Juvenile granulosa cell tumor of the ovary associated with tuberous sclerosis

BACKGROUND: Tuberous sclerosis is a neurocutaneous syndrome characterized by benign tumors that can affect many organs. Juvenile granulosa cell tumors of the ovary are rare neoplasms that typically occur in the first three decades of life and have excellent prognosis for early-staged disease. CASE REPORT: We report the first case of an 8-year-old white female with tuberous sclerosis and juvenile granulosa cell tumor of the ovary. She presented with a 20 x 22 cm pelvic mass and received a right salpingo-oophorectomy. Three months later, she recurred and underwent a left salpingo-oophorectomy, lymphadenectomy, and omentectomy followed by four cycles of Bleomycin, Etoposide, and Cisplatin chemotherapy. She is currently free of disease 8 years after her recurrence. CONCLUSION: Treatment options and a review of the literature pertaining to juvenile ovarian granulosa cell tumors and tuberous sclerosis are discussed.     

Tumor ovárico virilizante mixto de células de Sertoli-Leydig/granulosa (ginandroblastoma) en adolescente de 15 años

Sertoli-Leydig cell tumors constitute less than 5% of ovarian tumors. We report the case of a 15-year-old girl with virilization, amenorrhea, and abdominal pain, who was diagnosed with a left annexal tumor. Laboratory investigations revealed isolated testosterone elevation. Because the tumor was unilateral, the capsule was intact, and the patient wished to preserve her fertility, left salpingooophorectomy was performed. Histopathological examination revealed a mixed Sertoli-Leydig/juvenile granulosa cell tumor with a cartilaginous heterologous component, which could be considered a gynandroblastoma. Symptoms of virilization progressively improved.     

Early isosexual precocious pseudopuberty revealing a juvenile granulosa cell tumor in a six-year-old girl

Juvenile granulosa cell tumors of the ovary are a rare form of neoplasm that makes up less than 5% of ovarian tumors in childhood and adolescence. About 90% are diagnosed in stage I (FIGO) with a favorable prognosis, whereas those at higher stages have a less favorable outcome. The authors describe a juvenile granulosa cell tumor expressed by an early pseudopuberty occurring in a 6-year old child. Clinically, an endocrine syndrome was associated with a pelvic mass. Hyperoestrogenia and serum alphafoetoprotein level were biologically detected. Tumor was localized strictly to the ovary, so conservative surgery was applied and proved sufficient to remove all tumor tissue. Histological examination showed typical microscopic aspect of a juvenile granulosa cell tumor. The patient is well 14 years after surgery with normal growth and mental development.     

Cystic juvenile granulosa cell tumor of the ovary

Sex cord-stromal tumors comprise approximately 5% of ovarian neoplasms and among these the granulosa cell tumor is the one most commonly seen (1). Two histopathologically well defined patterns of granulosa cell tumor are known: the common adult granulosa cell tumor (AGCT), and the less frequent juvenile granulosa cell tumor (JGCT) (1, 2, 3, 4). In addition to morphological variation, the two tumor types differ in prognosis and clinical course (4, 5, 6, 7, 8).     

Trisomy 12 in juvenile granulosa cell tumor of the ovary during pregnancy. A report of two cases.

BACKGROUND: Granulosa cell tumors constitute only 5% of ovarian neoplasms, and their coexistence with pregnancy is extremely rare. Juvenile granulosa cell tumor has a good prognosis if it is confined to the ovary, but this type behaves more aggressively than the adult type at advanced stages. CASES: We report on successful completion of two singleton pregnancies and deliveries of normal infants in two young women with juvenile granulosa cell tumor diagnosed and treated during pregnancy. This tumor has rarely been described in association with pregnancy. The presence of trisomy 12 as a single chromosomal abnormality was detected in these two tumors. Both tumors were localized strictly to the ovary, so conservative surgery was applied and proved sufficient to remove all tumor tissue. Follow-up showed no signs of recurrence 18 and 53 months after the interventions. CONCLUSION: These cases support the contention that trisomy 12 is a nonrandom chromosome abnormality in juvenile granulosa cell tumors and that pregnancy may affect nuclear stability in this tumor.     

CD56 is a sensitive and diagnostically useful immunohistochemical marker of ovarian sex cord-stromal tumors.

