for recurrent GCTs. A 32-year-old woman suffering from GCT was first treated by surgery in 2004 and staged as IA disease. Two subsequent pelvic relapses were diagnosed in 2006 and 2007, and the patient underwent surgery and chemotherapy to treat both recurrences. Overall, she underwent five subsequent surgical interventions and two chemotherapy instances. A third single pelvic relapse above the vaginal cuff was diagnosed in 2013. Based on the patient’s refusal to undergo further surgery we proposed an anti-estrogen therapy consisting of combined GnRH analogue leuprolide and the aromatase inhibitor letrozole. Complete remission was obtained after 3 months from the start of therapy. Subsequently, we found that disease-free survival was maintained over 9 years of treatment. Although recent reports indicate poor effectiveness of hormone therapy to treat recurrent GCTs, the success of this case indicates that a subset of patients with recurrent GCT maintain a tumor phenotype highly responsive to anti-estrogen drugs.

A Descriptive Analysis of Patients Undergoing Cytoreductive Surgery for the First Peritoneal Recurrence from Adult Granulosa Cell Tumours: Focus on Disease Distribution, Morphology of Peritoneal Disease and the Role of HIPEC - a Retrospective Study by INDEPSO.

The aim of the present study was to report the clinical outcome and factors affecting survival in patients with first recurrence of AGC treated with cytoreductive surgery with or without HIPEC. The second aim was to study the disease distribution in the peritoneal cavity according to the peritoneal carcinomatosis index (PCI) and the morphology of peritoneal deposits. In this retrospective multicentric study, all patients of adult granulosa cell tumor with peritoneal recurrence were treated with CRS with or without HIPEC. Relevant clinical and demographic data were captured. Multivariable logistic regression was performed to evaluate the factors affecting recurrence after CRS ± HIPEC. Factors affecting survival and second recurrences were evaluated in addition to studying the disease distribution at first recurrence. In the period from January 2013 to December 2021, 30 consecutive patients of recurrent adult type granulosa cell tumor of the ovary undergoing CRS ± HIPEC were included in this study. The median follow-up duration was 55months [12-96months]. The median rPFS and rOS were both not reached. HIPEC (p = 0.015) was the only factor independently associated with a longer rPFS. CRS with or without HIPEC can be performed with an acceptable morbidity in patients with the first recurrence from adult granulosa cell tumours. The role of HIPEC, patterns of peritoneal spread and impact of other prognostic factors on the treatment outcome all need further evaluation in larger series of patients.

Hormonal Therapy in Pretreated Patients With Recurrent Ovary Granulosa Cell Tumor

Objective: To evaluate the effectiveness of hormonal therapy (HT) in patients with recurrent adult ovary granulosa cell tumors. Methods: The clinical and treatments features of the patients who received HT were studied retrospectively. The efficacy and safety of HT were evaluated. The Kaplan-Meier technique was used to conduct survival analysis. Results: The research involved a total of thirteen patients. The median age of the participants was 49 years (range: 34-61). Since diagnosis, the median number of surgeries has been three (range: 2-8). At least one chemotherapy regimen has been administered to 12 (92.3%) patients. Ten of the patients (76.9%) had at least two metastatic areas. Lung metastases were found in two (15.4%) of the patients. Inhibin B levels were elevated in 81.2% of patients before hormone treatment. The patients received different HTs (Leuprolide acetate + anastrozole-three patients, leuprolide acetate + tamoxifen-six patients, only anastrozole-three patients, only tamoxifen-one patients). The median progression-free survival was found 17.7 months (95 % CI: 14.7-20.6). In four (33.4%) patients, an overall response (complete or partial) was identified. A stable response was observed in eight (66.7%) patients. Conclusions: HT is effective in pretreated individuals with recurrent ovarian granulosa cell tumors, according to this research. Despite the limited number of patients and treatment variability, disease control was achieved in all patients. Also, we found that Inhibin B levels were associated with treatment response.

