Type Of Sex Cord-stromal Tumor Research Articles

A clinicopathological study about the epidemiology of granulosa cell tumors in Lebanon

BackgroundGranulosa Cell Tumors (GCT) are considered the most frequent type of sex-cord stromal tumors. These tumors constitute 3-6% of neoplasms of the ovaries. GCTs are divided into 2 types: Juvenile GCT (JGCT) and Adult GCT (AGCT). Most patients are diagnosed early in the course of the disease and tend to have a favorable prognosis. In the surgical treatment of GCT, two main factors play role in the determination of feasibility of the surgery: age and tumor stage.MethodsA retrospective study was conducted on 65 consecutive female patients diagnosed with ovarian GCT at different hospitals across Lebanon who were referred to the National Institute of Pathology, Beirut-Lebanon, between January 2000 and January 2020. Then, they were divided according to types: adult versus juvenile type. Statistical analysis was carried out using Stata, version 16.ResultsThe incidence of GCT in a Lebanese population was 16.2 per million per year. The mean age of the studied population was 55.6 years. AGCT was the most common with a prevalence of 91% versus 19% for JGCT. Also, inhibine (the most important immunomarker) was found in 77.2% of adult cases. High mitotic index and high tumor size which are predictors for poor prognosis were respectively 20% and 36.9%. Concerning the histopathological features, Grooved nuclei and Exner bodies were less frequently observed in juvenile type (16.7% for both) compared to adult type (36.9%). Most patients with GCT were diagnosed in the early course of disease mainly due to the manifestation of the symptoms as abdominal pain, postmenopausal bleeding or intermenstrual bleeding, and the good diagnosis and screening practices in Lebanon. Regarding the recurrent cases, a significant correlation with high mitotic index (76.9%), high tumor size (92.3%) and advanced stage (46% for stage 3 and 46% for stage 4) was found with a p < 0.05.ConclusionsThe incidence of GCT in the Lebanese population is 16.2 per million per year. The majority of patients with GCT in Lebanon are of Adult type representing around 90% of cases. Older age, high mitotic index and big tumor size are predictors for poor outcomes.

Abstract #1406879: Not Always PCOS: A Case of Virilizing Steroid Cell Ovarian Tumor

Ovarian steroid cell tumors (SCTs) are a rare type of sex-cord stromal tumors that account for 0.1% of all ovarian tumors. These tumors can occur at any age and typically secrete hormones such as androstenedione and testosterone. We report a young woman with known microprolactinoma who presented with secondary amenorrhea and virilization and was found to have a steroid secreting ovarian SCT. A 32-year-old nulligravid woman with history of infertility presented for evaluation for amenorrhea. Three years ago, she developed oligomenorrhea and was subsequently found to have hyperprolactinemia and an 8mm pituitary microadenoma. Thyroid function tests and IGF-1 at the time were normal, no other workup was obtained. She was started on cabergoline, though after developing full body hives was switched to bromocriptine. Despite prolactin normalization from 69.9 to 14.7 ng/mL and shrinkage of pituitary adenoma to 7mm after 1 year of therapy, she developed amenorrhea, acne, and new facial hair. Her testosterone was found elevated 212ng/dL and she states was then diagnosed with PCOS. In light of no clinical improvement and mental health issues, she self-discontinued her bromocriptine and was lost to follow up. Upon current presentation she reported last menstrual period 24 months ago, continued acne and facial hair, and now temporal hair loss and deepening voice. Ferriman-Gallwey score was 20/36. She did not have clinical signs of Cushing’s syndrome. Repeat prolactin was 195ng/mL, pituitary MRI showed 3mm microadenoma, and bromocriptine was resumed. Workup for her hyperandrogenism revealed testosterone of 137ng/dL (ref 8-60), androstenedione 972 ng/dL (41-262), DHEA-S 284 mcg/dL (84.8-378), 17-OH-progesterone 23ng/dL, and hCG <0.5mIU/mL. Late night salivary cortisol levels were elevated to 0.213, 0.429, and 0.552mcg/dL (<0.090) with ACTH 27.3pg/mL (9.72-63.3). CT scan showed normal adrenal glands. A pelvic ultrasound revealed a 2.2cm left ovarian vascular mass. She underwent left salpingo-oophorectomy and pathology confirmed a 2.4cm benign steroid cell tumor. Follow up after surgery is currently ongoing. Amenorrhea despite prolactin normalization and signs of severe hyperandrogenism such as testosterone >150ng/dL, male pattern baldness, and vocal deepening should prompt physicians to consider androgen-secreting tumors. Our patient was found to have a rare ovarian SCT—these tumors can lead to precocious puberty in adolescents, virilization in adults, Cushing’s syndrome, and infertility. Our patient reports significant clinical improvement postoperatively.