Ovarian sex cord-stromal tumors comprise a heterogeneous group of neoplasms with wide morphological diversity, and they can be mistaken for a variety of other tumors. Some types, including granulosa and Sertoli cell tumor, may be confused with a neuroendocrine neoplasm. CD56 is a widely used neuroendocrine marker with a high sensitivity for neuroendocrine tumors and is commonly used as part of a panel to distinguish between a neuroendocrine neoplasm and other tumors in the differential diagnosis. In this study, we investigate CD56 staining in ovarian sex cord-stromal tumors. CD56 staining has not previously been studied in this group of neoplasms. We stained a large series of ovarian sex cord-stromal neoplasms (n = 85) with CD56. Neoplasms studied were adult granulosa cell tumor (n = 40), juvenile granulosa cell tumor (n = 8), Sertoli cell tumor (n = 1), Sertoli-Leydig cell tumor (n = 14), Leydig cell tumor (n = 2), steroid cell tumor, not otherwise specified (n = 2), sclerosing stromal tumor (n = 1), sex cord tumor with annular tubules (n = 2), and fibroma (n = 15). Three uterine tumors resembling ovarian sex cord tumor were also studied. Nonneoplastic ovaries, including 3 cases of pregnancy-related granulosa or Sertoli cell proliferation, were also included. In nontumorous ovaries, granulosa cells of follicular and corpus luteum cysts were consistently negative. The normal ovarian stroma was diffusely positive, as were the 3 pregnancy-related proliferations. All sex cord-stromal tumors except one were positive with CD56; staining ranged from focal to diffuse but was usually diffuse involving more than 50% of tumor cells. Staining was usually membranous with weaker cytoplasmic positivity. CD56 immunoreactivity is almost universal in ovarian sex cord-stromal tumors of all the major morphological types and is of no value in distinguishing a sex cord-stromal and a neuroendocrine neoplasm. Since CD56 is an extremely sensitive marker of ovarian sex cord-stromal tumors, it may be useful in the diagnosis of this group of neoplasms, especially in cases which are alpha inhibin or calretinin negative, and in distinguishing these from mimics which are CD56 negative.     

Juvenile granulosa cell tumor in association with a high serum inhibin level

Inhibin is a glycoprotein hormone produced mainly by ovarian granulosa cells. Recently measurement of serum inhibin levels was made possible by radioimmunoassay. We describe a patient with a juvenile granulosa cell tumor, a distinctive and rare form of granulosa cell tumor. This patient's serum inhibin level was extremely high preoperatively and returned to normal after the tumor was resected. This case suggests that serum inhibin level may be a useful marker of granulosa cell tumors.     

Endocrinological and clinico-pathologic study of granulosa-theca cell tumors of the ovary

Nine granulosa-theca cell tumors (four pure theca cell tumors, one granulosa cell tumors, two granulosa-theca tumors and two juvenile granulosa-theca tumors) were studied endocrinologically and clinico-pathologically. The cases of juvenile granulosa-theca tumors developed precocious pseudopuberty. Three of seven other cases were re-feminized and four cases showed no hormonal manifestation clinically. The peripheral vein serum values of estradiol, progesterone, testosterone and prolactin were elevated in six of eight cases, three of four cases, four of six cases, and two of three cases, respectively. The concentration ratios between tumor harboring ovarian vein samples and peripheral vein (or opposite normal ovarian vein) samples was 2.7 to 16.9 for estrone, 8.8 to 28.6 for estradiol, 3.6 to 4.7 for progesterone, 1.6 to 6.6 for testosterone and 0.6 to 1.0 for prolactin. Estradiol was localized in both granulosa cells and theca cells, and testosterone was localized in granulosa cells in half of the cases and in theca cells in 60% of the cases. Also, testosterone was localized in all three cases in which luteinized theca cells were present. There were no cases with positive prolactin localization. These results are compatible with the concept that in granulosa-theca cell tumor, both granulosa and theca cells can produce a wide range of steroid hormones.     