Mismatch Repair Deficiency in Adult Granulosa Cell Tumors: an Immunohistochemistry-based Preliminary Study.

Adult granulosa cell tumors (AGCTs) are rare ovarian malignant neoplasms; their etiopathogenetic mechanisms remain largely unelucidated. Lately, defects in mismatch repair (MMR) have been implicated in the pathogenesis of AGCTs. Demonstration of MMR deficiency in these tumors can help identify patients potentially eligible for immune checkpoint inhibition therapy. The present study was done to explore the role of MMR deficiency in the etiopathogenesis of AGCTs. This was a retrospective study conducted on histopathologically confirmed AGCT cases. MMR protein expression was evaluated by immunohistochemistry (IHC) on tissue microarrays using an antibody panel of MSH2, MSH6, MLH1, and PMS2. Of a total of 40 ovarian AGCTs evaluated for MMR deficiency, none demonstrated loss of expression of any of the 4 MMR proteins. The results of our preliminary study show that there is no association between MMR deficiency with AGCT. Nevertheless, larger multicenter studies are needed to confirm or refute this observation.

Tumor reductive surgery and survival outcomes in recurrent adult type granulosa cell tumors of the ovary (152)

Tumor reductive surgery and survival outcomes in recurrent adult type granulosa cell tumors of the ovary (152)

Anatomic patterns of recurrence in adult type granulosa cell tumors of the ovary (161)

<b>Objectives:</b> The objective of this study was to describe the anatomic patterns of recurrence, through multiple relapses, of adult-type granulosa cell tumors of the ovary (aGCTs). <b>Methods:</b> This was a retrospective cohort study that included women over the age of 18 with a histologic diagnosis of aGCT who were seen at one of two academic centers for the treatment of recurrent disease. Following IRB approval, demographic and clinical data were obtained from the medical records. Descriptive statistics were used to compare variables by treatment modality; p<0.05 was considered significant. <b>Results:</b> A total of 81 women met our study criteria and was included in the final cohort. The median age at initial diagnosis was 45 years (interquartile range [IQR]: 36-53 years). The median age at first recurrence was 53 years (IQR: 40-60 years). A total of 73 (90%) women had documented disease sites at first recurrence, which included the pelvis and pelvic lymph nodes (PLN) (37/73, 51%), paraaortic lymph nodes (PALN) (4/73, 6%), extra-pelvic abdomen or bowel (35/73, 48%) liver parenchyma (8/73, 11%), and lung (3/73, 4%). Of these patients, 58 (80%) received secondary tumor reductive surgery (TRS), while 45 (62%) received cytotoxic chemotherapy. A total of 48 (91%) women with a second recurrence had documented disease sites, of whom 30 (62%) received TRS and 21 (44%) received chemotherapy. Sites of disease in the second recurrence included pelvis/PLN (27/48, 56%), extra-pelvic abdomen or bowel (24/48, 50%), liver parenchyma (5/48, 10%), and/or lung (1/48, 2%). A total of 42 (79%) women with a third recurrence had documented sites of disease, of whom 21 (50%) received TRS and 14 (33%) received chemotherapy. Sites of disease include pelvis/PLN (21/42, 50%), extra-pelvic abdomen or bowel (17/42, 40%), liver parenchyma (4/42, 10%), and/or lung (2/42, 5%). A total of 31 (82%) women with a fourth recurrence had documented disease sites, with involvement of the pelvic cavity pelvis/PLN (14/31, 45%), extra-pelvic abdomen or bowel (14/31, 45%), liver parenchyma (5/31, 16%), and/or lung (1/31, 3%). Only nine women (29%) received TRS, and seven (23%) received chemotherapy for a fourth recurrence. Rates of TRS significantly decreased with each relapse (p<0.001). Rates of cytotoxic chemotherapy also decreased significantly (p<0.001). There were also no significant differences in the rate of locoregional disease (p=0.8) or distant metastases (p=0.9) between recurrences (Figure 1). No women in this cohort had documented central nervous system metastases.Fig. 1 <b>Conclusions:</b> Distant metastases of aGCT are rare, even after multiple lines of relapse, with the most recurrent disease confined to the abdomen and pelvis. Despite this, the frequency of TRS decreased through subsequent lines of treatment, suggesting that additional patient-related factors, such as performance status, may impact the decision to perform surgery for recurrent disease.