Molecular Correlates of Aggressive Behavior and Biological Progression in Testicular Sertoli Cell Tumors

Sertoli cell tumor (SCT) is the second most common type of sex cord-stromal tumor in men, and ∼10% exhibit malignant behavior. Although CTNNB1 variants have been described in SCTs, only a limited number of metastatic cases have been analyzed, and the molecular alterations associated with aggressive behavior remain largely unexplored. This study evaluated a series of nonmetastasizing and metastasizing SCTs using next-generation DNA sequencing to further characterize their genomic landscape. Twenty-two tumors from 21 patients were analyzed. Cases were divided into metastasizing SCTs and nonmetastasizing SCTs. Nonmetastasizing tumors were considered to have aggressive histopathologic features if they exhibited ≥1 of the following: size >2.4 cm, necrosis, lymphovascular invasion, ≥3 mitoses per 10 high-power fields, severe nuclear atypia, or invasive growth. Six patients had metastasizing SCTs, and the remaining 15 patients had nonmetastasizing SCTs; 5 nonmetastasizing tumors had ≥1 aggressive histopathologic feature(s). Gain-of-function CTNNB1 or inactivating APC variants were highly recurrent in nonmetastasizing SCTs (combined frequency >90%), with arm-level/chromosome-level copy number variants, loss of 1p, and CTNNB1 loss of heterozygosity occurring exclusively in CTNNB1-mutant tumors with aggressive histopathologic features or size >1.5 cm. Nonmetastasizing SCTs were almost invariably driven by WNT pathway activation. In contrast, only 50% of metastasizing SCTs harbored gain-of-function CTNNB1 variants. The remaining 50% of metastasizing SCTs were CTNNB1-wild-type and harbored alterations in the TP53, MDM2, CDKN2A/CDKN2B, and TERT pathways. These findings suggest that ∼50% of aggressive SCTs represent progression of CTNNB1-mutant benign SCTs, whereas the remaining ones are CTNNB1-wild-type neoplasms that exhibit alterations in genes of the TP53, cell cycle regulation, and telomere maintenance pathways.

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.

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

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

Tumor de células de Leydig puro de ovario en mujer premenopáusica

Los tumores de células de Leydig del ovario son un tipo raro de tumores del estroma del cordón sexual, con menos de 0,1% de todos los tumores de ovario. Representan un desafío diagnóstico, no solo por su incidencia esporádica sino también por presentar imágenes aparentemente normales. Aunque son más comunes en las mujeres menopaúsicas, también se ha descrito casos en mujeres premenopáusicas. La característica clínica más común es la aparición de virilización rápida y progresiva; más de 75% de las pacientes muestra signos de virilización debido a la sobreproducción de testosterona. La concentración sérica de testosterona representa el marcador más útil en el diagnóstico del tumor ovárico secretor de andrógenos. El tumor de células de Leydig ovárico siempre debe ser considerado en mujer en edad reproductiva con síntomas de virilización. Se presenta un caso de tumor de células de Leydig puro de ovario en mujer premenopáusica.

MP76-08 LEYDIG CELL TUMOR OF THE TESTIS: PATHOLOGICAL CHARACTERISTICS AND TREATMENT PATTERNS FROM THE NATIONAL CANCER DATABASE

INTRODUCTION AND OBJECTIVE:Leydig cell tumors are a rare type of sex-cord stromal tumor that comprise 1-3% of all testicular neoplasms. Due to its rarity, limited data is available to guide treatme...

Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary

Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic–phenotypic correlation in ovarian neoplasms.

Multimodality imaging and genomics of granulosa cell tumors.

The purpose of this article is to review the imaging findings and genomics of granulosa cell tumors (GCTs) in order to aid in diagnosis and management of GCTs. GCTs are the most common type of sex cord-stromal tumors of the ovary. They are usually diagnosed initially with ultrasound and are subsequently further characterized with CT and MRI. PET/CT is often ordered as well to measure the extent of disease and for follow-up, but its usefulness is in question as some GCTs lack FDG avidity. There is significant variability in imaging phenotypes of GCTs, ranging from mostly cystic to almost solid. More resources have recently been dedicated to understanding the genetics and molecular mechanisms of GCT development. Current research shows that the main cause of GCT carcinogenesis is the FOXL2 mutation, but there are several other noteworthy mutations that contribute to the pathogenesis of this disease. Certain mutations, like GATA4, are known to be associated with more aggressive disease and higher rates of recurrence. Using this information, imaging protocols can be altered depending on the genotype of the tumor. Further understanding of the genetic alterations that underpin the development of GCTs is indicated as genotypic knowledge could be used to guide optimal imaging and management strategies.