Juvenile granulosa cell tumor associated with pregnancy: Report of a case and review of the literature

BACKGROUND: Juvenile granulosa cell tumors account for about 5% of all granulosa cell tumors and are diagnosed in nearly 80% of cases during the first two decades of life. Only 10% of granulosa cell tumors present during pregnancy. The incidence of ovarian malignancies during pregnancy varies from 0.05 to 0.07 per 1000 pregnancies. CASE: A 31-year-old pregnant woman was admitted to our university hospital due to an adnexal mass, 9.5 cm in diameter, which was detected at 34 weeks of gestation. At 37 + 5 weeks of gestation, a cesarean section with right salpingo-oophorectomy and removal of the tumor was performed. Histopathological findings, including immunohistochemical study, led to the diagnosis of juvenile granulosa cell tumor (JGCT). CONCLUSION: The histological features and the differential diagnosis of the JGCT are discussed. The optimal management of such adnexal masses during pregnancy is also discussed. A JGCT that is confined to the ovary appears to have an excellent prognosis and can be treated by unilateral salpingo-oophorectomy.     

Ovarian granulosa cell tumorigenesis in SWR-derived F1 hybrid mice: preneoplastic follicular abnormality and malignant disease progression

A high incidence (27.5%; 174 of 633) of spontaneous, malignant ovarian granulosa cell tumors develop in (SWR x SWXJ-9)F1 hybrid females between 3 and 6 weeks. Granulosa cell tumors developed in predictable stages, starting as preneoplastic lesions appearing as hyperemic follicles on the ovarian surface. These follicles were characterized by hypertrophied theca, degenerating oocytes, and large fluid- or erythrocyte-filled antra lined by irregular masses of granulosa cells. Rapidly proliferating granulosa cells filled the antra and the theca/interstitial cells became more dysplastic as granulosa cell tumors developed. Thus the morphology of the preneoplastic lesion suggests that disturbed mechanisms for normal follicular development underlie granulosa cell tumor initiation. Estradiol treatment before but not after preneoplastic lesions appeared inhibited granulosa cell tumor formation. By 6 to 9 months 42% of these mice show metastases in major abdominal and thoracic organs. Thus this model can be experimentally analyzed both for mechanisms of granulosa cell tumor initiation and subsequent malignant progression.     

A clinicopathologic study of ovarian tumors (author's transl)

A clinicopathologic study was undertaken on 504 ovarian tumors which were treated in Osaka University Hospital during the past 18 years period. Also, marker substances were examined with some tumors. Most of the ovarian tumors were benign and cystic; 191 dermoid cysts, 106 serous cystadenomas, and 68 mucinous cystadenomas. Among the intermediate and malignant tumor groups, common epithelial tumors were the commonest and seen in older ages. Androblastomas, a granulosa cell tumor arising in dermoid cyst, and a possible juvenile granulosa cell tumor were rarely seen. Dysgerminomas and embryonal carcinomas were fairly popular in young ages. Malignant changes of dermoid cyst were rare and in older ages; the include an insular carcinoid, a strumal carcinoid, squamous cell carcinomas, an adenocarcinoma, and a malignant fibrous histiocytoma. Ovarian tumors in pregnancy were mostly dermoid cyst and fibroma. Bilaterality was more frequent in malignant tumors (20%) than others. The serum levels of marker substances have recently been utilized for the diagnosis, treatment and follow-up studies. Immunohistology was useful for the classification of some tumors. Radical operation and chemotherapy were chosen for the treatment of malignant ovarian tumors except some low grade malignancies, but the prognoses were generally poor.     

Juvenile Granulosa and Theca Cell Tumor of the Ovary as a Rare Cause of Precocious Puberty: Case Report and Review of Literature

BackgroundThe differential diagnosis for precocious puberty in a young female includes peripheral causes. This case documents a rare cause of peripheral precocious puberty—a juvenile granulosa and theca cell ovarian tumor—and a brief review of the literature for this tumor type.CaseA 7-year-old girl presented with rapid onset of pubertal development and elevated estradiol levels. Menarche occurred 5 months after thelarche. A thorough workup revealed a large multicystic left ovary. Other causes of precocious puberty were excluded. She underwent an exploratory laparotomy and left salpingo-oophorectomy. Pathology reported a juvenile granulosa and theca cell tumor of the ovary, FIGO stage 1A. Postoperatively, she experienced a cessation of vaginal bleeding and estradiol levels normalized. A literature review found that early stage disease has an excellent prognosis and that adjuvant chemotherapy is not indicated in this setting.Summary and ConclusionJuvenile granulosa and theca cell tumor of the ovary is a rare cause of peripheral precocious puberty, even more so than juvenile granulosa cell tumor, due to the theca component. Treatment is surgical and an excellent prognosis is possible for early stage disease.     