Response to Systemic Therapies in Ovarian Adult Granulosa Cell Tumors: A Literature Review.

Simple SummaryAdult granulosa cell tumors (aGCTs) are a rare subtype of ovarian cancer. First choice of treatment is surgery; when this is not possible, chemotherapy and anti-hormonal therapy are often used. There is limited evidence on the effect of systemic therapy in aGCT. The aim of our systematic review is to provide an overview of the response to chemotherapy and anti-hormonal therapy in patients with aGCT. We found very few articles reporting the response to chemotherapy and anti-hormonal therapy in only aGCT. The available data showed a moderate response to chemotherapy and anti-hormonal therapy, but if patients who achieve stable disease are also taken into account, the response is higher. This may mean that surgery can be postponed for a longer period of time.For adult granulosa cell tumors (aGCTs), the preferred treatment modality is surgery. Chemotherapy and anti-hormonal therapy are also frequently used in patients with recurrent aGCT. We aimed to review the existing literature on the response to chemotherapy and anti-hormonal therapy in patients with aGCT. Embase and MEDLINE were searched from inception to November 2021 for eligible studies. Objective response rate (ORR) was calculated as the total number of cases with a complete response (CR) or a partial response (PR). Disease control rate (DCR) was defined as the sum of cases with CR, PR or stable disease (SD). A total of 10 studies were included that reported on chemotherapy and 13 studies were included that reported on anti-hormonal therapy. The response rates of the 56 chemotherapy regimens that could be evaluated resulted in an ORR of 30% and DCR of 58%. For anti-hormonal therapy, the results of 73 regimens led to an ORR of 11% and a DCR of 66%. Evidence on systemic therapy in aGCT only is limited. For both chemotherapy and anti-hormonal therapy, the ORR is limited, but the response is considerably higher when patients achieving SD are included. New approaches are needed to provide more evidence and standardize treatment in aGCT.

Ruptured granulosa cell tumor of the ovary presenting with catastrophic intra-abdominal hemorrhage: A case report.

Introduction and importanceAdult granulosa cell tumor (GCT) is a rare stromal cell neoplasm that most often arises from the ovary. Presenting symptoms are related to external compression of adjacent structures (mass effect) or secretion of hormones such as estrogen. Patients most commonly present with irregular menstruation, postmenopausal bleeding, and abdominal pain. Prolonged estrogen exposure can contribute to endometrial adenocarcinoma development in untreated patients. The highly vascular nature of GCTs can lead to hemorrhagic rupture in rare cases.Presentation of caseWe describe a case of adult GCT in a 44-year-old female with a history of irregular menstrual bleeding and anemia. The patient presented with shortness of breath and abdominal pain. Computed tomography (CT) scan demonstrated possible hemorrhagic ascites of unclear etiology and a pelvic mass. The patient was brought to the operating room in hemorrhagic shock for surgical exploration where she was found to have active bleeding of a ruptured ovarian tumor for which she underwent left salpingo-oophorectomy. Postoperative course was unremarkable, and pathology demonstrated ruptured GCT.Clinical discussionAlthough rare, ovarian tumors can present with massive bleeding following rupture. Granulosa cell tumors are surreptitious as they grow slowly, and symptoms such as distention, abdominal pain, and irregular vaginal bleeding are nonspecific.ConclusionCT findings demonstrating a pelvic mass in the setting of spontaneous intra-abdominal bleeding should raise clinical suspicion, particularly in patients with histories of menstrual abnormalities. Patients with suspected intra-abdominal hemorrhage due to any cause are best treated by prompt surgical exploration and aggressive resuscitation.