Sclerosing Stromal Tumor of Ovary: A Case Report and Review of the Literatures

Sclerosing stromal tumor (SST) is a rare benign ovarian neoplasm classified as a type of sex cord-stromal tumor, accounting for approximately 2% of sex cord-stromal tumors. We present a 23 year old virgin female in this article as an SST case that came with complaint of menstrual abnormalities and right lower quadrant abdominal pain then the US, MRI and pathological findings will be described.

Wnt signaling in granulosa cell tumors of the ovary

Granulosa cell tumors (GCT), a malignant type of sex-cord stromal tumor, account for approximately 2-5% of all ovarian malignancies. They are often identified before they have spread beyond the ovary, but advanced disease can be quite challenging to treat. Wnt signaling has been suggested to contribute to the formation of GCT. We hypothesized Wnt signaling was involved in human GCT.

Granulosa Cell Tumors of the Ovary: Retrospective Analysis of 17 Cases

Background: Granulosa cell tumors (GCTs) are rare neoplasms with a relatively favorable prognosis. They are characterized by a prolonged history and a tendency to late recurrences. It is the most common type of sex cord-stromal tumors. Aims: To analyze, to report and to better understand the clinico-pathologic features and results of treatment, and prognostic factors of these tumors. Materials and Methods: A retrospective single-institutional review 17 cases of GCTs were treated in National Cancer Institute—Cairo University from January 2010 till December 2014. The clinical and pathological characteristics, treatment, and outcomes of patients with ovarian GCTs were analyzed. Results: Data from 17 patients were obtained. The median age was 54 years (range; 14 - 72). Abdominal pain was the most common presentation (64.7%). The mean tumor size was 14 cm (range; 7 - 23 cm). The majority of our patients were stage I (n = 11; 64.7%), while (n = 3; 17.6%) had stage III and (n = 2, 11.8%) were stage IV. Only one case (5.9%) had an unknown stage (explored outside NCI). The majority of cases were of adult type disease (n = 14) and low grade pathology (n = 10). In follow-up period (median = 42 months; ranging 9 - 60) three patients relapsed; the median overall survival time was not reached yet, however, the estimated 3-year survival was 72.5%. Conclusion: Granulosa cell tumors are rare neoplasms of the ovaries. They progress slowly and often are diagnosed in an early stage. Surgery is the main line of treatment. Prolonged post-therapeutic follow-up is necessary. Definition of proper prognostic factors is mandatory.

Identification of the Most Sensitive and Robust Immunohistochemical Markers in Different Categories of Ovarian Sex Cord-stromal Tumors