CD56 expression in ovarian granulosa cell tumors, and its diagnostic utility and pitfalls

OBJECTIVE: The purpose of this study is to investigate CD56 staining in ovarian granulosa cell tumor and its morphological mimics in order to determine the value of CD56 staining in a diagnostic setting. MATERIALS AND METHODS: Tissue samples taken from 82 ovarian tumors, 26 extra-ovarian tumors and 11 normal ovaries were immunohistochemically stained using monoclonal anti-CD56 antibody. Ovarian tumors comprised 32 granulosa cell tumors, 3 Sertoli-stromal cell tumors, 14 fibrothecomas, 6 carcinoid tumors, 1 large cell neuroendocrine carcinoma, 17 endometrioid adenocarcinomas and 9 poorly differentiated serous adenocarcinomas. Extra-ovarian tumors comprised 22 uterine endometrial stromal sarcomas and 4 pulmonary small cell carcinomas. Normal ovaries contained 47 ovarian follicles. RESULTS: All of the 32 granulosa cell tumors, all of the 3 Sertoli-stromal cell tumors, all of the 4 small cell carcinomas, 1 of 1 large cell neuroendocrine carcinoma, 11 of 14 fibrothecomas, 5 of 6 carcinoid tumors, 17 of 22 endometrial stromal sarcomas and 7 of 9 poorly differentiated serous adenocarcinomas were positive for CD56. No immunoreactive cells were observed in 17 endometrioid adenocarcinomas or 47 ovarian follicles. All the immunoreactive cells showed membranous staining except for fibrothecomas where vague cytoplasmic staining was seen. CONCLUSION: CD56, known as a neuroendocrine marker, is a sensitive marker of granulosa cell tumors, but since granulosa cell tumors and neuroendocrine tumors may be morphologically similar, CD56 positivity represents a significant diagnostic pitfall. CD56 is useful in distinguishing between granulosa cell tumor and normal ovarian follicles or endometrioid adenocarcinoma. Lack of membranous CD56 expression in fibrothecoma may help differentiate it from granulosa cell tumor. However, CD56 is of limited use for distinguishing between granulosa cell tumor and poorly differentiated carcinoma or endometrial stromal sarcoma. Appropriate and cautious interpretation of CD56 expression should lead to a more accurate diagnosis of granulosa cell tumor.     

No Activating Mutations of FSH Receptor in Four Children with Ovarian Juvenile Granulosa Cell Tumors and the Association of These Tumors with Central Precocious Puberty

Study ObjectiveThe stimulation of the follicle-stimulating hormone receptor (FSHR) by circulating FSH or some activating mutations of the FSHR may play a causal role in the development of granulosa cell tumors of ovaries.Study designWe evaluated four patients with ovarian juvenile granulosa cell tumors (age range, 2.4 to 7.2; median, 2.9 years) and five healthy pubertal girls (age range, 16 to 18.5; median, 16.8 years) for activating mutations in exon 10 of the FSHR. The patients were followed and evaluated clinically. Genomic DNA was extracted from the peripheral blood. Exon10 of the FSHR was evaluated for mutations.ResultsAll four patients presented with signs of precocious puberty. One patient, who had markedly accelerated growth velocity and advanced bone age, developed central precocious puberty after the removal of her tumor. Another patient was diagnosed to have a left ovarian cyst without tumor recurrence approximately 3.3 years after the removal of the tumor. Activating mutations were not found, but previously reported polymorphisms (Ser680Asn and Ala307Thr) of the FSHR were detected in three of four patients and in three of five controls. The follow-up period of these four patients ranged from 4.5 to 8.8 years, with a median value of 6.7 years.ConclusionsWe did not find any activating mutation in exon 10 of the FSHR in our patients, and one patient developed precocious puberty after removal of her tumor. The development of ovarian tumors in these patients may have been caused by mutations at other exons of the FSHR and G protein subunits, so the association noted between central precocious puberty and granulosa cell tumors might not be coincidental.     