Molecular assessment of testicular adult granulosa cell tumor demonstrates significant differences when compared to ovarian counterparts

Testicular adult granulosa cell tumor (AGCT) is a rare type of sex-cord stromal tumor that affects patients of a wide age range and has the potential for late metastasis. In the testis, the diagnosis of AGCTs often requires the exclusion of other more common types of sex-cord stromal tumors. Immunohistochemistry is of limited utility, being used mostly to confirm sex-cord lineage and to exclude other entities when morphology is not typical. Unlike ovarian AGCTs, which are molecularly homogeneous and harbor a specific activating FOXL2 mutation (c.7558C > T p.C134W) in >90% of cases, the molecular characteristics of testicular AGCTs remain largely unknown. In the current study, we analyzed 13 testicular AGCTs diagnosed at multiple institutions using massively parallel DNA sequencing to evaluate single nucleotide variants, copy number alterations, and structural variants. In all, 10/13 cases were sequenced successfully. Notably, the FOXL2 c.7558C > T (p.C134W) mutation was identified in only a single case (1/10, 10%). The remaining cases were molecularly heterogeneous, with largely nonrecurrent genetic variants. Putative driver events in individual cases included a well-characterized gain-of-function NRAS mutation, as well as inactivation of ATM and TP53, among others. The only highly recurrent finding was single copy loss of 22q (7/10 cases, 70%). Comparatively, the frequencies of FOXL2 c.7558C > T (p.C134W) and 22q loss in 12 metastatic ovarian AGCTs identified in our database were 92% (11/12) and 42% (5/12), respectively. The results of the present study suggest that testicular AGCTs are different from their ovarian counterparts in that they appear to be molecularly heterogeneous and only rarely harbor FOXL2 mutations.

Transcriptomic Profiling of Gene Expression Associated with Granulosa Cell Tumor Development in a Mouse Model.

Simple SummaryOvarian granulosa cell tumors are rare ovarian tumors, with poorly understood etiology. The aim of this study is to define the molecular changes in ovarian granulosa cell tumors. We used a granulosa cell tumor mouse model that contains dysregulated transforming growth factor β signaling. Using RNA-sequencing technology, we identified differentially expressed genes between tumor tissues and normal controls. In addition, comparative analyses have been performed to reveal common genes altered in ovarian granulosa cell tumors between the mouse and the human. This study has revealed the molecular signature of ovarian granulosa cell tumors in a mouse model. The results are potentially important to understand cell signaling events that regulate the development of a class of rare ovarian tumors.Ovarian granulosa cell tumors (GCTs) are rare sex cord-stromal tumors, accounting for ~5% ovarian tumors. The etiology of GCTs remains poorly defined. Genetically engineered mouse models are potentially valuable for understanding the pathogenesis of GCTs. Mice harboring constitutively active TGFβ signaling (TGFBR1-CA) develop ovarian GCTs that phenocopy several hormonal and molecular characteristics of human GCTs. To determine molecular alterations in the ovary upon TGFβ signaling activation, we performed transcriptomic profiling of gene expression associated with GCT development using ovaries from 1-month-old TGFBR1-CA mice and age-matched controls. RNA-sequencing and bioinformatics analysis coupled with the validation of select target genes revealed dysregulations of multiple cellular events and signaling molecules/pathways. The differentially expressed genes are enriched not only for known GCT-related pathways and tumorigenic events but also for signaling events potentially mediated by neuroactive ligand-receptor interaction, relaxin signaling, insulin signaling, and complements in TGFBR1-CA ovaries. Additionally, a comparative analysis of our data in mice with genes dysregulated in human GCTs or granulosa cells overexpressing a mutant FOXL2, the genetic hallmark of adult GCTs, identified some common genes altered in both conditions. In summary, this study has revealed the molecular signature of ovarian GCTs in a mouse model that harbors the constitutive activation of TGFBR1. The findings may be further exploited to understand the pathogenesis of a class of poorly defined ovarian tumors.