Different immunohistochemical sex cord-stromal markers have been previously studied in various types of ovarian sex cord-stromal tumors; however, the sensitivity for sex cord-stromal lineage may vary between markers, and some markers may not be as sensitive in some types of sex cord-stromal tumors compared with other tumors in this spectrum of neoplasms. The goals of this study were to determine which immunohistochemical markers are the most sensitive and immunohistochemically robust for sex cord-stromal lineage within a given type of ovarian sex cord-stromal tumor, and to establish whether there are substantial differences of expression of these markers between different types of sex cord-stromal tumors. Immunohistochemical stains for markers which have known variable specificity for sex cord-stromal lineage [inhibin, calretinin, MART-1/melan-A, CD99, steroidogenic factor 1 (SF-1, adrenal 4-binding protein), and WT1], were performed in 127 cases of 5 different types of ovarian sex cord-stromal tumors: adult granulosa cell tumor (n=32), Sertoli cell tumor (n=27), Sertoli-Leydig cell tumor (n=18), steroid cell tumor (n=25), and fibroma/fibrothecoma (n=25). All cases in each type of sex cord-stromal tumor expressed SF-1. Inhibin and calretinin were expressed in all groups of tumors but with a lesser frequency (56% to 100% and 36% to 100% of cases, respectively). All types of tumors except steroid cell tumor expressed WT1. Fibroma/fibrothecoma was the only type of tumor that did not express CD99. The only tumor groups that showed expression of MART-1 were Sertoli-Leydig cell tumor (restricted to the Leydig cell component) and steroid cell tumor (94% and 96% of cases, respectively). The type of sex cord-stromal tumor that was least frequently positive for several of the different markers studied was fibroma/fibrothecoma. Among all tumor groups combined, inhibin and WT1 were the 2 markers showing the most diffuse expression. Likewise, the single marker showing the most optimal combination of diffuse and strong staining (immunohistochemical composite score: possible range, 1 to 12) varied between tumors: adult granulosa cell tumor-inhibin (score 10.0); Sertoli cell tumor-WT1 (score 10.8); Sertoli-Leydig cell tumor (Sertoli cell component)-WT1 (score 10.4); steroid cell tumor-inhibin (score 11.2); and fibroma/fibrothecoma-WT1 (score 8.9). We conclude that most immunohistochemical sex cord-stromal markers have sufficient sensitivity for sex cord-stromal lineage. Although each of the different types of sex cord-stromal tumors has a slightly unique immunoprofile in terms of frequency and extent of expression, these differences are relatively minor for most types of tumors with certain exceptions (eg, WT1 is not diagnostically useful in steroid cell tumor; CD99 is not diagnostically useful in fibroma/fibrothecoma; the only sex cord-stromal tumor for which MART-1 is diagnostically useful is steroid cell tumor; inhibin and calretinin are less diagnostically useful in fibroma/fibrothecoma than in the other types of tumors, but expression in fibrothecoma was higher than in fibroma). SF-1 is the most sensitive sex cord-stromal marker among the most common types of sex cord-stromal tumors. Given the findings relating to sensitivity and extent of expression in this study, and known specificity in the literature, the most informative sex cord-stromal markers to be used for the distinction from nonsex cord-stromal tumors are inhibin, calretinin, SF-1, and WT1 (the exact number of markers to be used should be based on the degree of difficulty of the case and level of experience of the pathologist); however, the utility of immunohistochemistry for the diagnosis of fibroma/fibrothecoma is somewhat limited.

Granulosa cell tumor of the adult type: a case report and review of the literature of a very rare testicular tumor.

We report a case of testicular granulosa cell tumor of the adult type in a 48-year-old man. Microscopically, the tumor consisted of round to ovoid cells with grooved nuclei that were arranged in several patterns, including microfollicular, macrofollicular, insular, trabecular, gyriform, solid, and pseudosarcomatous. These cells demonstrated strong immunopositivity with MIC2 (O13) antibody, vimentin, and smooth muscle actin and focal positivity with cytokeratin. Although this type of sex cord-stromal tumor is relatively common in the ovaries, it is still extremely unusual in the testis, and it probably represents the rarest type of testicular sex cord-stromal tumor.

Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas.

Ovarian sex cord-stromal tumors are a morphologically diverse group of neoplasms that can mimic the appearance of other ovarian tumors. Because the treatment and prognosis of sex cord-stromal tumors differs substantially from those of other ovarian neoplasms, the development of an immunohistochemical panel to support the diagnosis of the former group of tumors would be useful. In this report, the utility of immunostaining for inhibin alpha, epithelial membrane antigen, MIC2 gene protein product, and keratin in the differential diagnosis of sex cord-stromal tumors was assessed in formalin-fixed, paraffin-embedded sections. In addition, the immunohistochemical staining pattern of ovarian small cell carcinomas (SCCs), hypercalcemic type, was analyzed in an attempt to clarify the histogenesis of these tumors. Thirty-two (97%) of 33 granulosa cell tumors (GCTs), 10 (91%) of 11 Sertoli-Leydig cell tumors (SLCTs), and 4 (8%) of 51 carcinomas showed inhibin alpha immunopositivity. None of the 3 lymphomas, 5 carcinoids, 6 dysgerminomas, or 12 SCCs showed inhibin alpha positivity. Eighteen (55%) GCTs, 6 (55%) SLCTs, 6 (12%) carcinomas, and 7 (58%) SCCs showed MIC2 gene expression. None of the GCTs and only one SLCT showed epithelial membrane antigen (EMA) positivity, although 92% of surface epithelial carcinomas and 75% of SCCs were immunoreactive. These data suggest that detection of inhibin immunoreactivity in an ovarian tumor that is EMA-negative provides both sensitive and specific support for the diagnosis of a sex cord-stromal tumor. Because SCCs generally stain for EMA but not for inhibin, it appears that SCCs probably represent a variant of surface epithelial tumor rather than a type of sex cord-stromal tumor.