Meigs’ syndrome and adult-type granulosa cell tumor

ObjectiveAdult-type granulosa cell tumors (GCT) are sex cord-stromal tumors and often accompanied with abdominal distention and hyperestrogenism-related symptoms. Adult-type GCT-presenting ascites and pleural effusion is extremely rare.Case reportA 56-year-old perimenopausal woman presented with abdominal distention and abnormal vaginal spotting. Ultrasound and abdominal computed tomography showed a complex cystic mass in the left ovary accompanied with bilateral pleural effusion and ascites. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, left pelvic lymph node dissection, omentectomy and appendectomy. Final histopathological diagnosis was adult-type GCT. The patient had postoperative hormone and anti-angiogenesis agent therapy with free of disease.ConclusionOvarian cystic complex mass accompanied with ascites and pleural effusion often results from malignant ovarian tumors or benign ovarian fibroma. Based on the aforementioned report, the rare types of ovarian tumors, such as adult-type granulosa cell tumor of the ovary should be taken into consideration.     

Association of ovarian juvenile granulosa cell tumor with Maffucci's syndrome

The authors report a rare case of the ovarian juvenile granulosa cell tumor associated with Maffucci's syndrome (enchondromathosis + hemangiomas), no heriditary mesodermal dysplasia. Sarcomatous changes of chondromas are encountered most frequently; however other various typed neoplasma have been reported: ovarian juvenile granulosa cell tumor may occur not infrequently in female patients with Maffucci's syndrome in the first or second decades. Sarcomatous changes of choromas established prognosis of the Maffucci's syndrome.     

Expression of cytokeratins in granulosa cell tumors and ovarian carcinomas

Summary One of the problems in histopathology of ovarian tumors is differential diagnosis between the poorly differentiated carcinomas and granulosa cell tumors of the sarcomatoid type. Hence we evaluated the expression of various cytokeratins (CK 1–19; CK 10, 13, 14, 15, 19; CK 8, 18, 19; CK HMW 1, 5, 10, 11; CK 8; CK 1–19 St?hli; CK AE1/AE3) immunohistochemically in 53 ovarian malignancies (11 of them poorly differentiated carcinomas and 12 granulosa cell tumors). CK HMW was not detected in granulosa cell utmors, and in only half of the carcinomas. AE1/AE3 was expressed by more than 90% of ovarian carcinomas but by one granulosa cell tumor only. The other keratins we investigated showed higher expression rates in granulosa cell tumors and/or lower expression rates in ovarian carcinomas. We think that cytokeratin immunohistochemistry is of value in differentiating between granulosa cell tumors and ovarian carcinomas.     

Immunohistochemical differentiation between ovarian granulosa cell tumors and ovarian carcinomas

Summary Differential diagnosis is a major problem in histopathology of ovarian tumors. Difficulties may arise if the tumor is a poorly differentiated carcinoma or a granulosa cell tumor of the sarcomatoid type. It was the aim of the present study to evaluate the usefulness of immunohistochemistry in differentiating between granulosa cell tumors of the ovary and ovarian carcinomas. We investigated 56 ovarian malignancies (13 granulosa cell tumors, 17 serous, 14 mucinous and 12 poorly differentiated carcinomas) and performed immunohistochemical detection of Vimentin, Keratin, CA125, CA19-9, CEA, S100 and Ber-EP4. Expression of Vimentin was highest and expression of Keratin was lowest in granulosa cell tumors in contrast to carcinomas. CA125 and CA19-9 were not expressed in granulosa cell tumors, whereas the detection rate in carcinomas (except for CA125 in mucinous carcinomas) was high. CEA, S100 and Ber-EP4 do not seem to be useful markers in differential diagnosis. A marker profile of Vimentin, Keratin, CA125 and CA19-9 allows a quite strict differentiation between poorly differentiated ovarian carcinomas and granulosa cell tumors of the ovary.     

Ovarian granulosa cell tumors--immunohistochemical localization of estradiol and ultrastructure, with functional correlations

The authors studied immunohistochemical localization of estradiol and ultrastructure in 11 ovarian granulosa cell tumors in an effort to establish the cellular source of increased estrogen in patients with granulosa cell tumors. Estradiol was identified by the immunoperoxidase method in 10 tumors, and staining was confined to scattered groups of granulosa cells or isolated granulosa cells. The majority of tumor cells in all 5 cases examined by electron microscopy were undifferentiated cells, but in 2 cases, a small percentage of tumor cells contained mitochondria with tubular cristae and well-developed smooth endoplasmic reticulum. Interpreted in conjunction with in vitro studies of granulosa cells, the results suggest that neoplastic granulosa cells may resemble ovarian follicular granulosa cells of all stages of maturation and are capable of estrogen production.