Can adjuvant chemotherapy improve the prognosis of adult ovarian granulosa cell tumors?: A narrative review.

Adult granulosa cell tumors (aGCTs) are rare ovarian neoplasms with a relatively favorable prognosis. They follow an indolent course, characterized by a prolonged natural history and a tendency to late recurrences, Around a quarter of patients develop recurrence and More than 70% of women with recurrence die from their disease, The percentage of patients received chemotherapy increases over time, whether adjuvant chemotherapy improve the prognosis of aGCTs is equivocal? The purpose of this review is to summarize the previously published evidence to evaluate whether adjuvant chemotherapy improve the prognosis of aGCTs to provide guidance for clinical practice. EMBASE, PubMed, Web of Science, WanFang Data and Chinese National Knowledge Infrastructure are searched up to December 2020, used the search strategy of ovar* and granulosa cell* and (tumor* or tumour* or malignan* or cancer* or carcinom* or neoplasm*) and chemotherapy. The screening process was conducted strictly based on inclusion and exclusion criteria. Clinical studies based on human including randomized controlled trial, quasi-randomised controlled trials, nonrandomised trials cohort study and case control study were included without restriction of time. The percentage of patients received chemotherapy increases over time, but the benefit of adjuvant chemotherapy is lack of high-grade evidence of prospective study, based on the current retrospective studies, we still do not have the evidence to confirm the survival benefit of adjuvant chemotherapy in early stage, advanced stage or recurrent aGCT with no residual tumor, but for inoperable disseminated disease or disease with suboptimal cytoreduction, adjuvant chemotherapy maybe an Optable options. Multinational prospective randomised controlled trials are urgently needed to validate the role of adjuvant chemotherapy. Further research on molecular mechanisms and developing novel targeted medicines may improve the survival of aGCTs.

A rare collision tumor of ovary – Mucinous cystadenoma with adult granulosa cell tumor

Though collision tumors have been reported earlier like serous cystadenoma and mature cystic teratoma, combination of mucinous cystadenoma and adult granulosa cell tumor is rarely reported in the literature. Collision tumors lack the histological cellular intermingling which is seen in composite tumors. Both involve two morphologically and immunohistochemically distinct neoplasms coexisting within a single organ. Mucinous cystadenoma is a benign cystic surface epithelial tumor of ovary. Granulosa cell tumor(GCT) is a low grade malignancy arising from sex cord stromal cells of ovary and need a close follow up for recurrences which may be late. Here we present a case of 50 year old female who presented with lower abdominal pain. Patient underwent staging laporotomy and ovarian specimen sent for histopathological examination, where it was diagnosed as mucinous cystadenoma coexisting with adult granulosa cell tumor. This case report emphasis upon the fact that multiloculated cyst have to be extensively examined grossly, so as not to miss any solid component which might have a bearing on prognosis of the patient. Here the association of mucinous cystadenoma and granulosa cell tumor need close follow up of patient.

High-grade Transformation in Adult Granulosa Cell Tumor: Potential Diagnostic Challenges and the Utility of Molecular Testing

Adult granulosa cell tumor (AGCT) is the most common sex cord-stromal tumor, accounting for about 1% of all ovarian tumors. It has a propensity for recurrences, especially late in the disease course. High-grade or sarcomatoid transformation has been rarely described in AGCT. We present a case of a 65 year old woman who presented with hemodynamic shock and bowel obstruction from a large pelvic mass. Histologic examination revealed predominantly high-grade epithelioid and spindled cells with high mitotic activity and necrosis. A minor component suggestive of AGCT was also identified. Molecular analysis confirmed the diagnosis of AGCT by revealing FOXL2 C134W mutations. Additionally, TP53 mutations were also detected which may contribute to the high-grade transformation. Our case is unique because the high-grade sarcomatous component constituted most of the tumor and the areas of "typical" AGCT were minor. Also, the clinical and operative findings did not suggest a specific site of origin leading to a broad differential diagnosis. High-grade transformation in AGCT is a rarely described phenomenon. The awareness of this presentation is helpful in reaching the correct diagnosis. Molecular analysis may be an extremely helpful adjunct in challenging cases.

Analysis of Non-Relapsed and Relapsed Adult Type Granulosa Cell Tumors Suggests Stable Transcriptomes during Tumor Progression.

Adult-type granulosa cell tumor (AGCT) is a rare ovarian malignancy characterized by slow growth and hormonal activity. The prognosis of AGCT is generally favorable, but one-third of patients with low-stage disease experience a late relapse, and over half of them die of AGCT. To identify markers that would distinguish patients at risk for relapse, we performed Lexogen QuantSeq 3′ mRNA sequencing on formalin-fixed paraffin-embedded, archival AGCT tissue samples tested positive for the pathognomonic Forkhead Box L2 (FOXL2) mutation. We compared the transcriptomic profiles of 14 non-relapsed archival primary AGCTs (follow-up time 17–26 years after diagnosis) with 13 relapsed primary AGCTs (follow-up time 1.7–18 years) and eight relapsed tumors (follow-up time 2.8–18.9 years). Non-relapsed and relapsed primary AGCTs had similar transcriptomic profiles. In relapsed tumors three genes were differentially expressed: plasmalemma vesicle associated protein (PLVAP) was upregulated (p = 0.01), whereas argininosuccinate synthase 1 (ASS1) (p = 0.01) and perilipin 4 (PLIN4) (p = 0.02) were downregulated. PLVAP upregulation was validated using tissue microarray RNA in situ hybridization. In our patient cohort with extremely long follow-up, we observed similar gene expression patterns in both primary AGCT groups, suggesting that relapse is not driven by transcriptomic changes. These results reinforce earlier findings that molecular markers do not predict AGCT behavior or risk of relapse.

Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements.

Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors. This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.

Imaging findings of uterine adenosarcoma with sarcomatous overgrowth: two case reports, emphasizing restricted diffusion on diffusion weighted imaging

BackgroundAdenosarcoma is classified as a mixed epithelial and mesenchymal tumor composed of a benign epithelial component and a malignant stromal component. The stromal component in adenosarcoma is usually low grade, and consequently the prognosis is relatively favorable. While, adenosarcoma with sarcomatous overgrowth (SO) is defined as an adenosarcoma in which the sarcomatous component constitutes more than 25% of the tumor. The stromal component is also high-grade sarcoma showing greater nuclear pleomorphism and mitotic activity, thus, it is associated with worse prognosis. MRI findings of adenosarcoma without SO have been described in previous literatures but the imaging findings in adenosarcoma with SO may be poorly defined. Therefore we present two cases of uterine adenosarcoma with SO.Case presentationPatient 1 was a 76-year-old woman referred to our hospital with complaint of abdominal distension and postmenopausal bleeding. Patient 2 was a 57-year-old woman with complaint of lower abdominal pain and abnormal uterine bleeding. On magnetic resonance imaging (MRI), T2 weighted imaging showed a large, heterogeneous high-intensity mass with hyperintense tiny cysts that expanded the uterine cavity and extended into the cervical canal for both patients. On diffusion-weighted imaging (DWI), both masses appeared as high signal intensity. Patient 2 also had a right ovarian adult granulosa cell tumor that may have contributed to development of the adenosarcoma. Patient 1 recurred with peritoneal sarcomatosis 6 months after surgery and died of the disease. Patient 2 also recurred with a left upper lung metastasis 3 months after surgery.ConclusionsDWI may depict pathological changes produced by SO of adenosarcoma as high signal intensity, even though SO does not seem to change MRI findings of adenosarcoma on other sequences. Therefore, DWI could potentially predict SO in presumptive adenosarcoma on MRI and the patient’s prognosis. It is also important for pathologists to know if SO can arise in adenosarcoma because they need to examine the tumor thoroughly to determine the percentage of SO component in the tumor volume when SO is present.